Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:20](=[O:21])[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[C:12]2=[O:13])=[C:4]([F:22])[CH:3]=1>C(O)(=O)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([N:11]2[C:20](=[O:21])[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[C:12]2=[O:13])[CH:6]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
A mixture of N-(4-chloro-2-fluoro-5-nitrophenyl)-1-cyclohexene-1,2-dicarboximide (10.6 g, 32.7 mmol) in acetic acid is heated to 65° C., treated portionwise with iron powder (7.30 g, 130.7 mmol) over 40 minutes, stirred for 10 minutes, and filtered through diatomaceous earth. The resultant filtrate is washed with ethyl acetate, concentrated in vacuo, diluted with ethyl acetate and saturated sodium hydrogen carbonate solution, and filtered through a filter pad. The phases are separated and the organic phase is washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow solid (8.94 g, 94% yield, mp 164-165° C.).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:16]1[CH:21]=[N:20][N:19]([CH2:22][CH3:23])[C:18](=[O:24])[C:17]=1[CH3:25].O>CN(C)C=O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][S:12][C:16]2[CH:21]=[N:20][N:19]([CH2:22][CH3:23])[C:18](=[O:24])[C:17]=2[CH3:25])=[CH:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCn1ncc(Cl)c(C)c1=O
Reactant: CC(C)(C)c1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc(SCc2ccc(C(C)(C)C)cc2)c(C)c1=O
Yield: 56.2 %

Procedure:
To 3 ml of dry N,N-dimethylformamide was added 0.024 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and was added dropwise with a solution of 1 g of p-t-butylbenzyl mercaptan dissolved in 5 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 0.67 g of 5-chloro-2-ethyl-4-methyl-3(2H)-pyridazinone dissolved in 5 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was allowed to stand over night. The resulting solution was poured into 30 ml of water and extracted twice with 30 ml of diethyl ether. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate, and freed of solvent by distillation under reduced pressure to give 1.42 g of a crude product. The crude product was separated and purified by thin layer chromatography (silica gel, benzene) to obtain 0.69 g of 5-(p-t-butylbenzylthio)-2-ethyl-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](Cl)=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][OH:20])[CH3:16]>C(Cl)(Cl)Cl>[N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([O:20][CH2:19][CH2:18][N:17]([CH2:21][CH3:22])[CH2:15][CH3:16])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: CCN(CC)CCO
Reactant: [N-]=[N+]=Nc1ccc(C=CC(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCOC(=O)C=Cc1ccc(N=[N+]=[N-])cc1

Procedure:
In 80 g of chloroform was dissolved 6.2 g (30 millimoles) of the p-azidocinnamic acid chloride obtained in Example 16, and 3.5 g (30 millimoles) of 2-diethylaminoethanol was added dropwise while maintaining the solution temperature at 10° to 20° C., after which the resulting mixture was allowed to react for 1 hour. The chloroform was distilled off under reduced pressure, and 100 ml of water was added to the resulting oily substance, after which a solution of 1.3 g of sodium hydroxyde in 20 ml of water was added thereto on an ice bath. The organic layer separated was extracted with chloroform, and the extract was further washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 7.2 g of an oily substance as the distillation residue. This oily substance decomposed at 130° C. with formation of bubbles and generation of heat. This oily substance was identified as the compound of this invention by analysis using the following spectral means. ##STR117##
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:29][CH2:28][N:27]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1)C3
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(S(C)(=O)=O)CC1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a solution of Example 3 (100 mg; 0.23 mmol; 1 eq.) and TEA (82 μL; 0.59 mmol; 2.5 eq.) in DCM (3 mL) at 0° C. was added methanesulfonyl chloride (22 μL; 0.28 mmol; 1.2 eq.). The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with DCM, washed successively with 0.1M HCl and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (42 mg, 35%) as a white solid. 1H NMR (CDCl3) δ 7.43-7.34 (m, 2H), 7.12-7.05 (m, 1H), 7.01-6.96 (m, 1H), 4.98 (s, 0.7H), 4.97 (s, 1.3H), 4.69-4.64 (m, 3H), 3.39-3.32 (m, 2H), 3.18-3.08 (m, 2H), 2.91 (s, 2H), 2.86 (s, 1H), 2.72 (s, 3H), 2.70 (s, 1H), 2.62 (s, 2H), 2.00-1.93 (m, 4H). HPLC (max plot) 98.0%, Rt 3.61 min. UPLC/MS: (MS+) 504.4 ([M+H]+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].Cl[C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:21][C:20]3[CH2:22][N:23]([C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:24][C:19]=3[CH2:18]2)=[CH:13][CH:12]=1>CN(C=O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][O:7][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:18][C:19]3[CH2:24][N:23]([C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:34])([F:36])[F:35])=[O:26])[CH2:22][C:20]=3[CH2:21]2)=[CH:13][CH:12]=1
Reactant: OCc1nccs1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(Cl)nn1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(OCc3nccs3)nn1)C2
Reaction time: 0.5 h

