Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][CH:13]1[CH2:15][CH2:14]1)[N:6]=[CH:5]2
Reactant: BrCC1CC1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(cnn2CC2CC2)c1
Temperature: 105 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
To a solution of 5-bromoindazole (15 g, 76.1 mmol) and (bromomethyl)cyclopropane (8.12 mL, 83.7 mmol) in 75 mL of DMF, K2CO3 (16 g, 114.0 mmol) was added. The mixture was heated to 105° C. After 24 hours, starting material was still observed. Additional (bromomethyl)cyclopropane (5.7 mL, 57.0 mmol) was added and reaction was heated to 105° C. for an additional 24 hours. 5-Bromoindazole was again observed so additional (bromomethyl)cyclopropane was added (4 mL, 38 mmol) and the reaction was heated at 95° C. for an additional 48 hours. After disappearance of 5-bromoindazole, the reaction mixture was poured onto DCM/brine. The two layers were separated and the aqueous layer was extracted with DCM (2×) and checked by TLC. No product was observed in aqueous layer. The combined organics were washed with H2O (2×) and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the resulting residue was purified by chromatography with 9.5:0.5 hexane/EtOAc to provide 5-bromo-1-cyclopropylmethyl-1H-indazole (8.74 g, 45% isolated yield). 1H NMR (400 MHz CDCl3) δ 7.93 (s, 1H), 7.86 (d, J=1.57 Hz, 1H), 7.43 (dd, J=8.61, 1.57 Hz, 1H), 7.31 (d, J=8.61 Hz, 1H), 4.24 (d, J=6.26 Hz, 2H), 1.37-1.26 (m, 1H), 0.62-0.55 (m, 2H), 0.43-0.37 (m, 2H); MS (APCI+) m/z 251/253 (M/M+2H, 1:1) was detected.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([CH:34]([C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][C:45]=3[F:46])[N:42]=[CH:41][CH:40]=[CH:39]4)[CH3:35])=[CH:32][N:33]=2)[N:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:46][C:45]1[CH:44]=[C:43]2[C:38]([CH:39]=[CH:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[CH:34]([C:31]1[N:29]2[N:30]=[C:25]([C:13]3[CH:12]=[N:11][N:10]([CH2:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:14]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1)[CH3:35]
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(c1cc2cccnc2cc1F)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of [2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 72.5 mg, 0.225 mmol), (rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-7-fluoro-quinoline (Stage 255.2, 49 mg, 0.15 mmol), and 2 M K2CO3 (0.203 mL) in DME (1 mL) stirred at 80-90° C. under argon atmosphere was added PdCl2(PPh3)2 (3.2 mg). After 1.5 h and cooling to rt the RM was taken-up in DCM and water, the aqueous phase was extracted with DCM, the combined organic layers were dried over MgSO4, filtered, evaporated to dryness and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/MeOH=100:0->80:20) to afford the title compound as a white solid (tR 4.14 min (conditions 3), MH+=487.2).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][C:16](/[CH:18]=[CH:19]/[CH3:20])=[CH:15][N:14]1[C:21]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[CH:25][C:24]=1[NH:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:71])[C@@H:55]([NH:57][C:58](=[O:70])[C@@H:59]([NH:63][C:64](=[O:69])[O:65][CH2:66][CH:67]=[CH2:68])[CH:60]([CH3:62])[CH3:61])[CH3:56])=[CH:49][CH:48]=1)=[O:44])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[OH:11][C@@H:12]1[N:42]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:71])[C@@H:55]([NH:57][C:58](=[O:70])[C@@H:59]([NH:63][C:64]([O:65][CH2:66][CH:67]=[CH2:68])=[O:69])[CH:60]([CH3:61])[CH3:62])[CH3:56])=[CH:49][CH:48]=2)=[O:44])[C:24]2[CH:25]=[C:26]([O:31][Si:32]([CH:39]([CH3:40])[CH3:41])([CH:36]([CH3:37])[CH3:38])[CH:33]([CH3:35])[CH3:34])[C:27]([O:29][CH3:30])=[CH:28][C:23]=2[C:21](=[O:22])[N:14]2[CH:15]=[C:16](/[CH:18]=[CH:19]/[CH3:20])[CH2:17][C@@H:13]12
