Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Yield: 68.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.5 g) and 6-bromo-1-(4-methoxyphenyl)-1-hexanone (1.4 g) were reacted and treated in the same manner as in Example 172 to give 1.4 g of 4-amino-5-chloro-N-((1-(6-(4-methoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Cl:11]N1C(=O)CCC1=O>C(Cl)Cl.O.C([O-])([O-])=O.[K+].[K+]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Nc1ccc2[nH]nc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-aminoindazole (1.373 g, 10.00 mmol) and N-chlorosuccinimide (1.381 g, 10.14 mmol) in methylene chloride (50 mL) was sonicated at rt for 30 min. The brown mixture was then stirred overnight at rt. The suspension was diluted with CH2Cl2 to ≈100 mL, water and aq. K2CO3 solution were added, and the insoluble brown material was filtered off and washed with CH2Cl2 and water. The layers of the filtrate were separated; the organic layer was washed with water (3×) and brine and dried over MgSO4. The dried solution was filtered through a pad of silica gel, washing with 5% MeOH in CH2Cl2 until no more product eluted as indicated by TLC. Concentrating and drying in vacuo gave the title compound as yellow solid. MS (ES+): m/z 168.2/170.2 (100/37) [MH+]. HPLC: tR=2.1 min (ZQ2000, polar—5 min). 1H NMR (CDCl3, 400 MHz): δ=5.06 (s, 2H), 6.96 (d, J=8.5 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.78 (s, 1H), 12.95 (brs, 1H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>ClCCl>[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2][N:3]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:4]1
Reactant: CCOC(=O)Cl
Reactant: c1ccc2c(c1)CCNCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccccc2CC1
Reaction time: 8 h

Procedure:
To a solution of 1.75 g of 2,3,4,5-tetrahydro-1H-3-benzazepine in 20 ml of dichloromethane was added 2.884 ml of pyridine. The reaction mixture was ice-cooled, and 1.705 ml of ethyl chloroformate which had been dissolved in 5 ml of dichloromethane was added dropwise thereto, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 2.15 g of ethyl 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a pale yellow oily substance.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:10]([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:12]3[S:11][CH:15]=[CH:14][CH:13]=3)=[CH:23][CH:22]=2)[C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: BrCc1ccc(-c2cccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1csc(-c2ccc(CN(Cc3ccc(-c4cccs4)cc3)c3ccc4[nH]cnc4c3)cc2)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-(thiophen-2-yl)benzylbromide (557 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.09 g (18.9%); MS m/z: 478.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.70 (s, 4H); 6.73 (br s, 1H); 6.78 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 7.10-7.11 (m, 2H); 7.33-7.36 (m, 5H); 7.45 (dd, 2H); 7.49 (dd, 2H); 7.59-7.60 (m, 4H); 7.91 (s, 1H); 11.99 (br s, 1H); HPLC (METHOD [A]): rt 19.76 min (100%)
Reaction SMILES: C[O:2][C:3](=[O:8])[C@@H:4]([NH2:7])[CH2:5][NH2:6].[F:9][C:10]([F:27])([F:26])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[F:26][C:10]([F:9])([F:27])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:7][C@@H:4]([CH2:5][NH:6][C:23]([C:20]3[CH:19]=[CH:18][C:17]([C:14]4[CH:15]=[CH:16][C:11]([C:10]([F:9])([F:26])[F:27])=[CH:12][CH:13]=4)=[CH:22][CH:21]=3)=[O:24])[C:3]([OH:2])=[O:8])=[O:24])=[CH:21][CH:22]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](N)CN
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: O=C(NC[C@H](NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 59.4 %

Procedure:
(2S)-2,3-Diamino-propionic acid methyl ester (0.080 g, 0.421 mmol) was reacted with 4′-trifluoromethyl-biphenyl-4-carboxylic acid (0.224 g, 0.841 mmol) as described in general procedure A yielding the corresponding (2S)-3-bis-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.150 g, 60%). 1H-NMR(400 MHz, DMSOd6): 4.16 (m, 2H), 5.0 (m, 1H), 8.17 (m, 8H), 8.28 (m, 8H), 9.18 (m, 1H), 9.21 (d, 1H); LC/MS (m/z): 601.2 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1.C(OC(Cl)=O)C(C)C>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:26]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[O:27])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1
Reactant: NC1CCN(CCC2CCOc3ccccc32)CC1
Reactant: O=C(O)c1cccnc1
Agent: CC(C)COC(=O)Cl
Product: O=C(NC1CCN(CCC2CCOc3ccccc32)CC1)c1cccnc1
Yield: 15 %