Procedure:
Thiazol-2-ylmethanol (64 mg, 0.56 mmol) was dissolved in 2 ml of anhydrous DMF. After adding sodium hydride (42 mg, 55 percent suspension in oil), the mixture was stirred for 30 min, [5-(6-chloropyridazin-3-yl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl](2-trifluoromethylphenyl)methanone (100 mg, 0.25 mmol) was added, and the mixture was stirred at 150° C. for 30 h. After concentrating, water and ethyl acetate were added, and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 6 mg (5%), M+H+: 474.01.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.C([Li])(C)(C)C.[CH2:19]([O:26][C:27]1[C:32]([CH:33]=[O:34])=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:19]([O:26][C:27]1[C:32]([CH:33]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:8][CH:9]=2)[OH:34])=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCOCCc1ccc(Br)cc1
Reactant: Cc1cc(C)c(C=O)c(OCc2ccccc2)n1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOCCc1ccc(C(O)c2c(C)cc(C)nc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of 4-(2-methoxymethyloxyethyl) bromobenzene (0.60 g) in tetrahydrofuran (6 mL) was added tert-butyllithium (1.5 mol/L solution in hexane, 2.0 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. Then, a solution of 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.49 g) in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was stirred for 3 hours at 0° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with dimethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-benzyloxy-4,6-dimethylpyridin-3-yl 4-(2-methoxymethyloxyethyl)phenyl methanol (0.74 g). To a solution of the obtained 2-benzyloxy-4,6-dimethylpyridin-3-yl 4-(2-methoxymethyloxyethyl)phenyl methanol (0.11 g) in ethanol (5.3 mL) was added 10% palladium carbon powder (0.065 g), and the mixture was stirred for 11 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloro-methane/methanol=10/1) to give 3-[4-(2-methoxymethyloxy-ethyl)benzyl]-4,6-dimethyl-1H-pyridin-2-one (0.074 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[C:14](=O)([O:27]C1C=CC=CN=1)[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O=C1C=CC=CN1C(OCCCCCC1CCCCC1)=O>O.C1COCC1>[CH:21]1([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14]([NH:1][C@H:2]([C@@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[O:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(OCCCCCC1CCCCC1)Oc1ccccn1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C(OCCCCCC1CCCCC1)n1ccccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](NC(=O)OCCCCCC1CCCCC1)C(=O)O
Reaction time: 15 h
Yield: 81 %

