Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][C:4](=[CH2:10])[C:5]([O:7]CC)=[O:6].CCOCC.C(#N)C.[Li+].[OH-]>C(O)C>[CH3:1][CH:2]([CH3:11])[CH2:3][C:4](=[CH2:10])[C:5]([OH:7])=[O:6]
Reactant: C=C(CC(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOCC
Solvent: CCO
Product: C=C(CC(C)C)C(=O)O
Reaction time: 8 h

Procedure:
The crude product, ethyl 4-methyl-2-methylenepentanoate containing some ether, was dissolved in absolute ethanol (250 mL) and treated with acetonitrile (250 mL), 1 M LiOH (9.7 g in 250 mL of water, 0.23 mol). After stirring overnight, the organic solvents were evaporated under reduced pressure and the aqueous residue was extracted with ethyl acetate (2×150 mL). The combined extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford 10.5 g of 4-methyl-2-methylenepentanoic acid as a colorless oil.
Reaction SMILES: N[C@H](C(O)=O)CC(=O)O.[NH:10](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>ClCCl.N1CCCCC1>[NH2:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: N[C@@H](CC(=O)O)C(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.1 %

Procedure:
Synthesis of Asp(OtBuj-OH. Fmoc-Asp(OtBu)-OH (500 mg, 1.2 mmole) was dissolved in a 9:1 mixture of dichloromethane-piperidine (5 mL) in a 25 mL round-bottomed flask. The reaction mixture was stirred overnight at room temperature. The next morning, TLC analysis indicated complete Fmoc deprotection. The reaction mixture was concentrated by rotoevaporation, coevaporated 2 times with toluene, and dried under vacuum to give a crude oil. This oil was purified by flash chromatography on silica gel (50 g) using a stepwise solvent gradient of 10%–50% methanol in dichloromethane to afford 250 mg (100%) of Asp(OtBu)-OH.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[S:17][C:16]=3[C:15]([Br:28])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:29])[C:3]=1[OH:30].O[C@@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35]C)=[O:34].BrBr>C(#N)C>[Br:29][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[S:17][C:16]=3[C:15]([Br:28])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:30][C@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([OH:35])=[O:34]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Agent: BrBr
Solvent: CC#N
Product: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 18) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: NMR (DMSO-d6); δ13.3 (broad band, 1H), 8.20 (d, J=8 Hz, 1H), 7.70(s, 2H), 7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.51(ddd, J=8, 7, 1 Hz, 1H), 7.40-7.25(m, 6H), 5.21(t, J=7 Hz, 1H), 3.75(s, 2H), 3.32(dd, J=4, 3 Hz, 2H), 2.55 (q, J=7 Hz, 4H), 1.63(s, 3H), 1.02 (t, J=7 Hz, 6H) MS [(+)FAB]: [M+H]+@ 758, 3 bromine isotope pattern, 758(25%), 760(80%), 762(75%), 764(35%), 689(100%); Anal HPLC, Primesphere 5C-18 column, eluent 62% acetonitrile for 15 minutes indicated 97.8%purity; High Resolution MS (FAB)+ve: Calculated Sample Mass: 759.95556 for formula C33H31NO3Br3 as [M+H], Measured Mass 759.97370 mass deviation: 18.14 mmu.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].[Cl:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([S:16](Cl)(=[O:18])=[O:17])=[C:11]([CH3:20])[CH:10]=1>>[CH:1]([N:4]([S:16]([C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([Cl:8])=[CH:10][C:11]=1[CH3:20])(=[O:17])=[O:18])[CH2:5][CH2:6][O:7][S:16]([C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([Cl:8])=[CH:10][C:11]=1[CH3:20])(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)NCCO
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)cc1Cl
Product: Cc1cc(S(=O)(=O)OCCN(C(C)C)S(=O)(=O)c2cc(C)c(Cl)cc2C)c(C)cc1Cl

Procedure:
The title compound was prepared from 2-isopropylamino ethanol and 4-chloro 2,5-dimethylphenylsulfonylchloride using the method described in Description 1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:8]=[C:9]([N:11]2[C:15]([CH:16]([CH3:18])[CH3:17])=[N:14][CH:13]=[N:12]2)[CH:10]=1)=[O:4].[Li+].[OH-]>>[CH:16]([C:15]1[N:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:8]=2)[N:12]=[CH:13][N:14]=1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2ncnc2C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3ncnc3C(C)C)c2)cc1