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)Nc2cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2CO)cc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O)cc1)C(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
Dry dimethyl sulfoxide (0.180 g, 2.3 mmol, 3.0 eq) was added dropwise to a solution of oxalyl chloride (0.147 g, 1.1 mmol, 1.5 eq) in DCM (10 mL) at −78° C. under an atmosphere of nitrogen. Maintaining the temperature at −78° C., after 20 minutes, a solution of the primary alcohol 15 (0.666 g, 0.77 mmol, 1.0 eq) in DCM (10 mL) was added dropwise. After a further 15 minutes, dry triethylamine (0.390 g, 3.85 mmol, 5.0 eq) was added, and the reaction mixture allowed to warm to room temperature. The reaction mixture was washed successively with cold 0.1N HCl (10 mL), saturated sodium hydrogen carbonate (10 mL) and brine (5 mL). The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, 50/50 v/v n-hexane/EtOAc to 25/75 v/v n-hexane/EtOAc) to afford the product as a white solid (0.356 g, 54%). LC/MS (3.487 min (ES+)), m/z: 862.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.34 (br s, 1H), 7.47 (d, 2H, J=7.6 Hz), 7.17 (s, 1H), 7.14 (d, 2H, J=7.5 Hz), 6.86 (br s, 1H), 6.65 (br s, 1H), 6.42 (d, 1H, J=7.6 Hz), 6.22 (d, 1H, J=14.4 Hz), 5.80 (m, 1H), 5.40 (m, 1H), 5.53 (m, 1H), 5.32 (m, 1H), 5.21 (d, 2H, J=9.6 Hz), 5.06 (d, 1H, J=12.3 Hz), 4.90 (m, 1H), 4.58 (m, 3H), 3.98 (m, 1H), 3.84 (m, 1H), 3.81 (s, 3H), 3.50 (m, 1H), 3.05 (dd, 1H, J=16.0, 10.3 Hz), 2.76 (m, 1H), 2.15 (m, 1H), 1.80 (dd, 3H, J=6.7, 0.8 Hz), 1.44 (d, 3H, J=7.1 Hz), 1.16 (m, 3H), 1.01 (d, 18H, J=6.6 Hz), 0.96 (d, 3H, J=6.8 Hz), 0.92 (d, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH2:12](O)[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C([O-])(O)=O.[Na+]>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])[O:14][CH2:13][CH2:12][O:3]1
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(c2cccc(C#N)c2)OCCO1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A stirred solution of 3-acetylbenzonitrile (1.05 g, 7.2 mmol), ethylene glycol (0.81 mL, 14.5 mmol) and TsOH (0.65 g, 7.2 mmol) was heated at reflux with a Dean-Stark for 15 h during which time the reaction became dark brown suspension. The reaction mixture was cooled to room temperature and diluted with saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc in hexanes) to provide 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (1.08 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](OC)=[O:20].CCCCCC>O1CCCC1>[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](=[O:20])[CH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccn1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ncccn1)c1ccc(F)cc1F
Yield: 17.3 %

Procedure:
Treatment of 2-methylpyrimidine (8.50 g) with lithium diisopropylamide (0.09 mole) in dry tetrahydrofuran followed by methyl 2,4-difluorobenzoate (15.5 g) according to the method of Example 11(i) gave the title compound (3.65 g), m.p. 86°-88° (from hexane).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:12][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6-Hydroxybenzofuran-3(2H)-one (6 g, 40.0 mmol) was dissolved in DMF (80 mL), then added potassium carbonate (6.07 g, 43.97 mmol) and methyl iodide (4.12 mL, 65.95 mmol). The reaction was stirred at RT for 2 days. The mixture was filtered and the filtrate was concentrated in vacuo. The remaining oil was dissolved in EtOAc and washed with water. The aqueous layer was back-extracted with EtOAc (2×). The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The remaining orange-red solid was purified by silica gel chromatography (1:4 EtOAc/hexane) to afford 6-methoxybenzofuran-3(2H)-one as a bright yellow crystalline solid. MS (ESI, pos. ion) m/z: 165.1 (M+1).
