Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14](OC)=O.[NH3:21]>>[NH2:21][C:1]1[CH:3]=[CH:14][C:13]2[C:12](=[C:11]([O:10][CH:5]([CH3:4])[CH2:6][CH2:7][CH2:8][O:9][C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[CH:20]=[CH:19][CH:18]=2)[N:2]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: N#Cc1cccc(O)c1
Reactant: N
Product: CC(CCCOc1cccc(C#N)c1)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting 3-cyanophenol for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.36 (d, 1H), 7.47 (m, 2H), 7.42 (m, 2H), 7.35 (m, 1H), 7.31 (m, 1H), 7.20 (m, 1H), 7.12 (d, 1H), 4.87 (m, 1H), 4.10 (m, 2H), 1.78–2.07 (m, 4H), 1.40 (d, 3H); MS (DCI/NH3) m/z 348 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10](O)=O)=[N:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].Cl>>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[NH:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:20]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1N
Reactant: Cn1c([N+](=O)[O-])cnc1C(=O)O
Agent: Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nc2ccccc2[nH]1

Procedure:
1.7 g. of 5-nitro-1-methyl-2-imidazolyl carboxylic acid and 1.08 g. of o-phenylenediamine are heated for 40 minutes in a bomb tube to 180° C. in 10 ml. of 25% hydrochloric acid. After evaporating the reaction mixture to dryness and column chromatography on 100 g. of silica gel with methanol-chloroform 1 : 1, 120 mg. of 2-(5-nitro-1-methyl-2-imidazolyl)-benzimidazole is obtained, m.p. 257° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)C.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>C(O)(=O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:23][CH2:22][CH2:21][O:20][CH3:19])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: COCCN
Solvent: CC(=O)O
Solvent: CCO
Product: COCCN=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Yield: 72.7 %

Procedure:
A suspension of 6-nitroveratraldehyde (84 g, 0.4 mole), 600 ml of ethanol, and 1 ml of acetic acid was refluxed with 2-methoxyethylamine (30 g, 0.44 mole) for 1.5 hrs. After cooling overnight filtration gave 78 g of the product; m.p. 65°-66°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6](B(O)O)[CH:7]=1.FC(F)(F)S(O[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1cc(Cl)ccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)ccc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 84 %

Procedure:
A mixture of (5-chloro-2-(trifluoromethyl)phenyl)boronic acid (0.453 g, 2.02 mmol), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.669 g, 2.02 mmol), tetrakis(triphenylphosphine)palladium (0.117 g, 0.1 mmol), sodium carbonate (2 M, 5 mL), and 1,2-dimethoxyethane (10 mL) was heated at 80° C. under microwave irradiation for 1.5 h. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-25% EtOAc in hexanes) to give tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as colorless oil (0.614 g, 84%): 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.5 Hz, 1H), 7.37-7.22 (m, 1H), 7.22 (d, J=1.68 Hz, 1H), 5.60 (br, 1H), 4.02 (br, 2H), 3.61 (br, 2H), 2.34 (br, 2H), 1.50 (s, 9H); MS (ESI+) m/z 306 [M+H]+.
Reaction SMILES: [Cl-:1].[Cl-:2].[Cl-].[Cl-].[Zr+4:5].[CH2:6]([C:9]1([Li])[CH:13]=[CH:12][CH:11]=[CH:10]1)[CH:7]=[CH2:8]>C1COCC1>[CH2:6]([C:9]1([Zr:5]([C:9]2([CH2:6][CH:7]=[CH2:8])[CH:13]=[CH:12][CH:11]=[CH:10]2)([Cl:2])[Cl:1])[CH:13]=[CH:12][CH:11]=[CH:10]1)[CH:7]=[CH2:8]
Reactant: [Zr+4]
Reactant: [Li]C1(CC=C)C=CC=C1
Reactant: [Cl-]
Solvent: C1CCOC1
Product: C=CCC1([Zr](Cl)(Cl)C2(CC=C)C=CC=C2)C=CC=C1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 0.105 mol of methyllithium in ether is added slowly to a solution, vigorously stirred at 0° C., of the β-propenylcyclopentadiene prepared in the preceding stage (a) in ether. The mixture is heated to ambient temperature (20° C.) and is kept stirred for 1 hours. A precipitate of β-propenylcyclopentadienyllithium is isolated by filtration, washed with ether 2′ 100 ml) and dried to give a white powder. 47.5 millimoles of zirconium tetrachloride dissolved in 100 ml of THF are added to a vigorously stirred solution of β-propenylcyclopentadienyllithium in 100 ml of THF at 0° C. The mixture is heated to ambient temperature (20° C.) and is stirred for 16 hours. The volatile compounds are removed under vacuum and the residue is extracted with ether (4′ 100 ml) and filtered. The product is obtained in the form of a white solid by slow cooling of the solution to −78° C. and recrystallization from cold ether.