Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[N:11][N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[NH2:21].N1C=CC=CC=1.[Cl:28][CH:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30](Cl)=[O:31]>CN(C)C=O>[Cl:28][CH:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30]([NH:21][C:9]1[N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[N:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:31]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Nc1c(-c2ccccc2F)nnn1CSc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1c(-c2ccccc2F)nnn1CSc1ccccc1)C(Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a cold (0° C.), stirred solution of 5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-ylamine (1.30 g, 4.32 mmol) in dimethylformamide (30 ml) under nitrogen was added pyridine (0.46 ml, 5.62 mmol) followed by rac-α-chlorophenylacetyl chloride (0.79 ml, 4.97 mmol). The reaction mixture was stirred at 0° C. for 1 hour and subsequently poured into distilled water (200 ml). The aqueous solution was extracted with ethyl acetate (2×100 ml) and the combined organic extracts were washed with citric acid (100 ml, 10% aqueous), sodium hydrogencarbonate (100 ml, sat. aqueous), water (100 ml), brine (100 ml) and dried (Na2SO4). The solvent was removed in vacuo and the resulting oil was crystallised from hot diethyl ether to afford 2-chloro-N-[5-(2-fluoro-phenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-yl]-2-phenylacetamide (1.514 g, 78%) as a pale solid. δH (400 MHz, CDCl3) 5.37 (1H, s, CHCl), 5.49 (1 H, d, J=14.4, PhSCH2A), 5.61 (1H, d, J=14.4, PhSCH2B), 7.11 (1H, dd, J=11 and 8.6, ArH), 7.24-7.44 (12H, m, ArH), 7.82 (1H, td, J=7.6 and 1.4, ArH), 8.21-8.19 (1H, m, NH); m/z (ES+) 453 (35 ClM+H+) and 455 (37 ClM+H+).
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C(O)=O>[ClH:14].[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2([CH:1]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH3:2])[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: C1CCNC1
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: O=CO
Product: CC(N1CCCC1)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (7.0 g) prepared as described in Example 1 was slowly added to a mixture of pyrrolidine (25 ml) and 98% formic acid (15 ml) heated to 130°-135° C. for five hours. The mixture was stirred and heated at 160°-165° C. for sixteen hours. After cooling the mixture was poured into 5N hydrochloric acid (200 ml). The solution was washed with ether, basified with aqueous sodium hydroxide solution and extracted with ether. The ether extract was washed with water, dried and hydrogen chloride gas was passed into the extract which was then evaporated to dryness. The residue was triturated with dry ether to give a solid which was recrystallised from propan-2-ol to give N-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethyl pyrrolidine hydrochloride (m.p. 233°-235° C.) (Formula I R1 =Me; R2 =H; R3 and R4 together with the nitrogen to which they are attached form a pyrrolidine ring; R5 =4-Cl and R6 =3-Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10](=[CH:13][C:33]2[C:28]([NH2:27])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:9][C:8]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccccn1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)C1=C(c2ccccc2)CC(=Cc2cccnc2N)C=C1

Procedure:
A mixture of the resultant aldehyde from Example 16E (1.0 equivalent), 2-aminopyridine (1.0 equivalent) and NaCNBH3 (1.5 equivalents) in methanol/acetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHCO3 and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[Cl:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[O:22][C:21]([CH2:23][NH:16][CH2:15][CH2:14][NH:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=2[Cl:2])=[CH:20][CH:19]=1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)o1
Agent: [Cl-]
Product: Clc1ccc(CNCCNc2ccc3ccccc3c2Cl)o1
Yield: 67 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and 5-chlorofuran-2-carbaldehyde in 67% yield as a yellow oil.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:8][C@@H:9]([CH3:12])[CH2:10][O:11][C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a cooled (0° C.), stirred solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mol), and Ph3P (15.13 g, 0.06 mol) in THF (100 ml) was added DIAD (11.4 ml, 0.06 mol), and the reaction mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (30 ml) and TFA (30 ml). The solution was stirred at room temperature for 30 min. and the solution was concentrated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3-MeOH (9:1, v/v) as eluent to give benzyl (S)-4-(2-amino-1-propoxy)benzoate (6.63 g, 2 steps, 60%) as a yellow oil. 1H-NMR (CDCl3) δ 1.18 (d, J=6.3 Hz, 3 H), 3.35–3.39 (m, 1 H), 3.71–3.75 (m, 1 H), 3.90–3.93 (m, 1 H), 5.34 (s, 2 H), 6.90–6.93 (m, 2H), 7.32–7.46 (m, 5H), 8.01–8.04 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:6]=[CH:7][CH:8]=1>C1COCC1.CO.[Li+].[OH-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(C)(C)c1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(C(C)(C)C(=O)O)c1
Temperature: 60 °C

