Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([Cl:21])[C:12]=1[C:13](Cl)=[O:14].C(N(CC)CC)C>O1CCOCC1>[Cl:10][C:11]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([Cl:21])[C:12]=1[C:13]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: Nc1ccnc(Cl)c1F
Reactant: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cc(I)cc1Cl
Temperature: 100 °C
Yield: 53.8 %

Procedure:
A mixture of 2-chloro-3-fluoropyridin-4-ylamine (1.73 g, 11.8 mmol), 2,6-dichloro-4-iodobenzoyl chloride (5.90 g, 17.65 mmol) and triethylamine (3.1 mL, 22.4 mmol) in dioxane (35 mL) was heated to 100° C. for 18 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resultant residue was triturated with diethyl ether and dried under reduced pressure to give the desired compound as a pink solid (2.83 g, 54% yield). 1H NMR (300 MHz, CDCl3): δ 8.49-8.43 (m, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.82-7.73 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[N:5]([CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)[C:6](=[O:10])[C:7]=1[N:8]=O.[C:20](OC(=O)C)(=O)[CH3:21]>>[CH3:18][CH:17]([CH3:19])[CH2:16][N:3]1[C:2]2[NH:1][C:20]([CH3:21])=[N:8][C:7]=2[C:6](=[O:10])[N:5]2[CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=[C:4]12
Reactant: CC(C)CN1C2=NC(C)(C)CN2C(=O)C(N=O)=C1N
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2c([nH]1)N(CC(C)C)C1=NC(C)(C)CN1C2=O

Procedure:
The nitroso compound produced in Procedure 130 was catalytically hydrogenated and cyclized by the treatment with acetic anhydride according to the method of Procedure 63.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:10][C:11]1[O:12][C:13]2[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[C:16]([O:25][C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[C:14]=2[CH:15]=1.O>CN(C=O)C>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C:16]2[C:14]3[CH:15]=[C:11]([CH2:10][N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])[O:12][C:13]=3[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=2)=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: O=C1CCCN1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CBr)oc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CN3CCCC3=O)oc2c1
Yield: 24.8 %

Procedure:
To a solution of 2-ketopyrrolidine (75.1 mg, 0.882 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 44 mg, 1.1 mmol) at room temperature. After stirring the reaction for 30 min, ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (285a) (200 mg, 0.441 mmol) was added. The mixture was stirred at room temperature for another 2 h. Water was added to the reaction, and the product was extracted with CHCl3. The combined organic layer was dried and concentrated. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (100/0 to 95/5) to give the title compound (50 mg, 25%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 1.98-2.14 (m, 2 H) 2.42 (t, J=8.10 Hz, 2 H) 3.06 (s, 3 H) 3.44 (t, J=7.06 Hz, 2 H) 4.38 (q, J=7.16 Hz, 2 H) 4.58 (s, 2 H) 6.49 (d, J=0.75 Hz, 1 H) 7.04-7.12 (m, 2 H) 7.61 (d, J=1.13 Hz, 1 H) 7.83-7.94 (m, 2H) 8.05 (t, J=1.13 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][C:15]=2[O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][C:15]=2[O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1NC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccc(F)cc2C(=O)O)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of methyl 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzoate (7.8 g, 17 mmol) in EtOH (100 mL) and water (100 mL) was treated with KOH (4.8 g, 85 mmol) and stirred at 70° C. for 1 hour. The reaction was concentrated under vacuum, quenched with glacial acetic acid (5.1 g), and allowed to stand at ambient temperature for crystallization. The solid was filtered to recover 7.4 g (98%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:5][N:4]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:3]1=[O:27].Br[CH:29]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(OCC)(=O)C>C(Cl)Cl>[CH2:33]([O:32][C:30]([CH:29]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:5][N:4]([CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C:3]1=[O:27])[CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:31])[CH3:34]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccc3ccccc3c2)SCC(N)C1=O
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccc3ccccc3c2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.85 g of t-butyl α-[6-amino-2-(2-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] was subjected to N-alkylation with 1.08 g of ethyl 2-bromo-4-phenylbutyrate in the same manner as described in Example 36(h). The reaction product was subjected to silica gel column chromatography, using a 1:30 by volume mixture of ethyl acetate and methylene chloride, to separate it into two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH:2]=[CH:3][CH2:4][CH3:5].[CH3:8][C:9]1[C@H:14]2[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13]2)[CH2:11][CH:10]=1>C(Cl)CCl.[Cl-].[Zn+2].[Cl-]>[CH2:4]([CH:3]1[C:12]2([C:15]([CH3:17])=[CH2:16])[CH2:13][CH:14]([C:9]([CH3:8])=[CH:10][CH2:11]2)[C:1](=[O:6])[CH2:2]1)[CH3:5]
Reactant: CC1=CC[C@H]2C[C@@H]1C2(C)C
Reactant: CCC=CC(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: C=C(C)C12CC=C(C)C(C1)C(=O)CC2CC
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
At 30° C., a mixture of 7.35 g of 2-pentenoyl chloride (62 mmol) and 1.7 g of zinc chloride (12 mmol, 0.2 eq.) in 85 ml ethylene chloride was treated dropwise within 20 min. with a solution of 19.4 g of (−)-alpha-pinene (142 mmol, 2 eq.) in 20 ml ethylene dichloride. The reaction mixture was then stirred at 30° C. for 30 min., then at 50° C. for 2 h, and finally at 80° C. for 1 h. After cooling, the reaction mixture was washed with aq. sat. NaCl soln. and aq. sat. NaHCO3 soln. The aq. phases were extracted with Et2O, dried (Na2SO4), and concentrated. FC (SiO2, hexane/Et2O 20:1) of the crude (26 g) gave 1.74 g (13%) of compound 2. The boiling point of the end product is 95° C. at 0.06 torr (0.08 mbar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[CH:18](O)[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=[CH:6]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=[CH:6]2
Reactant: CCCCC(O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Yield: 60.1 %