Procedure:
To a stirred mixture of D-threonine (0.15 g, 1.25 mmol) and NaHCO3 (0.16 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing 5-cyclohexylpentyl 2-pyridyl carbonate and 5-cyclohexylpentyl 2-oxopyridine 1-carboxylate (0.55 g, 1.5 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.32 g, 81%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 316 [M−H]+; (ESI) m/z: 314 [M−H]−. 1H NMR (DMSO-d6): δ 0.77-0.93 (m, 2H), 1.02-1.37 (m, 13H), 1.45-1.72 (m, 7H), 3.88-3.99 (m, 3H), 4.01-4.11 (m, 1H), 6.66 (d, J=9.0 Hz, 1H), 11.77 (br s, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:14]([O:18][C:19]([N:21]1[CH2:26][C@@H:25]([CH3:27])[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][C@@H:22]1[CH:35]=[O:36])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][C@@H:25]([CH3:27])[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][C@@H:22]1[CH:35]([OH:36])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Brc1nccs1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CN1C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C(O)c2nccs2)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
2-Bromothiazole (0.500 g, 3.05 mmol) was dissolved in anhydrous THF (7.62 mL) and cooled to 4° C. (ice bath) under nitrogen. i-PrMgCl.LiCl in THF (2.0 M, 1.52 mL, 3.05 mmol) was added and the reaction stirred at this temperature for 30 minutes. The ice bath was removed and the reaction stirred for 30 minutes at room temperature. (2R,5R)-2-Formyl-5-methyl-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.500 g, 1.52 mmol) was added and the reaction stirred for 2 h. The reaction mixture was quenched with water and extracted with DCM (3×). The combined organic extracts were dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (473 mg). MS: [M+H]+=414.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12](Cl)=[N:13][C:14]2[N:15]([N:36]=[CH:37][CH:38]=2)[C:16]=1[N:17]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:26]=1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:40][C@H:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]1>C(#N)C>[C:20]([O:19][C:18]([N:17]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:26]=1)[C:16]1[N:15]2[N:36]=[CH:37][CH:38]=[C:14]2[N:13]=[C:12]([NH:40][C@H:41]2[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]2)[C:11]=1[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Solvent: CC#N
Product: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO[Si](C)(C)C(C)(C)C)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 22.9 %

Procedure:
To an acetonitrile (5 mL) solution containing tert-butyl {6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}[4-(2-methoxyethoxy)phenyl]carbamate (570 mg, 1.20 mmol), (S)-3-amino-1-tert-butoxycarbonylpiperidine (1.51 g) was added, and this mixture was stirred at 85° C. for 48 hr. The reaction solution was concentrated, and the residue was purified with column chromatography (35% ethyl acetate-hexane) to obtain the title compound (204 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([OH:26])=O)=[O:5])[CH3:2].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1CCNC1
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCC1

Procedure:
Starting materials: 19-ethoxycarbonyl-2,6,10,14,18-pentamethyl-2,6,10,14,18-nonadecapentaenoic acid and pyrrolidine.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][CH:35]1[CH2:39][NH:38][CH:37]([CH2:40][OH:41])[CH2:36]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH:35]([F:34])[CH2:36][CH:37]4[CH2:40][OH:41])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: OCC1CC(F)CN1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC(F)CC4CO)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 4-fluoro-2-(hydroxymethyl) pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 5.07 (m, 1H), 4.31 (m, 1H), 4.16 (s, 1H), 3.89 (m, 1H), 3.70 (m, 2H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 450 [M+H]
Reaction SMILES: [F-].[K+].[CH2:3](Br)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:27]([O:29][CH3:30])=[O:28])[CH:20]=2)[CH:15]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)C.C(OCC)(=O)C>[OH:13][C:14]1[C:23]([C:24]([O:26][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:27]([O:29][CH3:30])=[O:28])[CH:20]=2)[CH:15]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1ccc2cc(O)c(C(=O)O)cc2c1
Agent: O=C([O-])O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc2cc(O)c(C(=O)OCC(=O)c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 48.1 %