Procedure:
To methyl 2-(3-methoxyphenyl)-2-methylpropanoate (800 mg, 4 mmol) in THF (10 ml) and MeOH (10 ml), aqueous LiOH (excess) was added and the reaction mixture was heated at 60° C. for 7 h. Then volatiles were removed in vacuum and the aqueous layer was extracted with ether. Ether layer was discarded. Then the aqueous layer was acidified and extracted with ethyl acetate. Organic layer was dried with sodium sulfate and volatiles removed under vacuum to yield 2-(3-methoxyphenyl)-2-methylpropanoic acid.
Reaction SMILES: [Cl-].[Li+].C(NC(C)C)(C)C.C([Li])CCC.[OH:15][CH:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]([N:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH3:22])[CH3:18].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[OH:15][CH:16]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:17]([N:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH2:22][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH3:31])[CH3:18]
Reactant: CCC(=O)N(C)C(C)C(O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccccc1CCC(=O)N(C)C(C)C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A dry 2 L 3-necked round-bottomed flask was equipped with a mechanical stirrer, and charged with lithium chloride (25.0 g, 596 mmol, 6.0 equiv), diisopropylamine (31.3 mL, 224 mmol, 2.25 equiv), and tetrahydrofuran (120 mL). The suspension was cooled to -78° C., and n-butyllithium (2.43M in hexanes, 85.1 mL, 207 mmol, 2.08 equiv) was added via cannula. After a brief warming to 0° C., it was recooled to -78° C. [S-[R*,R*]]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl propionamide (22.0 g, 99.41 mmol, 1.0 equiv) was added as a 0° C. solution in tetrahydrofuran (300 mL). The resulting solution was stirred at -78° C. for 1 hour, warmed to 0° C. for 15 minutes, warmed to 23° C. for 5 minutes, and cooled to 0° C. Benzyl bromide (17.74 mL, 149 mmol, 1.5 equiv) was added, and the reaction was stirred at 0° C. The reaction was quenched after 15 minutes with saturated ammonium chloride, and the amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (500 mL, 150 mL, 150 mL). The combined organic extracts were dried over sodium sulfate, and after removal of the solvent under reduced pressure, a yellow solid was obtained. Recrystallization from toluene (100 mL) yielded the desired product as a white powder (27.77 g, 90% yield). GC analysis of the TMS ether indicated a diastereomeric purity of the amide of greater than 99% de: mp 136°-137° C.; 1H NMR (300 MHz, C6D6) δ6.9-7.4 (m, 10 H), 4.45 (m, 1H), 4.25 (br, 1H), 3.96 (m, 1H), 3.80 (m, 1H), 3.36 (dd, 2H, J=13.1 Hz, 6.92 Hz), 3.01 (m, 1H), 2.75 (m, 1H), 2.70 (s, 3H), 2.45-2.59 (m, 3H), 2.08 (s, 3H), 1.05 (d, 3H, J=7.0 Hz), 1.02 (d, 3H, J=6.5 Hz), 0.83 (d, 3H, J=7.0 Hz), 0.59 (d, 3H, J=6.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ178.2, 177.2, 142.3, 141.1, 140.5, 139.9, 129.2, 128.9, 128.6, 128.31, 128.26, 127.5, 126.8, 126.4, 126.2, 76.4, 75.2, 58.0, 40.3, 40.0, 38.9, 38.1, 32.3, 27.1, 17.7, 17.4, 15.5, 14.3; FTIR (neat film) cm-1 3384 (br, m), 3027 (m), 2973 (m), 2932 (m), 1617 (s), 1493 (m), 1453 (m), 1409 (m), 1080 (m), 1050 (m), 701 (s); HRMS (FAB) Calcd for C20H26NO2 (MH+): 312.1965. Found: 312.1972; Anal. Calcd for C20H25NO2: C, 77.14, H, 8.09, N, 4.50. Found: C, 76.87, H, 8.06, N, 4.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:32][CH:31]5[CH:26]([N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][CH2:30]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:32][CH:31]5[CH:26]([NH:27][CH2:28][CH2:29][CH2:30]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCCN(C(=O)OC(C)(C)C)C2C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCCNC2C1
Yield: 140.7 %