Reaction SMILES: I.[CH3:2][NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.[C:16](#[N:20])[C:17]([CH3:19])=[CH2:18].C(N(CC)CC)C>ClCCl>[CH3:2][N:3]([CH2:18][CH:17]([CH3:19])[C:16]#[N:20])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: C=C(C)C#N
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C)CC(C)C#N)cc1OC
Temperature: 70 °C
Yield: 39.8 %

Procedure:
A mixture comprising 6.5 g of N-methyl-2-(3,4-dimethoxyphenyl)ethylamine hydroiodide, 1.6 g of methacrylonitrile and 2.4 g of triethylamine was heated at about 70° C. for 2.5 hours and cooled, followed by the addition of dichloromethane. The obtained mixture was washed with water, dried over magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane/ethanol (100:1)) to obtain 2.1 g of 3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino]-2-methylpropionitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13](O)=O)[CH:7]=1)[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[C:19]=1[SH:26]>>[F:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[C:13]([CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH:11]=[CH:10][CH:9]=3)[S:26][C:19]=2[C:20]=1[F:25]
Reactant: Nc1ccc(F)c(F)c1S
Reactant: CCOC(=O)Cc1cccc(CC(=O)O)c1
Product: CCOC(=O)Cc1cccc(Cc2nc3ccc(F)c(F)c3s2)c1
Yield: 51.8 %

Procedure:
The procedure of Example 16-i) was repeated using 1,3-phenylene diacetic acid monoethyl ester (2.87 g, 10.5 mmol) and 2-amino-5,6-difluorothiophenol (2.0 g, 11.7 mmol) to obtain ethyl 3-[(6,7-difluorobenzothiazol-2-yl)methyl]phenylacetate (1.89 g, 44%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1.CC(C[Al]CC(C)C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[OH:25])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)C2CCCCC2)c2ccccc2)CC1
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(c2ccccc2)C(O)C2CCCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a stirred solution of 1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine (0.11 g, 0.20 mmol) in methylene chloride (10 mL) at −78° C. under nitrogen was added Dibal-H™ solution (0.89 mmol). The mixture was stirred at −78° C. for 1 hour and then slowly warmed to room temperature for 16 hours. Workup followed by purification by flash chromatography gave pure 1-(2-methoxyphenyl)-4-[4-(cyclohexyl)-4-(hydroxy)-3-(phenyl)butyl]piperazine (0.086 g) in 78% yield. The oxalate salt was prepared as described above.
Reaction SMILES: [N:1]1([C:6]2[CH:20]=[CH:19][C:9]([C:10]([C:12]3[NH:13][C:14](=[O:18])[NH:15][C:16]=3[CH3:17])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:21]=[O:22]>>[OH:22][CH2:21][C:2]1[N:1]([C:6]2[CH:20]=[CH:19][C:9]([C:10]([C:12]3[NH:13][C:14](=[O:18])[NH:15][C:16]=3[CH3:17])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=O
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2)cc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2CO)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
1,3-Dihydro-4-[4-(1H-imidazol-1-yl)benzoyl]-5-methyl-2H-imidazol-2-one (5.85 g, 21.8 mmol) (Example I) is combined in a pressure tube containing a magnetic stir bar with 37% aqueous formaldehyde (300 mL) and the mixture heated with stirring at 120° C. for 18 hr. The mixture is cooled, the tube opened and the solution evaporated in vacuo. Chromatography of the residue on silica gel affords the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])=[C:2]([NH2:1])[N:3]=2)[CH2:30][CH2:31]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: COc1cc(C)c(F)cc1C(=O)c1ccc(Cl)nc1N
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)c(C)cc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 43) and ethyl-4-amino- 1-piperidine carboxylate (Aldrich 96%) using the procedure described in Step B. Example 6. HRMS, observed: 431.2090, Calcd for (M+H)+: 431.2089.
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][C:10]=2[CH2:19][CH:20]([CH3:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][C:9]2[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[CH:11][C:10]=2[CH2:19][CH:20]([CH3:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(OC(c2ccccc2)c2ccccc2)c(CC(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1cc(CO)ccc1OC(c1ccccc1)c1ccccc1
Yield: 101 %

Procedure:
To a solution of methyl 4-(diphenylmethoxy)-3-isobutylbenzoate (0.45 g, 1.20 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (60 mg, 1.58 mmol) by small portions under ice-cooling. The mixture was stirred under ice-cooling for 2 hr, sodium sulfate decahydrate (1.2 g, 2.30 mmol) was added to the reaction solution by small portions, and the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (420 mg, yield 100%) as a colorless oil.
