Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C[Mg+].[Br-].[CH3:41]CN(CC)CC.CS(Cl)(=O)=O>C1COCC1.C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)=[CH2:41])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCN(CC)CC
Reactant: Cc1c(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)ccc2cccnc12
Agent: CS(=O)(=O)Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2cccnc2c1C
Yield: 59.8 %

Procedure:
A solution of (8-methylquinolin-7-yl)(1-trityl-1H-imidazol-4-yl)methanone (Intermediate M4) (3.59 g, 7.49 mmol) in THF (100 mL) at 0° C. was treated with MeMgBr (5.0 mL, 3M in ether) for 16 h. The reaction mixture was quenched with NH4Cl (aq) and extracted with EtOAc. The layers were separated and dried over MgSO4, filtered, evaporated and purified by column chromatography on silica gel with 3 to 4% NH3-MeOH. The alcohol in CH2Cl2 (100 mL) was treated with Et3N (8.4 mL, 60.3 mmol) and methane sulfonyl chloride (1.75 mL, 22.6 mmol) at 0° C. for 3 h. The mixture was quenched with water and extracted with CH2Cl2. The organic layers were pooled and evaporated to give 8-methyl-7-[1-(1-trityl-1H-imidazol-4-yl)vinyl]quinoline (Intermediate M5) 2.14 g (60% over two steps). This material was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][C:21]2([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:27][C:21]1([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([CH3:15])=[CH:29][CH:28]=2)[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[O:6])[CH2:23][CH2:22]1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)CCCN2CCC(O)(Cc3ccc(C)cc3)CC2)cc1
Temperature: 107.5 °C
Yield: 77.6 %

Procedure:
A mixture of 1.62 g of 4-chloro-1-(4-methoxy-phenyl)-butan-1-one (1), 1.20 g of 4-(4-methyl-benzyl)-piperidin-4-ol (2), 1.62 g of K2CO3, and 0.49 g of KI in acetonitrile (30 mL) was stirred and refluxed at 105 to 110° C. for 9 hours under nitrogen atmosphere. After the solvent was removed, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine and dried over MgSO4. After the solvent was removed, the obtained oily residue was purified by silica gel chromatography (chloroform:methanol=20/1 to 10/1) and the purified product was recrystallized from AcOEt/Et2O to afford 1.73 g of compound (3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]3=[N:14][NH:15][CH:16]=[C:17]23)[CH:9]=1
Reactant: COc1ccc(F)cc1C=O
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2cc(F)ccc2OC)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 5-fluoro-2-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [C:1]1([OH:7])C=CC=CC=1.[CH2:8]=[O:9].C(S)C.C(SC[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])C>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]=[O:7].[OH:9][CH2:8][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: CCSCc1ccccc1O
Reactant: Oc1ccccc1
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCS
Product: OCc1ccccc1O
Reaction time: 12 h