Procedure:
5-(5-Isopropyl-[1,2,4]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester was hydrolysed with LiOH following the procedure of step 2, Example 8, to give 5-(5-Isopropyl-[1,2,4]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][C@@:8]1([C:32]([O:34]C(C)(C)C)=[O:33])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:9]1)(C)(C)C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[NH:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]([O:19][C:15]2[CH:14]=[C:13]([C:10]3[CH2:9][C@:8]([CH2:7][C:6]([OH:39])=[O:5])([C:32]([OH:34])=[O:33])[O:12][N:11]=3)[CH:18]=[CH:17][CH:16]=2)=[O:31])=[CH:26][CH:25]=1)[C:28]([NH2:30])=[NH:29]
Reactant: CC(C)(C)OC(=O)C[C@]1(C(=O)OC(C)(C)C)CC(c2cccc(OC(=O)c3ccc(NC(=N)N)cc3)c2)=NO1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ccc(C(=O)Oc2cccc(C3=NO[C@@](CC(=O)O)(C(=O)O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl (5S)-5-(2-tert-butoxy-2-oxoethyl)-3-(3-((4-carbamimidamidobenzoyl)oxy)phenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (3.29 g) and TFA (30 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then, the residue was washed with diethyl ether to obtain the title compound (3.01 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:30]4[CH:43]=[CH:42][C:33]5[C@H:34]([CH2:37][C:38]([O:40]C)=[O:39])[CH2:35][O:36][C:32]=5[CH:31]=4)[CH:23]=3)=[C:17]([CH3:44])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH3:44])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:30]4[CH:43]=[CH:42][C:33]5[C@H:34]([CH2:37][C:38]([OH:40])=[O:39])[CH2:35][O:36][C:32]=5[CH:31]=4)[CH:23]=3)=[C:19]([CH3:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(=O)OC(C)(C)C)CC5)cc4C)c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Yield: 51 %