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][CH:10]([OH:13])[CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH:10]([O:13][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])[CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CNc2cccc(Br)c2OC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CNc2cccc(Br)c2OC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of 9-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ol (0.456 g, 1.868 mmol) and imidazole (0.280 g, 4.11 mmol) in DMF (5.0 mL) was added TBSCl (0.619 g, 4.11 mmol). The reaction was stirred at room temperature for 18 h. The mixture was diluted with a solution of saturated sodium bicarbonate (15 ml) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (648 mg, 1.718 mmol, 92% yield) as clear oil. LCMS, [M+H]+=360.1. 1H NMR (400 MHz, CDCl3) δ 6.99 (dd, J=7.8, 1.4 Hz, 1H), 6.69 (t, J=7.9 Hz, 1H), 6.57 (dd, J=7.9, 1.5 Hz, 1H), 4.39 (dd, J=11.9, 4.8 Hz, 1H), 4.19 (tt, J=6.5, 4.7 Hz, 1H), 3.94 (dd, J=11.9, 6.8 Hz, 1H), 3.67 (br. s., 1H), 3.54 (dt, J=13.2, 4.1 Hz, 1H), 3.17 (dd, J=12.3, 5.5 Hz, 1H), 0.93-0.90 (m, 9H), 0.11 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1.[CH3:32][C:33]1([CH3:40])[CH2:37][C:36](=[O:38])[O:35][C:34]1=[O:39].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[CH3:32][C:33]([CH3:40])([CH2:37][C:36](=[O:38])[N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:23])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1)[C:34]([OH:39])=[O:35]
Reactant: O=C(Nc1ccc(OC2CCCNC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)N1CCCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)C1)C(=O)O
Yield: 68.5 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-phenyl]-amide (52.3 mg, 0.121 mmol), 3,3-dimethyl-dihydro-furan-2,5-dione (17 mg, 0.133 mmol) and triethylamine (34 uL, 0.242 mmol) in 1 mL DMSO were stirred at room temperature for 30 minutes and then diluted with 30 ml ethyl acetate. The organic phase was washed with 2.5% KHSO4 (5 mL) and saturated sodium chloride (2×5 mL), dried over MgSO4, filtered and evaporated to dryness under vacuum. The crude product was purified by flash chromatography to yield 2,2-dimethyl-4-oxo-4-(3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidin-1-yl)-butyric acid as a white solid (46.4 mg, 68%). ES-MS calcd for C28H28F3N3O6 (m/e) 559.55, obsd 560 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Br:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17]>>[BrH:12].[C:16]([O:15][CH2:14][CH2:13][N:3]1[CH:4]=[C:5]([C:8]([F:9])([F:11])[F:10])[CH:6]=[CH:7][C:2]1=[NH:1])(=[O:18])[CH3:17]
Reactant: CC(=O)OCCBr
Reactant: Nc1ccc(C(F)(F)F)cn1
Product: Br
Product: CC(=O)OCCn1cc(C(F)(F)F)ccc1=N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 3.0 g of 2-amino-5-trifluoromethylpyridine and 7 ml of bromoethylacetate was stirred at 80° C. for 1 hour, and concentrated under reduced pressure. The resulting residue was suspended in a mixed solvent of acetonitrile and t-butyl methyl ether, and filtered. The resulting solid was washed with t-butyl methyl ether to obtain 2.46 g of (2-imino-5-trifluoromethyl-2H-pyridin-1-yl)ethyl acetate hydrobromide.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]([CH3:28])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[CH3:28]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine hydrochloride (CAN 1240526-27-5) as starting materials, and isolated (64 mg, 84%) as light yellow solid; LC-MS (UV peak area, ESI) 100%, 358.1869 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([CH2:25][C:26](O)=[O:27])[C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:44]([O:46][C:47](=[O:53])[CH2:48][C@@H:49]([C:51]#[CH:52])[NH2:50])[CH3:45].CCN(CC)CC>>[CH2:44]([O:46][C:47](=[O:53])[CH2:48][C@@H:49]([C:51]#[CH:52])[NH:50][C:26](=[O:27])[CH2:25][N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[C:21]1=[O:24])[CH3:45]