Procedure:
A mixture of 450 g of phenol, 0.8 g of zinc acetate and 24 g of paraformaldehyde was warmed for 6 hours to 70° C. in a flask equipped with a stirrer and a reflux condenser. 49.6 g of ethylmercaptan were then added to the reaction mixture and the reaction temperature in the flask was raised progressively so that there was always a slight reflux. After about 12 hours, when a final temperature of 120° C. had been reached, the reaction was stopped by cooling and the reaction mixture was worked up by distillation. The phenol could be re-used in a subsequent reaction. The yield of isolated 2-ethylthiomethyl-phenol was 70% of theory, relative to paraformaldehyde, and about 95%, relative to the 2-hydroxymethyl-phenol formed as an intermediate.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C>CO>[N+:20]([C:17]1[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:19][C:18]=1[NH:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a mixture of L-phenylalanine (8.88 g, 53.7 mmol) and 1-fluoro-2,4-dinitrobenzene (3.24 ml, 26.9 mmol) was added triethylamine (7.86 ml, 56.4 mmol). The resulting mixture was warmed using a Biotage Initiator microwave to 100° C. for 4 min. The solid was diluted with MeOH and the slurry was dropped into distilled water. Dichloromethane was added to the slurry and the organic phase was separated. The organic phase was further extracted with 1.2 M hydrogen chloride solution and brine. The organic phase was dried over Na2SO4, filtered and the solvents were evaporated. The residue was diluted with dichlormethane and the slurry was filtered. The precipitate was then washed with a small amount of dichlormethane. The combined filtrates were evaporated and the residue was purified by flash chromatography using a dichloromethane/methanol gradient (0% to 5%) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)[CH:17]=[CH:16]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-n2ccc3cc(Br)ccc32)cn1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
5-Bromo-2-(trifluoromethyl)pyridine (2.075 g, 9.18 mmol) was added to a solution of 5-bromo-1H-indole (1.5 g, 7.65 mmol) and in DMF (20 mL) followed by cesium carbonate (7.48 g, 22.95 mmol), and the mixture was stirred at 90° C. for 15 min. Insoluble solids were filtered, filtrate was concentrated and partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 5% ethyl acetate in pet ether to afford title compound (1.1 g, 42.1%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.09 (d, J=2.4 Hz, 1H), 8.37 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.91 (m, 2H), 7.68 (d, J=9.0 Hz, 1H), 7.37 (dd, J1=1.8 Hz, J2=8.4 Hz, 1H), 6.82 (d, J=3.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(CCCc1ccccc1)NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2) The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (501 mg, 76%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[C:25]([F:46])=[CH:26][C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[C:25]([F:46])=[CH:26][C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1c(F)cc(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1c(F)cc(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cc(F)cc1-c1cccc-3c1
Yield: 85 %

Procedure:
Prepared in 85% yield from Methyl(2S)-2-(tert-butoxy)-2-[(22S,24Z)-17,19-difluoro-4,5,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure for Methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 690.30.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].OS(O)(=O)=O>S([O-])([O-])(=O)=O.[Ag+2].O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[Br:1])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reaction time: 3 h

Procedure:
Bromine (17.4 ml) was added dropwise over 40 min to a stirred mixture of 4-tert-butylnitrobenzene (59.5 g, 332 mmol), silver(II) sulfate (56.5 g, 181 mmol), H2SO4 (300 ml), and H2O (33 ml) at RT. The mixture was stirred for a further 3 h and then poured into 0.1 M Na2S2O5/H2O (1 L)
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].N12CCCN=C1CCCCC2.O1CCOCC1.N[C:24]([C:36]1[CH:37]=[N:38][C:39]([Cl:42])=[CH:40][CH:41]=1)([CH3:35])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([F:34])[CH:28]=1)=O>C(OCC)(=O)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:24]2([CH3:35])[C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([F:34])[CH:28]=3)=[N:5][S:1](=[O:3])(=[O:2])[NH:4]2)=[CH:37][N:38]=1
Reactant: CC(N)(C(=O)c1ccc(Cl)c(F)c1)c1ccc(Cl)nc1
Reactant: NS(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(c2ccc(Cl)nc2)NS(=O)(=O)N=C1c1ccc(Cl)c(F)c1
Temperature: 95 °C
Yield: 80 %

Procedure:
A molecular sieve 4 A (4.5 g), sulfamide (2.75 g, 28.6 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.45 g, 9.52 mmol) were added to a dioxane (60 ml) solution of the compound (2.99 g, 9.55 mmol) obtained in Step 6 above and the resulting mixture was stirred under heating at 95° C. for 18 hours. Further sulfamide (2.75 g, 28.6 mmol) was added and the resulting mixture was stirred under heating for 24 hours. The reaction mixture was concentrated under reduced pressure and then the residue obtained was diluted with ethyl acetate, washed with 10% aqueous citric acid solution and saturated brine, and then dried over anhydrous magnesium sulfate. A diisopropyl ether/ethyl acetate mixed solvent was added to the residue obtained and the resulting precipitate was collected by filtration and dried to give the title compound (2.86 g, 80%) as a colorless solid.
Reaction SMILES: [CH2:1](Br)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[I-].[Na+].O1CCCC1>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCC1CCCO1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1COC(CN2CCOCC2)C1
Yield: 92 %