Procedure:
Methyl (S)-2-(6-((4′-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3j (26 mg, 0.04 mmol) was dissolved in 5 mL of methanol, followed by addition of 1M aqueous sodium hydroxide solution (0.5 mL, 0.43 mmol). The reaction solution was reacted for 1.5 hours. The solution was concentrated under reduced pressure, mixed with 3 mL of water, 1M citric acid was added dropwise to adjust the pH to 4-5, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (S)-2-(6-((4′-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 3 (12 mg, yield 47.4%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:35])[C:21](=[O:34])[CH2:22][N:23]4C(=O)C5=CC=CC=C5C4=O)[C:14]=3[Cl:36])[C:5]2=[N:4][C:3]=1[CH3:37].O.NN>CO>[NH2:23][CH2:22][C:21]([N:20]([C:15]1[C:14]([Cl:36])=[C:13]([C:18]([Cl:19])=[CH:17][CH:16]=1)[CH2:12][O:11][C:10]1[C:5]2[N:6]([C:2]([Br:1])=[C:3]([CH3:37])[N:4]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:35])=[O:34]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)cccn2c1Br
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Yield: 95.8 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-(N-methyl-N-phthalimidoacetylamino) benzyloxy]-2-methylimidazo[1,2-a]pyridine (450 mg) and hydrazine hydrate (41 mg) in methanol (5 ml) were refluxed for 30 minutes, and hydrazine hydrate (41 mg) was added thereto, and further, the mixture was refluxed for 1.5 hours. The resulting precipitates were filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform and the solution was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized with diethyl ether to give 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (338 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18].C(N(CC)CC)C.[C:26](O)(=[O:28])[CH3:27]>ClCCl>[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:26](=[O:28])[CH3:27])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18]
Reactant: CC(=O)O
Reactant: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
4-Chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (84.0 mg, 0.208 mmol) was suspended in dichloromethane, and the suspension was added with triethylamine (0.090 mL, 0.648 mmol) and anhydrous acetic acid (0.031 mL, 0.324 mmol), followed by stirring at room temperature for 12 hours. The solvent was evaported under reduced pressure and the residue was purified by slurry using water and acetonitrile to obtain 4-chloro-5-[3-(acetylamino)propoxy]-7-iodoisoindolinone (78.6 mg, yield 92%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([O:36][C:37]([F:40])([F:39])[F:38])[CH:27]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][S:32]([C:29]2[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][C:28]=2[O:36][C:37]([F:40])([F:38])[F:39])(=[O:34])=[O:33])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1 g, 0.0047 mol) in CH2Cl2 were added diisopropylethylamine (1.63 mL, 0.0093 mol) and 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (1.03 mL, 0.0051 mol). The reaction mixture was stirred at ambient temperature for 1 hr and then washed with water. The aqueous layer was extracted with CH2Cl2 (twice), the organic layers were combined, dried over MgSO4, and concentrated. The resulting precipitate was recrystallized with CH2Cl2 and hexanes to give trans-[4-(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-cyclohexyl]-carbamic acid tert-butyl ester (2.39 g, 0.0046 mol, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:24])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)N=C=O
Reactant: NCc1cncc(Br)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)NCc1cncc(Br)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of the hydrochloride salt of 5-bromo-3-pyridinemethanamine (CAS#135124-70-8, 176 mg, 0.65 mmol) in 1,4-dioxane (10 mL) at room temperature was added diisopropylethylamine (0.550 mL, 3.27 mmol) followed by isopropyl isocyanate (CAS#1795-48-8, 0.13 mL, 1.3 mmol). The reaction was then heated to 80° C. and stirred for 15 minutes. The reaction was then cooled to room temperature, quenched with methanol, and stirred for an additional 15 minutes. The resulting solution was then concentrated in vacuo to near dryness, and diluted with dichloromethane and brine. The layers were separated and the aqueous layer was extracted two additional times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to furnish 1-(5-bromo-pyridin-3-ylmethyl)-3-isopropyl-urea without the need for further purification; MS: (ES+) m/z 271.9 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Br:37]C(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][Br:37])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
Under nitrogen atmosphere, a solution of triphenylphosphine (0.94 g) in THF (4 ml) was added slowly to a mixture of 4-(3-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester (0.80 g) and tetrabromomethane (1.19 g) in THF (15 ml). The mixture was stirred at room temperature for 16 hours, then ethyl acetate (100 ml) and a saturated solution of sodium carbonate (30 ml) were added and the organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 8/2) to afford 4-(3-bromo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (0.66 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[N+:21]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[NH2:21])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])C1CCCCC1NC1CCN(Cc2ccccc2)CC1
Agent: [Ni]
Solvent: CCO
Product: NC1CCCCC1NC1CCN(Cc2ccccc2)CC1
Yield: 98.3 %

Procedure:
In this reference example, 1.0 g of 1-benzyl-4-(2-nitro-cyclohexylamino)-piperidine obtained in Reference Example 16 is dissolved in 25 ml of ethanol. Then, 1.0 g of a Raney-nickel catalyst is added thereto and the mixture is stirred at room temperature in the atmosphere of hydrogen under the atmospheric pressure. The stirring is ceased when the solution has absorbed the theoretical amount of hydrogen, and the reaction solution is filtered. The filtrate is concentrated. Consequently, 0.89 g of 1-benzyl-4-(2-aminocyclohexylamino)-piperidine is obtained as the residue.
Reaction SMILES: C([N:20]([CH2:34][CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:45][C:46]3[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=3[N:48]=2)=[CH:40][CH:39]=1)[CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.[ClH:56]>C(Cl)Cl.CCO.CO>[ClH:56].[O:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=[C:44]1[C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:36][CH2:35][CH2:34][NH:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1
Reactant: Cc1ccc(C#CCOCCN(CCOCc2ccc(-c3nc4ccccc4o3)cc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C#CCOCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1

Procedure:
N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methylphenyl)-2-propynyloxy]ethanamine (600 mg) is dissolved in a solution of CH2Cl2 (10 ml) and EtOH (10 ml) and is treated with a solution of EtOH/HCl until acidic by pH paper. The solution is concentrated in vacuo, then purified by column chromatography using 5% MeOH/CH2Cl2. The residue is isolated, dissolved in methanol and acidified with acidic methanol. The solution is concentrated to obtain N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methylphenyl)prop-2-ynyloxy]ethanamine hydrochloride (m.p. 161°-162° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CO)cn1
Reaction time: 4 h