Reactant: C#C[C@@H](N)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)CC3)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C#C[C@H](CC(=O)OCC)NC(=O)CN1CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-5 (150 mg, 0.39 mmol), HOBT (63 mg, 0.46 mmol) and EDC (111 mg, 0.58 mmol) was added 3(S)-(ethynyl)-β-alanine ethyl ester hydrochloride (1-32) (U.S. Pat. No. 5,272,162; 82 mg, 0.46 mmol) and Et3N (80.7 μl, 0.58 mmol). The mixture was stirred at room temperature under argon for 16 hours and then partitioned between EtOAc and 10% citric acid. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers then washed with saturated aqueous NaHCO3 followed by brine. Removal of the dried (MgSO4) solvent afforded a yellow oil which was purified by column chromatography (silica gel; hexane/EtOAc 1:1) to give 1-33 as an oil. Rf (silica; EtOAc/hexane 2:1) 0.57 ##STR51## N-{[7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl]acetyl}-3(S)-(ethynyl)-β-alanine ethyl ester (1-34)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:30])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (5.70 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (2.85 g) and methyl iodide (930 μL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (5.67 g, yield 96%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 434 (MH+).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[NH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1.N1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC=CC=1>C([O-])([O-])OC>[C:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[NH:11][C:12](=[O:17])/[CH:13]=[C:14](\[O:16][CH3:21])/[CH3:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCC(=O)Oc1cccc(NC(=O)CC(C)=O)c1
Agent: COC([O-])[O-]
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: CCCCC(=O)Oc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 140 °C
Yield: 2955.3 %

Procedure:
A solution of 47 g of m-valeryloxy-acetylacetanilide in 50 ml of methyl orthoformate and 0.5 g of p-toluene sulfonic acid stood at room temperature for 16 hours and then 1 g of quinoline and 200 ml of toluene were added thereto. The mixture was heated at 140°C. for 4 hours while removing the methanol formed and the solvent was then evaporated. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-acetone mixture to obtain 25 g of m-valeryloxy-3-methoxy-crotonanilide (isomer E) melting at 84°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH2:17])[CH2:5][N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[NH:14][N:15]=[CH:16][C:8]=2[CH2:7]1.[C:19](C1NC=CN=1)(C1NC=CN=1)=[O:20].[NH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][C:38]2=[O:47])[CH2:33][CH2:32]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:17][C:19]([N:31]1[CH2:32][CH2:33][CH:34]([N:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][C:38]2=[O:47])[CH2:35][CH2:36]1)=[O:20])[CH2:5][N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[NH:14][N:15]=[CH:16][C:8]=2[CH2:7]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: COC(=O)C(N)CN1Cc2cn[nH]c2C(C)(C)C1
Solvent: C1CCOC1
Product: COC(=O)C(CN1Cc2cn[nH]c2C(C)(C)C1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-3-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester (250 mg, 1 equiv) in tetrahydrofuran (4 mL, 0° C.) was added carbonyl diimidazole (162 mg, 1 equiv). After 5 min, the ice bath was removed and the reaction stirred at room temperature for 30 min. To this was added 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (250 mg, 1.1 equiv) in one portion, and the reaction stirred overnight. The reaction was concentrated and purified by column chromatography to give 228 mg (45%). 1H-NMR (CDCl3, 500 MHz) δ 1.30 (s, 3H), 1.31 (s, 3H), 1.60–1.80 (m, 4H), 2.43 (d, J=11.6, 1H), 2.53 (d, J=11.3, 1H), 2.80–2.95 (m, 4H), 3.51 (dd, J=20.4, 13.1, 2H), 3.74 (s, 3H), 4.00 (d, J=13.7, 1H), 4.10 (d, J=12.2, 1H), 4.25 (dd, J=16.2, 14.4, 2H), 4.86 (m, 2H), 6.66 (d, J=7.6, 1H), 6.92 (dd, J=7.6, 7.3, 1H), 7.02 (d, J=7.3, 1H), 7.14 (dd, J=7.6, 7.6, 1H), 7.24 (s, 1H). Mass spec.: 510.27 (MH)+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:14]=[C:15]([C@@H:21]2[CH:30]=[CH:29][CH2:28][C@@H:27]3[N:22]2[C:23](=[O:31])[CH2:24][CH2:25][CH2:26]3)[CH:16]=[C:17]([F:20])[C:18]=1[F:19].O.C(OCC)(=[O:35])C>C(Cl)Cl>[F:20][C:17]1[CH:16]=[C:15]([C@H:21]2[N:22]3[C@H:27]([CH2:26][CH2:25][CH2:24][C:23]3=[O:31])[CH2:28][C@@H:29]3[O:9][C@H:30]23)[CH:14]=[C:13]([F:12])[C:18]=1[F:19].[F:20][C:17]1[CH:16]=[C:15]([C@H:21]2[N:22]3[C@H:27]([CH2:26][CH2:25][CH2:24][C:23]3=[O:31])[CH2:28][C@H:29]3[O:35][C@@H:30]23)[CH:14]=[C:13]([F:12])[C:18]=1[F:19]