Reaction SMILES: [C:1]([NH:5][C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])[CH3:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@H](C(O)=O)C)=O)C1C=CC=CC=1.C(N1CCC[C@H]1C(O)=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[C:61]([NH:69][CH:70]([S:74][C:75](=[O:82])[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:71](O)=[O:72])(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(#N)C.O1CCCC1>[C:1]([N:5]([C:71](=[O:72])[CH:70]([S:74][C:75](=[O:82])[C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1)[NH:69][C:61](=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(NC(SC(=O)c1ccccc1)C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)N1CCC[C@H]1C(=O)O
Agent: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)O)N(C(=O)C(NC(=O)c1ccccc1)SC(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
12.1 g (50 millimoles) of tert.-butyl alanylproline (prepared by coupling benzyloxycarbonylalanine with tert.-butyl proline using dicyclohexylcarbodiimide, followed by hydrogenolytic elimination of the protective group) were dissolved in 150 ml of dry acetonitrile, a solution of 15.8 g (50 millimoles) of N-benzoyl-α-(benzoylthio)-glycine in 150 ml of dry tetrahydrofuran and 10.3 g (50 millimoles) of dicyclohexylcarbodiimide were added and the mixture was stirred overnight at room temperature. The precipitated dicyclohexylurea was filtered off under suction, and the filtrate was evaporated down under reduced pressure. The residue was chromatographed with 1:1 cyclohexane/ethyl acetate over a column containing deactivated silica gel. 20.2 g (75%) of tert.-butyl N-[N-benzoyl-α-(benzoylthio)glycyl]-alanylproline were obtained as a diastereomer mixture. Crystallization from cyclohexane/ethyl acetate gave 7.5 g of a low-melting isomer of melting point 97°-100° C.; 7.8 g of a high-melting isomer of melting point 147°-150° C. were obtained from the mother liquor after crystallizing the product twice from cyclohexane/ethyl acetate. Cleavage of the two isomers separately, using 6 N HCl/dioxane in a procedure similar to that described in Example 1b, gave N-[N-benzoyl-α-(benzoylthio)-glycyl]-alanylproline as diastereomer I (obtained in crystalline form from ethyl acetate, melting point 185°-188° C., Rf=0.18 in system I, [α]D20 =+29° (c=1 in chloroform)) and diastereomer II (obtained in crystalline form from ethyl acetate, melting point 203°-206° C., Rf=0.18 in system I, [α]D20 =-167° (c=1 in chloroform)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1.O.[OH-].[Na+]>C(O)(=O)C>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[CH:20]=[CH:24][CH:23]=[CH:22]2)[CH2:11][CH2:10]1
Reactant: COC1CCC(OC)O1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: c1cnc(N2CCN(CCCCn3cccc3)CC2)nc1
Yield: 45.3 %

Procedure:
A mixture of 4 g (17 mmol) of 2-[4(4-aminobutyl)-1-piperazinyl]pyrimidine and 3.3 g of 2,5-dimethoxytetrahydrofuran in 10 ml of acetic acid is refluxed for 1 hour. The reaction mixture is poured into cold water, neutralized with 10% sodium hydroxide solution and extracted with chloroform, the extract is dried and evaporated and 2.2 g of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}pyrrole are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:49]1([CH2:55][C@H:56]([NH2:65])/[CH:57]=[CH:58]/[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:65][C@H:56](/[CH:57]=[CH:58]/[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@H](/C=C/c1ccccc1)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3E)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]-pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 7.1 mg (32 μmol) (2S,3E)-1,4-diphenylbut-3-en-2-amine (intermediate 13).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([CH:35]1[CH2:40][CH2:39][CH:38]([CH2:41]O)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:41][CH:38]4[CH2:39][CH2:40][CH:35]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:36][CH2:37]4)=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC1CCC(CO)CC1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCc1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(OCc4ccccc4)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol (970 mg, 2.53 mmol), 4-pentylcyclohexylmethanol (699 mg, 3.79 mmol) and triphenylphosphine (994 mg, 3.79 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (956 mg, 3.79 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as a solid. 1.11 g (yield: 79.9%)