Procedure:
To a solution of tert-butyl 6-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (0.60 g) in CH2Cl2 was added a saturated solution of HCl in MeOH. Solid was precipitated out after 2 h reaction. The reaction mixture was filtered, and the residue was dried to give the title compound as a pale yellow solid (0.70 g, 80.00%), HPLC: 96.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.13-1.96 (m, 6H), 2.09-2.43 (m, 2H), 3.29 (m, 2H), 3.68-3.70 (m, 6H), 3.83 (s, 3H), 4.06 (m, 2H), 6.93 (t, J=8.2 Hz, 1H), 7.06 (s, 1H), 7.27 (m, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.87 (d, J=4.2 Hz, 1H), 8.45 (s, 1H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[NH2:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: NC[C@H](O)COc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: NC[C@H](O)COc1ccc(O)cc1
Reaction time: 2 h

Procedure:
A mixture of (2S)-1-amino-3-(4-benzyloxy-phenoxy)-propan-2-ol (0.9 g, 3.3 mmol) 0.2 mL of acetic acid and 10% Pd/C (0.3 g) in 70 mL of ethanol was pressurized with 20 psi hydrogen and shaken over 2 hours. The catalyst was then removed by filtering through a short pad of silica gel and the solvent was removed to give the title compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.86 (s, 1H), 2.66 (dd, J=12.8, 5.3 Hz, 1H), 2.85 (dd, J=12.8, 3.5 Hz, 1H), 3.79-3.95 (m, 3H), 6.67 (d, J=6.6 Hz, 2H), 6.75 (d, J=6.6 Hz, 2H); MS (ES) m/z: 183.1 (M++H); HRMS Calcd. for C9H13NO3(M++H): 183.0895. Found: 183.0892.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][C:9]#[N:12])=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Product: N#CCCOc1ccc(F)cc1
Yield: 70 %

Procedure:
A mixture of 11.2 g of 4-fluorophenol, 10.6 g of acrylonitrile and 2.02 g of triethylamine was refluxed for 16 hours with stirring and then acrylonitrile, triethylamine and 4-fluorophenol were removed under reduced pressure. The obtained residue was diluted with ether, washed successively with 10% aqueous solution of sodium hydroxide and 2N hydrochloric acid and dehydrated with anhydrous magnesium sulfate. Ether was distilled away to give 11.51 g of colorless liquid of 3-(4-fluorophenoxy)propionitrile (yield: 70%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:22]NC(=O)C)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[C:6]=1[Br:7].O(Cl)[Cl:28].O>C(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:22][Cl:28])[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:12])[F:13])(=[O:10])=[O:9])[C:6]=1[Br:7]
Reactant: CC(=O)NCn1c(Br)c(Br)c(S(=O)(=O)C(F)(F)F)c1-c1ccc(Cl)cc1
Reactant: ClOCl
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1c(Br)c(Br)n(CCl)c1-c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
N-{{2,3-Dibromo-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrol-1-yl}methyl}acetamide (4.5 g, 0.00835 mol) is added to phosphoros oxychloride (15 mL). The reaction mixture is refluxed for 31/2 hours, poured into water, stirred overnight and filtered to obtain a solid. The solid is dissolved into methylene chloride and the solution is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a yellow solid (3.8 g, mp 153°-156° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:20]=3[CH3:19])[CH2:28][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4cccs4)n(C(C)(C)C)n3)CC2)c1C

Procedure:
86 mg (96%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(2,3-dimethylphenyl)piperazine (36 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:33])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[C:27]([NH2:28])=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]2)[CH:18]=1)[CH3:12]>O=S(Cl)Cl.C(Cl)Cl>[CH2:11]([O:13][C:14](=[O:33])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[C:27]([NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]2)[CH:18]=1)[CH3:12]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of 4-chlorobenzoic acid (312 mg, 2.0 mmol) in SOCl2 (10 mL) was heated to reflux for 2 h. After removal of the solvent, the residue was dissolved into CH2Cl2 (5 mL) and was dropped into a solution of Example Z (315 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C., was then stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried (NaSO4) and filtered. After concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionic acid ethyl ester (290 mg, 64%). 1H-NMR (CDCL3): 8.02 (s, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.36 (t, J=8.4 Hz, 3H), 6.87 (s, 1H), 4.06 (q, J=7.6 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.40 (s, 9H), 1.12 (t, J=7.6 Hz, 3H); MS (ESI) m/z: 454 (M+H+).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:53][CH2:54][CH2:55][C:56]#[N:57].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:56]([CH2:55][CH2:54][CH2:53][O:51][C:42]1[CH:41]=[C:40]([CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=1)[CH2:39][N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]([C@@H:7]1[C@@H:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[Cl:31])=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]1)=[O:6])#[N:57]
Reactant: N#CCCCBr
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCC#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.2 M) was added 4-bromobutanenitrile (1.2 eq.) and cesium carbonate (1.3 eq.). The reaction was stirred at rt for 18 h, then heated to 65° C. for 4 h. After cooling to rt, the reaction was diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NH4Cl solution, 5% aqueous HCl, saturated aqueous NaHCO3 solution, and brine. The organic solution was dried over MgSO4 and concentrated in vacuo to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH:16](=[O:20])[CH:17]([CH3:19])[CH3:18].Cl>O1CCCC1.CCCCCC>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CC(C)C=O
Reactant: CCOc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(C(O)C(C)C)cc1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 100.4 %