Procedure:
A mixture of 165 g of tetrahydrofurfuryl bromide, 348 g of morpholine, 5 g of sodium iodide and 500 g of tetrahydrofuran was heated under reflux for 50 hours. After cooling, diethyl ether was added to the reaction solution, which was filtered, concentrated in vacuum and purified by vacuum distillation, whereby 158 g of 4-tetrahydrofurfuryl-morpholine, designated [B-44], was obtained (boiling point 64° C./15 Pa, yield: 92%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[OH:16][C:15](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C#N)=C(O)Cc1ccccc1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
A solution of malononitrile (4.0 g, 60 mmol) in tetrahydrofuran (25 ml), was added dropwise over an hour to an ice-cooled suspension of sodium hydride (4.80 g, 60%, 120 mmol) in tetrahydrofuran (75 ml), and the mixture stirred at room temperature for an hour, and then re-cooled to 0° C. A solution of phenylacetyl chloride (8.0 ml, 60 mmol) in tetrahydrofuran (20 ml) was added dropwise over an hour, maintaining the temperature below 10° C., and the reaction mixture then stirred at room temperature for 36 hours. Water (10 ml) was added, the mixture concentrated under reduced pressure, the residue partitioned between ether (50 ml), and 1N hydrochloric acid (50 ml) and the phases separated. The aqueous layer was extracted with ether (2×50 ml), the combined organic layers washed with brine (50 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was dissolved in acetonitrile (100 ml), filtered to remove residual silicon oil, and the filtrate evaporated under reduced pressure, to afford the title compound as a brown oil, (11.20 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:12][CH:11]=1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
1,2,4-Triazole (7.5 g, 0.109 mol) was dissolved in dimethylformamide (50 mL) and stirred under a nitrogen atmosphere in an ice bath at 10° C. while partially ground pellets of sodium hydroxide (17.5 g, 0.438 mol) were added in one portion causing an exotherm to about 25° C. A solution of 4-methoxybenzyl chloride (15 mL, 0.111 mol) in DMF was added dropwise over five minutes at 25° C. After stirring at room temperature for four hours, ethyl acetate and water were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed four times with water and once with brine and dried over magnesium sulfate. The mixture was filtered and the filtrate solvent evaporated in vacuo to afford the title product as an oil in 69% yield; 14.15 g; 1H NMR (CDCl3) δ 8.00 (s, 1), 7.93 (s, 1), 7.19 (d, 2), 6.88 (d, 2), 5.23 (s, 2), 3.78 (s, 3). mass spectrum: m/z 109 (M+1).
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)N1CCC(C#N)(c2ccccc2C)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N1CCC(CN)(c2ccccc2C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Cyano-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine (504 mg) was dissolved in ethanol (10 ml), added with 10% palladium/carbon (500 mg) and 5 N aqueous hydrochloric acid (0.74 ml) and stirred at room temperature for 15 hours under hydrogen gas pressure (30 psi) by using the Parr apparatus. After insoluble matters were removed by filtration, ethanol was evaporated under reduced pressure. The residue was added with dichloromethane (50 ml) and adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate. The organic layer was separated, and the aqueous layer was further extracted with dichloromethane (50 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 4-aminomethyl-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][Br:16])[CH:8]=[O:9])[C:2]#[CH:3].[BH4-].[Na+]>CO.C1COCC1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][Br:16])[C:2]#[CH:3]
Reactant: C#CCOc1cc(C=O)ccc1OCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C#CCOc1cc(CO)ccc1OCCBr
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a two-neck flask with a nitrogen inlet, compound 9 (5.2 g, 18 mmol, 1 equiv) was dissolved in 200 mL methanol/THF (10/1). The solution was cooled to −10° C. in a salted ice bath, followed by the addition of sodium borohydride (0.8 g, 21 mmol, 1.2 equiv). The mixture was stirred at 0° C. for 20 min, then allowed to warm to rt and stirred for an additional 20 min. The mixture was concentrated under vacuum, cooled to 0° C. and acidified with diluted HCl solution. The aqueous solution was extracted with ethyl acetate. The combined organic extracts were washed with brine (200 mL) and dried over MgSO4. After filtration the solvent was removed under vacuum to afford crude product as a yellowish solid. This was chromatographed on a silica gel column (eluent: 0% to 5% of methanol in CH2Cl2) to give 10 as a white solid (4.95 g, yield: 95%). 1H NMR δ=7.10 (d, J=1.8, 1H), 6.97 (dd, J1=1.8, J2=8, 1H), 6.93 (d, J=8, 1H), 4.78 (d, J=2.3, 2H, —OCH2C≡CH), 4.64 (d, J=5.8, 2H, —CH2OH), 4.34 (t, J=6.6, 2H, —OCH2CH2Br), 3.66 (t, J=6.6, 2H, —OCH2CH2Br), 2.51 (t, J=2.3, 1H, —C≡CH), 1.68 (t, J=5.8, 1H, —CH2OH). 13C NMR δ=147.90, 145.60, 135.34, 121.32, 115.46, 114.92, 78.78 (—C≡CH), 76.12 (—C≡CH), 70.54 (—CH2OH), 66.28 (—OCH2CH2Br), 57.38 (—OCH2C≡CH), 29.32 (—OCH2CH2Br). HRMS calculated for C12H11BrO3 (M+Na+), 354.9807; found, 354.9810.
Reaction SMILES: [C:1](Br)([CH3:4])([CH3:3])[CH3:2].[Mg:6].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]>O1CCCC1>[C:1]([Mg:6][Br:7])([CH3:4])([CH3:3])[CH3:2].[CH3:2][C:1]([CH3:4])([CH3:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]
Reactant: BrCCCCCCCCCCCCBr
Reactant: [Mg]
Reactant: CC(C)(C)Br
Solvent: C1CCOC1
Product: CC(C)(C)CCCCCCCCCCCCBr
Product: CC(C)(C)[Mg]Br
Temperature: -10 °C