Reactant: O=C1CCC[C@@H]2CC=C[C@@H](c3cc(F)c(F)c(F)c3)N12
Reactant: CCOC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=C1CCC[C@@H]2C[C@@H]3O[C@@H]3[C@@H](c3cc(F)c(F)c(F)c3)N12
Product: O=C1CCC[C@@H]2C[C@H]3O[C@H]3[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
mCPBA (1.04 g) was added to a solution of (6S*,9aR*)-6-(3,4,5-trifluorophenyl)-1,2,3,6,9,9a-hexahydroquinolizin-4-one (681 mg) in methylene chloride (30 mL), and the reaction solution was stirred at room temperature for three days. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain (1aR*,2R*,6aR*,7aS*)-2-(3,4,5-trifluorophenyl)octahydro-1-oxa-2a-aza-cyclopropa[b]naphthalen-3-one (283 mg) and (1aS*,2R*,6aR*,7aR*)-2-(3,4,5-trifluorophenyl)octahydro-1-oxa-2a-aza-cyclopropa[b]naphthalen-3-one (235 mg). The physical properties of (1aR*,2R*,6aR*,7aS*)-2-(3,4,5-trifluorophenyl)octahydro-1-oxa-2a-aza-cyclopropa[b]naphthalen-3-one are as follows.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:6]2[C:2]([CH3:1])=[CH:3][C:4]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:16][CH:17]=4)[N:8]=3)=[N:5]2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a mechanically stirred solution of 5-(5-methyl-1H-pyrazol-3-yl)-3-[4-(trifluoromethoxy)-phenyl]-1,2,4-oxadiazole (Intermediate C, 60 mg, 0.193 mmol) and 1-(bromomethyl)-4-chlorobenzene (53 mg, 0.215 mmol) in dry THF (2 mL) was added potassium tert-butoxide (24 mg, 0.213 mmol) at a temperature of 0° C. The cooling bath was removed, and the reaction mixture was stirred at rt over night. After the addition of DMF (1 mL), the complete reaction mixture was subjected to preparative HPLC affording the title compound in pure form (68 mg, 81%): 1H NMR (400 MHz, CDCl3) 8.25 (d, 2H), 7.33 (d, 2H), 7.31 (d, 2H), 7.11 (d, 2H), 6.82 (s, 1H), 5.42 (s, 2H), 2.27 (s, 3H); ES-MS m/z 435, HPLC RT (Method K) 1.63 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([Br:16])=[C:13]([C:17]([NH2:19])=O)[CH:12]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C[N:22]([CH:24](OC)OC)C.[NH2:29]N>C1(C)C=CC=CC=1>[Br:16][C:14]1[O:15][C:11]([C:9]2[C:8]([CH3:20])=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=2)=[CH:12][C:13]=1[C:17]1[N:22]=[CH:24][NH:29][N:19]=1
Reactant: CC(=O)Nc1cc(-c2cc(C(N)=O)c(Br)o2)c(C)cn1
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(-c2cc(-c3nc[nH]n3)c(Br)o2)c(C)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a suspension of 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furamide (8.5 g, 25.2 mmol) in dry toluene (260 mL) was added DMF-DMA (8.85 g, 74.0 mmol). The reaction mixture was allowed to stir at 50° C. overnight and then concentrated. The residue was resuspended in AcOH (90 mL) and hydrazine (3.77 g, 117.6 mmol) was added dropwise at rt. The reaction mixture was allowed to stir for 2 h and then concentrated. The mixture was azeotroped several times with toluene and then the residue was suspended in EtOAc and water. The mixture was basified with saturated aqueous NaHCO3 to pH=8.5. The mixture was filtered and the solid was dried to give N-{4-[5-bromo-4-(1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (6.0 g, 66%).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][C:8]#[N:9].[C:10]1([C@H:20]([NH:22][C@H:23]2[CH2:27][CH2:26][C@@H:25]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[CH2:24]2)[CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:10]1([C@H:20]([NH:22][C@H:23]2[CH2:27][CH2:26][C@@H:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:7][C:8]#[N:9])=[CH:32][CH:33]=3)[CH2:24]2)[CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#CCCl
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc(O)cc2)C1)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCC#N)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 120 h
Yield: 68.7 %

Procedure:
Under a nitrogen stream, N,N-dimethylformamide (3 mL) and chloroacetonitrile (0.11 mL, 1.8 mmol) were added to 4-[(1R,3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}cyclopentyl]phenol (500 mg, 1.5 mmol) obtained in Example 10 (Step 3) and potassium carbonate (250 mg, 1.8 mmol), and the mixture was stirred for 5 days at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (NH silica; ethyl acetate/hexane:20/80-50/50) to give the title compound (382 mg, 68%).