Procedure:
The solution of 1-[2-(6-methoxy-naphthalen-2-yl)-benzofuran-3-yl]-pentan-1-ol (15.5 g, 43 mmol) and triethyl silane (10 g, 86 mmol) in methylene chloride (300 mL) was cooled in an ice bath. Trifluoro acetic acid (50 mL) was added gradually. The mixture was stirred at while cooling for 2 hours then was allowed to warm to room temperature. The solvent was evaporated. The residue was dissolved in ether and washed with sodium bicarbonate solution, then with water. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using 4% ethyl acetate in hexane as the mobile phase. The product was obtained as a clear oil (8.9 g). 1HNMR (300 MHz, DMSO-d6): δ8.22 (s, 1H), 7.98-7.92 (m, 2H), 7.95-7.90 (m, 2H), 7.64 (d, 1H, J=8.8 Hz), 7.65 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=8.8 Hz), 7.38-7.20 (m, 4H), 3.90 (s, 3H), 2.96 (t, 1H, J =9.9 Hz), 1.70 (p, 1H, J=7.0 Hz), 1.42-1.26 (m, 4H), and 0.82 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([CH:12]=[O:13])[C:3]=1[Cl:14].CC(=CC)C.P([O-])([O-])(O)=[O:21].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([C:12]([OH:21])=[O:13])[C:3]=1[Cl:14]
Reactant: CCCc1nc(C=O)c(Cl)c(N)c1F
Reactant: O=P([O-])([O-])O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCc1nc(C(=O)O)c(Cl)c(N)c1F
Temperature: 85 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-6-propyl-5-fluoropicolinaldehyde (15.9 mg, 0.072 mmol) and t-butanol (1.0 mL). The mixture was treated with H2O (0.40 mL), 2-methylbut-2-ene (100 μL, 0.10 mmol), sodium hydrogenphosphate (21.6 mg, 0.100 mmol), and finally sodium chlorite (19.28 mg, 0.206 mmol) was added in one portion. The mixture was heated to 85° C. for 16 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was evaporated to dryness under N2. Purification via reverse phase chromatography yielded 4-amino-3-chloro-6-propyl-5-fluoropicolinic acid (4.7 mg, 27.9%): 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 4.98 (m, 2H), 2.76 (m, 2H), 1.75 (m, 2H), 0.99 (m, 3H); 19F NMR (376 MHz, CDCl3) δ−139.98; ESIMS m/z 231.2 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1>O.C(O)(C)(C)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][NH:25][C:2]2[N:1]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([OH:3])=[CH:5][N:6]=2)=[CH:20][CH:21]=1
Reactant: Nc1ncc(C(=O)c2ccccc2)o1
Reactant: NCCCc1ccc(Cl)cc1
Solvent: CC(C)(C)O
Solvent: O
Product: Oc1cnc(NCCCc2ccc(Cl)cc2)nc1-c1ccccc1
Yield: 0 %