Procedure:
A solution of t-butylmagnesium bromide is prepared by reacting 13.7 g. of t-butyl bromide with 2.67 g. of magnesium turnings in 50 ml. dry tetrahydrofuran. The solution of Grignard reagent is dropwise added to a stirred, cold (-10° C.) solution of 36.1 g. of 1,12-dibromododecane and 0.2 g. of Li2CuCl4 in 75 ml. dry tetrahydrofuran at a rate such that the reaction temperature does not exceed -5° C. After one additional hour of stirring at -10° C., the solvent is evaporated and the resultant liquid is fractionated in vacuo to yield 13,13-dimethyltetradecyl bromide as a colorless liquid.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH2:35][C@H:36]([C:42]([NH:44][C@H:45]([C:50]([NH2:52])=[O:51])[CH2:46][CH2:47][S:48][CH3:49])=[O:43])[CH2:37][CH2:38][CH:39](C)C.Cl.[CH:54]1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@@H:2]([C:15]([NH:35][C@H:36]([C:42]([NH:44][C@H:45]([C:50]([NH2:52])=[O:51])[CH2:46][CH2:47][S:48][CH3:49])=[O:43])[CH2:37][CH:38]([CH3:39])[CH3:54])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)CCC(C)C)C(N)=O
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Yield: 87 %

Procedure:
Condensation of FmocDLys(Boc)OH (1.00 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 0.63 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave FmocDLys(Boc)-Leu-MetNH2 in 87% yield. De-9-fluorenylmethoxycarbonylation of FmocDLys(Boc)-Leu-MetNH2 (1.00 g.) using piperidine in dimethylformamide gave HDLys(Boc)-Leu-MetNH2 in 100% yield.