Procedure:
To anhydrous N,N-dimethylformamide (hereinafter referred to as "DMF") (10.0 g) were added potassium fluoride (0.209 g) and phenacyl bromide (0.647 g), followed by stirring on an oil bath at 25° C. for about 1 minute. 2-Hydroxy-3-hydroxycarbonyl-6-methoxycarbonylnaphthalene (0.80 g) was dissolved in anhydrous DMF (5.20 g) and the resulting solution was added to the reaction solution. After the completion of the reaction, ethyl acetate, diethyl ether and aqueous 5% sodium hydrogencarbonate were added. Then, an insoluble matter was removed by filtration and the residue was partitioned. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure. The resultant residue was purified by subjecting to silica gel chromatography to obtain 0.57 g of 2-hydroxy-3-phenacyloxycarbonyl-6-methoxycarbonylnaphthalene (DSC analysis value: 177.7° C.).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]([NH:28]C(=O)OC(C)(C)C)([CH3:27])[CH3:26])=[CH:19][CH:18]=1)[CH3:9]>ClCCl>[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]([CH3:27])([CH3:26])[NH2:28])=[CH:19][CH:18]=1)[CH3:9]
Reactant: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl [2-({6-[(2-ethylphenyl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 77, 88.6 mg) was dissolved in dichloromethane (2 mL) to give a yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 minutes, the solvent was evaporated under vacuum affording a yellow oil that was charged on a 5 g SCX cartridge and was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (67.1 mg).
Reaction SMILES: [N:1]1([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[N:1]1([CH:10]2[CH2:15][CH2:14][CH:13]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(n2ncc3ccccc32)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3ncc4ccccc43)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-indazol-1-yl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[C:37]1([C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CCCCCC=C(c1ccccc1)c1ccccc1
Yield: 70.5 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.36 g); dimethylsulfoxide (100 mL), (6-carboxyhexyl)triphenylphosphonium bromide (37.7 g), benzophenone (17.5 g); and tetrahydrofuran (100 mL). The crude product, isolated in the usual way, was recrystallized from hexane (200 mL) to yield 16.6 g of 8,8-diphenyl-7-octenoic acid, mp 88°-89° C. Anal. Calculated for C20H22O2 : C, 81.60; H, 7.53. Found: C, 81.34; H, 7.25.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11](=[O:13])[CH3:12].[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:29]OS(C)(=O)=O)[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O[Li])(C)(C)C>CC(OC)(C)C.[Br-].[Zn+2].[Br-]>[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:29][CH:10]([C:3]1[C:4]([F:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C:11](=[O:13])[CH3:12])[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(=O)Cc1c(F)ccc(F)c1F
Reactant: CC(C)OC(=O)C(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Li]OC(C)(C)C
Agent: [Zn+2]
Solvent: COC(C)(C)C
Product: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1c(F)ccc(F)c1F
Temperature: 35 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
To a solution of 18 (195 g, 1.03 mol) in MTBE (1.8 L) was added zinc bromide (67 g, 0.30 mol) followed by 2 (390 g, 1.2 mol). tert-BuOLi (290 g, 3.6 mol) was then added in several portions while maintaining the reaction temperature below 40° C. The resulting mixture was stirred at 35° C. for 24 h and quenched into a mixture of 2 N HCl (5.6 L) and heptane (5 L) at 0° C. The organic layer was separated and washed with 5% aqueous NaHCO3 (5 L) twice. The resulting organic solution was concentrated under vacuum. The residue was dissolved in heptane (2 L) and the solution was concentrated again under vacuum. The resulting oil was dissolved in DMSO (2.5 L) and the solution was used in the next step without further purification. HPLC analysis indicated that the solution contained the desired product 19 (290 g, 67% yield) as the major component along with 5% of starting material 18. The analytically pure product 19 as one pair of diastereomers was isolated by chromatography on silica gel with ethyl acetate and heptane mixture as an eluant. HRMS: m/z calcd for C20H26F3NO5 418.1836 (M+H). found 418.1849.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C@H:12]12[CH2:18][C@H:15]([NH:16][CH2:17]1)[CH2:14][N:13]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>COCC(O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:16]2[CH2:17][C@@H:12]3[CH2:18][C@H:15]2[CH2:14][N:13]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1ccnc2ccccc12
Solvent: COCC(C)O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccnc2ccccc12
Temperature: 115 °C
Reaction time: 72 h

Procedure:
4-Chloroquinoline (163.6 mg, 1 mmol) dissolved in 1-methoxy-2-propanol (4 ml) was added to tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (237 mg, 1.2 mmol) and stirred at 115° C. for 72 hours. The solvent was removed under reduced pressure and the residue obtained (325 mg) was used directly in the next step. MS (APCI) m/z=326.0 [M+H]+.