Procedure:
A solution of p-bromophenetole (2.01 g, 0.01 mol) in tetrahydrofuran is cooled to −65° C., treated dropwise with a 2.5 M solution of n-butyllithium in hexane (4 mL), stirred for 20 minutes at −55 to −65° C., treated dropwise with a solution of isobutyraldehyde (0.91 mL, 0.01 mol) in tetrahydrofuran, stirred overnight at room temperature, diluted with an ice-water mixture, acidified with 10% hydrochloric acid, and extracted with methylene chloride. The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a tan oil (1.95 g) which is identified by NMR spectral analyses.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)#[CH:19]>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]#[C:19][C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:21]=1
Reactant: C#Cc1cccnc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: C(#Cc1cccc2c3c([nH]c12)C1CCN(CC1)C3)c1cccnc1

Procedure:
The product of Example 1B (130 mg, 0.45 mmol) and 3-ethynylpyridine (74 mg, 0.72 mmol; Aldrich) were processed according to the method described in Example 3 and purified by reverse-phase HPLC (Waters XBridge™ C18 5 μm OBD 30×100 mm column, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% trifluoroacetic acid over 15 minutes) to afford the title compound as the bis trifluoroacetate: 1H NMR (500 MHz, methanol-d4) δ ppm 2.26-2.35 (m, 2 H), 2.36-2.45 (m, 2 H), 3.44-3.48 (m, 1 H), 3.48-3.56 (m, 2 H), 3.69 (ddd, J=13.8, 8.9, 5.3 Hz, 2 H), 4.77 (s, 2 H), 7.12 (t, J=7.6 Hz, 1 H), 7.39 (d, J=7.0 Hz, 1 H), 7.51 (d, J=7.9 Hz, 1 H), 7.74 (dd, J=8.1, 5.3 Hz, 1 H), 8.37 (dt, J=8.0, 1.6 Hz, 1 H), 8.65 (d, J=4.6 Hz, 1 H), 8.96 (s, 1 H); MS (APCI) m/z 314 (M+H)+. Anal. Calcd. for C21H19N3.2.85 TFA: C, 50.24; H, 3.45; N, 6.58. Found: C, 49.97; H, 3.54; N, 6.80.
Reaction SMILES: Cl[C:2]1([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3(Cl)[N:22]=[C:21](Cl)[N:20]=[CH:19][NH:18]3)[CH:11]=2)[N:7]=[C:6](Cl)[N:5]=[CH:4][NH:3]1.[C:25]1([CH3:32])[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC.C(OCC)(=O)C>[CH3:32][C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][C:30]=1[C:4]1[N:5]=[C:6]([C:30]2[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[N:7]=[C:2]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[N:22]=[C:21]([C:30]4[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[CH3:32])[N:20]=[C:19]([C:30]4[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[CH3:32])[N:18]=3)[CH:11]=2)[N:3]=1
Reactant: Cc1cccc(C)c1
Reactant: ClC1=NC(Cl)(Oc2cccc(OC3(Cl)N=C(Cl)N=CN3)c2)NC=N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccc(-c2nc(Oc3cccc(Oc4nc(-c5ccc(C)cc5C)nc(-c5ccc(C)cc5C)n4)c3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Temperature: 25 °C

Procedure:
To a 500 mL round-bottomed flask fitted with a magnetic stirrer, a condenser and a nitrogen atmosphere are added 2.33 g (5.74 mmol) of the product of Example 11 and 25 mL of m-xylene. The mixture is stirred with warming and, when it becomes homogeneous at about 40° C., 1.84 g (0.0138 mol) of aluminum chloride are added all at once. The mixture is brought to reflux and stirred at this temperature for three hours. After cooling to room temperature, a 100 mL portion of 2N hydrochloric acid is added. The mixture is heated with stirring for 15 minutes and allowed to cool. Portions of ethyl acetate and heptane are added and the solids formed are collected by vacuum filtration. The solids are washed with ethyl acetate and water, then dried to afford 2.58 g of the title compound as an off-white solid.