Procedure:
N-[1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-aminopiperidine was coupled to pyridine-3-carboxylic acid utilizing the isobutylchloroformate protocol described in Example 6. The resulting residue was further purified by chromatography on silica (eluant: chloroform/ethanol/ammonium hydroxide; 85/14/1) and crystallization from diethyl ether to afford the title compound (15% yield), mp=126-8°, Anal: C22H27N3O2 0.25 H2O, Calc. C, 71.42; H, 7.49; N, 11.36; Found: C, 71.25; H, 7.50; N, 11.19.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[C:5]3[NH:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(Br)cc23)CC1
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(-c4cc(F)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, {6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]-7-fluoroquinolin-3-yl}(cyclopropyl)methanone (38 mg, 0.087 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35 mg, 0.131 mmol) to afford the desired product (39 mg, 90%) as a green solid: 1H NMR (300 MHz, CD3OD) δ 9.19 (s, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.60 (d, J=11.8 Hz, 1H), 7.49 (s, 1H), 7.42 (dt, J=11.6, 2.0 Hz, 1H), 4.18 (s, 1H), 2.86 (s, 6H), 2.85-2.78 (m, 1H), 2.42 (s, 2H), 2.19 (s, 2H), 1.76-1.62 (m, 4H), 1.22-1.07 (m, 5H); ESI MS m/z 500 [C27H28ClF2N3O2+H]+; HPLC 97.4% (AUC), tR=9.21 min.
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][C:5]2[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:21])[C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:51]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[N:50]=1>CN(C)C=O>[F:1][C:2]1[C:35]([F:36])=[CH:34][C:5]2[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:32])[CH3:33])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:21])[C:7](=[O:18])[CH:8]([CH2:48][C:49]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[N:51]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[N:50]=3)[C:9](=[O:17])[N:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3cc(F)c(F)cc32)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3cc(F)c(F)cc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
To a solution of 0.500 g of 2-(7,8-difluoro-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part B, (1.013 mmol) in 5 mL dimethylformamide at 0° C. under nitrogen is added 2.43 mL (1.22 mmol, 1.2 equiv) potassium bis(trimethylsilyl)amide (0.5M in toluene) dropwise over 5 min. After stirring 5 min., 346 mg of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole (1.11 mmol, 1.1 equiv) is added. After 1 h at 0° C., the reaction is quenched by addition to a stirring mixture of ethyl acetate, water and saturated aqueous brine. The mixture is transferred to a separatory funnel and the layers were separated. The organic layer is washed with 1:1 water/saturated aqueous brine. The aqueous layers were combined and washed twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous brine, dried over anhydrous sodium sulfate, and then evaporated in vacuo to an oil. The crude product is purified on flash grade silica gel using 25-30% ethyl acetate in hexane. The appropriate fractions were combined, evaporated in vacuo and triturated with hexane. The hexane is evaporated in vacuo and the residual solid is dried under high vacuum to provide 525 mg of the title compound as a white solid: 1H NMR (300 MHz, CDCl3) δ8.06 (d, 1H, J=8.3), 7.84 (d, 1H, J=7.9), 7.49 (m, 1H), 7.38 (m, 2H), 7.29 (m, 6H), 7.12 (m, 1H), 6.98 (m, 2H), 6.78 (dd, 1H, J=8.5, 10.6), 4.99 (m, 1H), 4.36 (dd, 1H, J=4.6, 8.7), 4.20 (s, br, 2H), 3.85 (s, 3H), 3.84 (m, 1H), 3.52 (dd, 1H, J=4.6 16.8), 1.67 (s, 9H), 1.08 (m, 6H); low resolution MS (FAB)m/e 724 (MH+).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]([F:46])([F:45])[C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][NH:37][N:36]=1>C(Cl)Cl.CN(C=O)C>[CH2:15]([O:14][C:13]([NH:12][C@@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][N:36]3[C:35]([C:34]([F:46])([F:33])[F:45])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=[N:37]3)[CH:4]=2)[CH2:8]1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N[C@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](NC(=O)OCc2ccccc2)C3)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.1 %