Procedure:
2-Amino-5-benzoyloxazole (3.0 g, 16 mmol) was combined with p-chlorophenylpropylamine (2.7 g, 16 mmol) in 15 ml of water and t-butanol (2:1) and heated under reflux in nitrogen for 16 hours. The solvents were removed in a vacuum, and the residue was treated with hot acetonitrile and filtered. After concentration in vacuum, the filtrate was chromatographed on silica gel using hexane and ethyl acetate (1:1) as eluent to give 0.24 mg (4.4%) of the title compound as an oil. NMR (CDCl3): 1.8-2.0 (m, 2H), 2.4-2.7 (m, 2H), 3.1-3.4 (m, 2H), 5.0 (b s, 1H), 7.0-7.5 (m, 7H), 7.8 (s, 1H), 7.9-8.0 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][CH2:13][CH2:12]1)[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:5]2[OH:27].C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:12][CH2:13][CH2:14]1)[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:5]2[OH:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Yield: 67.3 %

Procedure:
1,1-Dimethylethyl N-((6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclobutane-1,1′-naphthalen]-3′-yl)carbonyl)glycinate (151 mg, 385 μmol) was stirred in TFA (1 mL, 13462 μmol) for 20 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (87 mg). MS (m/e)=336.1 (M+H)+. Calculated for C16H15ClO4 335.06.
Reaction SMILES: ClC1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19]C1C=NC=CC=1.C1C=C(C=O)N=CC=1>>[N:19]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: c1ccc(-c2nnn(-c3cccnc3)n2)nc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, but using 3-amino pyridine (565 mg, 6.0 mmol) and 2-pyridyl carboxaldehyde (642 mg, 6.0 mmol), 2-(2-pyridin-3-yl-2H-tetrazol-5-yl)pyridine was obtained as an off white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:16][C:17]3[CH:28]=[CH:27][C:20]4[N:21]=[C:22](S(C)=O)[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[OH:39].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:16][C:17]3[CH:28]=[CH:27][C:20]4[N:21]=[C:22]([NH:32][C@@H:33]5[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]5[OH:39])[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Temperature: 138 °C
Yield: 59.5 %

Procedure:
A stirred mixture of 6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.48 g, 3.4 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol hydrochloride (1.29 g, 8.5 mmol), and DIEA (2.19 g, 17 mmol) in DMA (44 mL) was heated at 138° C. for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 6% MeOH in DCM to afford (1R,2R)-2-((6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (0.98 g, 59%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 7.43-7.46 (m, 3H), 7.29-7.39 (m, 4H), 7.25 (s, 1H), 7.13-7.16 (m, 2H), 6.96 (m, 1H), 5.75 (br s, 1H), 5.31 (s, 2H), 5.09 (s, 2H), 3.46-3.56 (m, 2H), 2.07-2.18 (m, 2H), 1.71-1.77 (m, 2H), 1.26-1.40 (m, 4H); LCMS (ESI) m/z 485 (M+H)+.
Reaction SMILES: I[CH2:2][CH:3]1[O:7][CH:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.CCOC(C)=O>[N:17]([CH2:2][CH:3]1[O:7][CH:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4]1)=[N+:18]=[N-:19]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(CI)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 36 h
Yield: 100.2 %