Procedure:
To a stirred, cooled (0° C.) solution of 6-methyl nicotinicacid (5.0 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (20 mmol; 20 mL of a 1M solution in tetrahydrofuran.) dropwise. The reaction was stirred for 4 hours, treated sequentially with 1 mL of H2O, 1mL of 15% aqueous sodium hydroxide, and 3 mL of H2O. The reaction was filtered and washed with tetrahydrofuran (3×50 mL). The filtrate was concentrated under reduced pressure to yield the alcohol as a clear viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:21]=[CH:22]/[N+:23]([O-])=O)=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:21][CH2:22][NH:23][C:32](=[O:34])[CH3:33])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(OCc2ccccc2)cc1-c1ccccc1
Yield: 63.6 %

Procedure:
Nitrostyrene 7a (182 mg, 0.55 mmol) in THF (0.7 mL) was added dropwise to a solution of Lithiumaluminium hydride (42 mg, 1.12 mmol) in THF (2 mL) under organ atmosphere at RT. Upon completion (nearly immediately) the reaction was quenched by the addition of water (42 μL), 3M NaOH (42 μL), and water (84 μL). The resulted mixture was filtered through a plug of celite, washed with DCM, and dried over K2CO3. Upon filtration the mixture was concentrated to oil and used without further purification. Acetic anhydride (58 μL, 0.62 mmol) and triethylamine (93 μL, 0.67 mmol) were added to a solution of the crude amine in DCM (5.6 mL) under an organ atmosphere at RT. After 3 h the reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM (3×10 mL); combined organic fractions were washed with saturated aqueous sodiumchloride, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2; 3:1, Hex:EtOAc) to afford acetamide 8a (0.12 g, 0.35 mmol, 64%). 1H NMR (400 MHz, CDCl3) δ 7.50-7.38 (m, 8H), 7.38-7.30 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.01-6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.93 (d, J=2.7 Hz, 1H), 5.71 (br s, NH), 5.08 (s, 2H), 3.42-3.16 (q, J=7.0 Hz, 2H), 2.89-2.64 (t, J=7.2 Hz, 2H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 157.2, 143.4, 141.4, 137.0, 130.8, 129.1, 128.7, 128.6, 128.4, 128.0, 127.6, 127.2, 116.6, 114.2, 70.1, 40.7, 31.9, 23.2; HRMS m/z: [M+K+] for C23H23NO2K calcd, 384.1361. found, 384.1359.
Reaction SMILES: C[O:2][C:3](=O)[NH2:4].[CH2:6]([CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH2:14])[CH3:7].N>O1CCOCC1>[CH2:6]([CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:3](=[O:2])[NH2:4])[CH3:7]
Reactant: CCC1CCCC1CN
Reactant: COC(N)=O
Agent: N
Solvent: C1COCCO1
Product: CCC1CCCC1CNC(N)=O
Reaction time: 2 h

Procedure:
4.33 g of N-[4-(β-<3-methoxy-5-chlorothiophene-2-carboxamido>-ethyl)-benzenesulfonyl]-carbamic acid methyl ester (melting point 186° - 188° C) were dissolved in 100 ml of dioxane and, after addition of 1.2 g of 2-ethyl-cyclopentylmethylamine, kept for 2 hours under reflux. The clear solution was poured into dilute aqueous ammonia solution, filtered and acidified with 2N-hydrochloric acid. The N-[4-(β-<3-methoxy-5-chlorothiophene-2-carboxamido>-ethyl)-benzenesulfonyl]-N'-(2-ethyl-cyclopentyl-methyl)-urea so obtained was found to melt at 160° - 161° C after recrystallization from methanol.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[NH2:33][CH:34]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35]#[N:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([CH:34]([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#[N:36]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: N#CC(N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CC(Cc1ccccc1)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 20 mg, 0.046 mmol), (R/S)-2-amino-3-phenylpropanenitrile hydrochloride (8.47 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (2 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.2 min) to provide (R/S)-N-(1-cyano-2-phenylethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.012 mmol, 26.2% yield) as a mixture of diastereomers: LCMS=546.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.05-8.17 (2 H, m), 7.18-7.72 (12 H, m), 5.08-5.15 (1 H, m), 5.02 (1 H, t, J=7.70 Hz), 3.11-3.27 (2 H, m); HPLC peak RT=11.0 min (Method A).