Procedure:
(S)-Benzyl 5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-ylcarbamate (2.96 mmol, 880 mg) was dissolved in DCM (10 mL) and thionyl chloride (5.92 mmol, 0.432 ml, 704 mg) added. The mixture was stirred at room temperature for 30 min TLC before the solvent was removed under reduced pressure and residual thionylchloride azeotroped with DCM (×3). To the residue was added potassium carbonate (8.88 mmol, 1227 mg) followed by DMF (8 ml) then ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.96 mmol, 616 mg) and the mixture heated to 60° C. After 1 h the mixture was concentrated and partitioned between EtOAc/H2O and the organic layer was washed with water (×3). The organic layer was dried, filtered and concentrated to give a yellow oil which was purified by flash chromatography eluting with 15% EtOAc/Heptane to give the desired isomer as a colourless oil (45 mg, 0.092 mmol, 3.1%). 1H NMR (400 MHz, CDCl3) δ 1.34 (t, 3H) 2.75 (m, 2H) 3.25 (m, 2H) 4.33 (q, 2H), 4.50 (m, 1H) 4.95 (m, 1H), 5.08 (s, 2H) 5.48 (s, 2H) 7.00 (m, 2H) 7.15 (d, 1H) 7.34 (m, 5H) 7.99 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])C.CCN(C(C)C)C(C)C.CS([C:25]1[N:30]=[C:29]([N:31]2[C:39]3[C:34](=[C:35]([O:40][CH2:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)[CH:28]=[CH:27][N:26]=1)=O.O>CC(N(C)C)=O>[CH3:1][O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:25]2[N:30]=[C:29]([N:31]3[C:39]4[C:34](=[C:35]([O:40][CH2:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:45])=[O:46])[CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32]3)[CH:28]=[CH:27][N:26]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 120 °C
Yield: 90 %

Procedure:
4-Amino-cyclohexanecarboxylic acid ethyl ester (550 g) and 815 mL DIPEA were added to 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (746.7 g) in 2.5 L DMA, and the mixture allowed to heat to 120° C. for 4 h and then allowed to cool to room temperature. Water (3 L) was added dropwise and the resulting precipitate was collected by filtration, washed with H2O and MeOH, and dried in vacuo at 48° C. overnight to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid methyl ester (90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:21])[NH:11][C:12]([CH3:20])=[CH:13][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:21])[N:11]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]([CH3:20])=[CH:13][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1cc(C)[nH]c(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)n(CC(=O)OC(C)(C)C)c(=O)c1OCc1ccccc1
Temperature: 4 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 3-benzyloxy-4-ethoxycarbonyl-6-methyl-2-pyridinone from step 1 above (17 g, 59 mmol) and tert-butyl bromoacetate (8.1 g, 59 mmol) in DMF (350 mL) at 0° C. was added cesium carbonate (19.3 g, 59 mmol). The mixture was stirred at 4° C. for 96 h. The salts were removed by filtration and the filtrate solvent was removed in vacuo. The residue was purified by flash column chromatography using 1:4 EtOAc:hexanes as eluant to give the title compound as an oil (9.5 g; HPLC RT=23.58, method B).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:17][C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22].ClC(OCC(C)C)=O>>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CCCC[C@H](N)C(N)=O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(N)=O
Yield: 75 %