Procedure:
To a solution of 5-(5-(iodomethyl)tetrahydrofuran-2-yl)-1-methyl-4-nitro-1H-pyrazole (640 mg, 1.90 mmol, intermediate 60) in dry DMF (10 mL) was added sodium azide (250 mg, 3.80 mmol) and the mixture stirred at room temperature for 36 hr. The mixture was diluted with EtOAc (25 mL) and washed with water (2×10 mL) and brine (20 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure to give 5-(5-(azidomethyl)tetrahydrofuran-2-yl)-1-methyl-4-nitro-1H-pyrazole as a yellow oil (480 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 5.84-5.70 (m, 1H), 4.49-4.45 (m, 1H), 4.03 (s, 3H), 3.56-3.39 (m, 2H), 2.66-2.65 (m, 1H), 2.29-2.22 (m, 1H), 2.02-1.92 (m, 2H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](O)=[O:12]>CN(C=O)C.C(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([Cl:4])=[O:12]
Reactant: O=C(O)C(CCCl)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.56 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-phenylbutyric acid (2.28 g) in methylene chloride (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid chloride. A solution of 4-chloro-2-phenylbutyric acid chloride in THF (10 mL) was added to a solution of tert-butyl carbazate (1.5 g) and triethylamine (7.8 mL) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). A solution of 4 N hydrogen chloride in ethyl acetate (50 mL) was added to tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g). A solution of 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g) and triethylamine (5.7 mL) in ethanol (40 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (3.00 g) and triethylamine (6.0 mL) in ethanol (50 mL) at room temperature, and the reaction solution was stirred at 80° C. for 24 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 231 mg of the racemic title compound. The property values of the compound are as follows.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[CH2:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>C1COCC1>[CH3:2][C:3]([CH3:4])=[CH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8]2
Reactant: O=Cc1ccc2c(c1)CCC2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=Cc1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
In a flamed dried flask under argon isopropyltriphenylphosphonium iodide (6.48 g, 15 mmol) in 30 mL of dry THF was cooled to 0° C. Then n-BuLi (2.5 M) in hexanes (6.0 mL) was added via syringe. The reaction mixture was stirred 0° C. for 45 min. Then a solution of the 2,3-dihydro-1H-indene-5-carboxaldehyde (J. Med. Chem. 1993, 36, 3700–3706) was added (1.7, 12.0 mmol) in THF (20 mL) was added drop-wise and the reaction was stirred under Argon at RT overnight. The reaction was filtered, the filtrate was concentrated in vacuo and the residue purified by flash colum chromatography (ethyl acetate/hexane, 1:99) to yield the above titled compound as a pale yellow oil (1.7 g, 67%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CN(C=O)C.[CH3:19][N:20]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:42]>C(OCC)(=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:20]([CH3:19])[C:21](=[O:42])[CH:22]=[CH:23]2)[CH2:35][C:36]1[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=1)[CH3:13]
Reactant: Cn1c(=O)ccc2cc(OCCCNCc3ccncc3)ccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (1.66 g) and ethyl bromoacetate (1.16 ml) were added to a DMF solution (50 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (1.5 g), and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→85:15). The purified product was condensed under reduced pressure to give the title compound (1.28 g) as a orange oil.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Br:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([N:15]([CH2:18][C:19](=O)[CH3:20])[CH:16]=O)=[CH:9][CH:8]=1.C(OCC)(=O)C.N>C(O)(=O)C>[Br:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([N:15]2[CH:18]=[C:19]([CH3:20])[N:5]=[CH:16]2)=[CH:9][CH:8]=1
Reactant: COc1nc(Br)ccc1N(C=O)CC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1nc(Br)ccc1-n1cnc(C)c1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A suspension of ammonium acetate (267 g) and N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (199 g) in glacial acetic acid (400 mL) was stirred at 130° C. for one hour and 10 minutes. The reaction solution was brought back to room temperature. Ethyl acetate and ice water were added to the reaction solution, and the mixture was ice-cooled. Then, concentrated aqueous ammonia (500 mL) was added dropwise and then the organic layer was separated. The resulting organic layer was sequentially washed with water and brine and dried over anhydrous magnesium sulfate. Then, the organic layer was purified by short silica gel column chromatography (carrier: Wakogel™ C-200 manufactured by Wako Pure Chemical Industries, Ltd.; elution solvent: ethyl acetate). The eluted fraction was concentrated. The resulting residue was triturated with ethyl acetate and tert-butyl methyl ether and dried under reduced pressure to obtain 107.7 g of the title compound.
Reaction SMILES: C(C1[C:12]2[C:7](=[CH:8][C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:10]([Cl:13])[CH:11]=2)[C:6](=[O:20])[CH2:5][CH2:4]1)#N.[C:21]([OH:24])(=[O:23])[CH3:22].S(=O)(=O)(O)O>O>[O:20]=[C:6]1[C:7]2[C:12](=[CH:11][C:10]([Cl:13])=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:8]=2)[CH:22]([C:21]([OH:24])=[O:23])[CH2:4][CH2:5]1
Reactant: N#CC1CCC(=O)c2cc(C3CCCCC3)c(Cl)cc21
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCC(C(=O)O)c2cc(Cl)c(C3CCCCC3)cc21

Procedure:
A mixture of 19 g of 4-cyano-6-chloro-7-cyclohexyl-3,4-dihydro-naphthalene-1(2H)-one, 36 ml of glacial acetic acid, 43 ml of concentrated sulfuric acid, and 29 ml of water is refluxed overnight. It is then poured into water, and the aqueous mixture is extracted with ethyl acetate. After drying and evaporation of the solvent, the residue is crystallized from toluene. There are obtained 14.3 g of 4-oxo-6-cyclohexyl-7-chloro-1,2,3,4-tetrahydro-naphthalene-1 -carboxylic acid melting at 204°-205°C, which product is identical with the compound of Example 3.