Procedure:
Condensation of BocLeuOH (2.0 g.) and HNleNH2 (1.0 g.) by the mixed anhydride method using isobutyl chloroformate gave BocLeu-NleNH2 in 75% yield. De-t-butoxycarbonylation of BocLeu-NleNH2 (1.42 g.) using hydrogen chloride in dioxane gave HLeu-NleNH2 in 88% yield. Condensation of ZGlyOSu (1.91 g.) and HLeu-NleNH2 (0.95 g.) by the activated ester method gave ZGly-Leu-NleNH2 in 79% yield. Debenzyloxycarbonylation of ZGly-Leu-NleNH2 (1.40 g.) by hydrogenation with palladium catalyst gave HGly-Leu-NleNH2 in 67% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33](=[O:36])[NH:34][CH3:35])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][NH:34][C:33]([C:31]1[N:32]=[C:20]2[N:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][N:21]2[N:30]=1)=[O:36]
Reactant: CNC(=O)c1nc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1nc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 8-7 (50 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 8-8.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]CC4C=CC=CC=4)=[O:28])=[CH:23][C:22]=3[O:37][CH3:38])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:22]=3[O:37][CH3:38])(=[O:19])=[O:20])[C:9](=[O:17])[N:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Yield: 73.5 %

Procedure:
4 g of 5-ethoxy-1,3-dihydro-1-(2-methoxy-4-benzyloxycarbonylbenzenesulfonyl)-3-cyclohexyl-2H-benzimidazol-2-one in 100 ml of AcOEt were hydrogenated at room temperature and at atmospheric pressure in the presence of 200 mg of Pd/C. The catalyst was filtered off on C elite® and the filtrate was concentrated under vacuum. 2.47 g of the expected compound were obtained in the form of a white solid by crystallization from iso ether. M.p.=205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[CH:12]([CH3:27])[CH2:13][CH2:14][N:15]([S:23]([CH3:26])(=[O:25])=[O:24])C(=O)OC(C)(C)C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(OCC)(=O)C.CCCCCC>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[CH:12]([CH3:27])[CH2:13][CH2:14][NH:15][S:23]([CH3:26])(=[O:25])=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(CCN(C(=O)OC(C)(C)C)S(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(CCNS(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.4 %

Procedure:
The t-butyl N-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-3-methylbutyl]-N-methylsulfonylcarbamate (136 mg, 0.246 mmol) obtained in Example 243 was dissolved in dichloromethane (4 ml), followed by the addition of trifluoroacetic acid (1 ml) at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was diluted with dichloromethane, washed successively with water, a saturated aqueous solution of sodium bicarbonate, and brine, dried over magnesium sulfate and then, concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (99.5 mg, 0.220 mmol, 89%) was obtained as colorless needle crystals.
Reaction SMILES: IC1C=CC(C)=CC=1S(O)(=O)=O.OOS([O-])=O.[K+].[C:19]1([CH:25]([OH:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CC(O)c1ccccc1
Agent: Cc1ccc(I)c(S(=O)(=O)O)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
8.9 mg (0.03 mmol) of 2-iodo-5-methylbenzenesulfonic acid prepared by Preparation Example 2, 1.48 g (2.4 mmol) of powdered Oxone (registered trademark) and 367 mg (3 mmol) of 1-phenylethanol were added to 3.75 ml of acetonitrile, and the mixture was heated at 70° C. while being stirred for one hour. The later treatment was carried out in the same way as in Example 1, and then acetophenone was obtained. The yield of the obtained acetophenone was determined and the result is shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)nc1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 70 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 70%). 1H NMR (300 MHz, CDCl3): δ 3.63-3.73 (m, 7H), 4.08-4.15 (m, 4H), 6.68 (d, J=8.7 Hz, 2H), 7.20-7.31 (m, 1H), 7.42-7.53 (m, 2H), 7.65-7.80 (m, 2H), 8.21 (d, J=3.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][C:42]1([CH3:50])[CH2:48][CH2:47][C:46](=[O:49])[O:45][C:43]1=[O:44]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:46](=[O:49])[CH2:47][CH2:48][C:42]([CH3:50])([CH3:41])[C:43]([OH:45])=[O:44])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)CCC(=O)OC1=O
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)CCC(C)(C)C(=O)O)CCC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 150 mg of the crude product of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate and 0.094 mL of triethylamine in 3 mL of THF was added 62.3 mg of 2,2-dimethylglutaric anhydride at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and then washed with 1 M hydrochloric acid, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 5-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-2,2-dimethyl-5-oxopentanoic acid (colorless foamy substance, 225 mg) as a crude product. ESI+: 587