Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:5][CH:4]([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:3][CH:4]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:13])=[CH:15][CH:16]=2)=[O:7])[CH2:5]1
Reactant: CC1(C)CC(C(=O)c2ccc(C(=O)O)cc2)C1
Solvent: ClCCl
Product: CC1(C)CC(C(=O)c2ccc(C(=O)OC(C)(C)C)cc2)C1
Yield: 113.3 %

Procedure:
To a flask containing 4-(3,3-dimethylcyclobutanecarbonyl)benzoic acid (1.89 g, 8.14 mmol) in anhydrous methylene chloride (20.3 mL) was added 2-tert-butyl-1,3-diisopropylurea (6.28 g, 31.3 mmol). The reaction was refluxed for 24 h. The reaction was then diluted with methylene chloride and quenched with a solution of saturated sodium bicarbonate. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were washed with brine and dried with sodium sulfate, filtered, and concentrated to afford 3.09 g of a crude oil. Purification by silica gel flash chromatography (0-10% ethyl acetate in heptane) provided tert-butyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (1.33 g, 57% yield) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.08-8.02 (m, 2H), 7.94-7.88 (m, 2H), 3.89 (quin, J=8.8 Hz, 1H), 2.24-2.16 (m, 2H), 2.11-2.02 (m, 2H), 1.62-1.59 (m, 9H), 1.27 (s, 3H), 1.08 (s, 3H). MS (M+1): 289.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH3:5].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)([CH3:5])[CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15]
Reactant: COC(=O)C(C)c1ccc(Cl)c(Cl)c1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(CC(OC)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 35 g (150 mmol) 2-(3,4-dichloro-phenyl)-propionic acid methyl ester (Journal of Medicinal Chemistry (2004), 47(23), 5753-5765), 31.7 g (188 mmol) bromoacetaldehyde dimethyl acetal (commercially available and 6.6 g (165 mmol) NaH (55%) in 100 mL DMF was stirred at room temperature and afterwards evaporated to dryness. Ice water and ethyl acetate was added and the organic fraction was washed with sat. NaCl aq., dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica eluting with a mixture of ethyl acetate and hexane. The product containing fractions were evaporated to yield 29.6 g (61%) of the title compound as yellow liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([O:31]COC)=[CH:27][CH:26]=2)=[C:15](\[CH:22]2[CH2:24][CH2:23]2)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.O>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[C:15](\[CH:22]2[CH2:24][CH2:23]2)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:11]=1
Reactant: COCOc1ccc(/C(C(=O)Nc2ccc(OCCN(C)C)cc2)=C(\c2ccccc2)C2CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCOc1ccc(NC(=O)/C(=C(/c2ccccc2)C2CC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of 8 (70 mg, 0.144 mmol) in MeOH (3 ml) was added 4N HCl in 1,4-dioxane (0.4 ml) under ice cooling, and the mixture was stirred at room temperature for 3 h. A solution of NaHCO3 in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residual solid was crystallized with Et2O to give 9 (88%). 9: colorless powder; 1H-NMR (CD3OD) δ 0.42 (2H, m), 0.73 (2H, m), 1.99 (1H, m), 2.35 (6H, s), 2.77 (2H, t, J=5.4 Hz), 4.10 (2H, t, J=5.4 Hz), 6.47 (2H, d, J=8.8 Hz), 6.91 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=9.1 Hz), 7.06 (2H, m), 7.13-7.23 (3H, m), 7.56 (2H, d, J=9.3 Hz). HRMS calcd for C28H31N2O3 [M+H]+: 443.2335. Found: 443.2353.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:31]3[CH2:32][CH2:33][CH:28]([N:27]([CH3:34])[CH3:26])[CH2:29][CH2:30]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: CN(C)C1CCNCC1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CCC(N(C)C)CC3)ccc2S(C)(=O)=O)c1OC
Yield: 19.4 %

Procedure:
N-(1-(5-Chloro-2,3-dimethoxyphenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (100.0 mg, 0.26 mmol), N,N-dimethylpiperidin-4-amine (66.0 mg, 0.51 mmol), N,N-diisopropylethylamine (133.0 mg, 1.03 mmol) were stirred at 100° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (25.0 mg, 19.6% yield). 1H NMR (400 MHz, CDCl3): δ 7.53 (d, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 6.50 (d, 1H), 6.21 (d, 1H), 5.90 (d, 1H), 4.85 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.74 (m, 2H), 3.24 (m, 1H), 3.05 (s, 3H), 2.76 (q, 2H), 2.26 (s, 6H), 1.78 (t, 2H), 1.55 (d, 3H), 1.45 (m, 2H); MS (ESI) m/z: 496.1 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[N:18]=[CH:17][C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[N:18]=[CH:17][C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:25][CH:24]=3)(=[O:21])=[O:22])=[CH:15][CH:14]=2)[CH2:9]1)[CH2:2][CH3:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc(C3CCN(Cc4ccccc4)C3)nc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCN1CCC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
0.088 g of N-[6-(1-benzyl-pyrrolidin-3-yl)-pyridin-3-yl]-4-isopropyl-benzene-sulfonamide (0.25 mmol) were dissolved in 10 ml of dichloromethane. 0.022 g of propionyl aldehyde (0.38 mmol), 0.023 g of acetic acid (0.38 mmol) and 0.081 g of sodium triacetoxyborohydride (0.38 mmol) were added and stirred for 1 h at room temperature. Water was added, the pH adjusted to 10 with 1 N sodium hydroxide, extracted three times with ethyl acetate, the organic layers combined and evaporated to dryness. The crude material was purified via silica gel chromatography with dichloromethane/methanol 20%. Fractions containing the product were combined and the solvent evaporated to yield 0.026 mg of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14](Br)=[C:13](Br)[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)[N:30](Br)[C:28](=O)C1.C([Cu])#N.CN1C(=O)CCC1.C([O-])=O.[NH4+]>CC#N.[Pd].CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[C:10]([C:28]#[N:30])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: N#C[Cu]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(F)c2)c1O

Procedure:
Prepared in analogy to that of Example 133(a) from 2,3-dibromo-1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NBS in MeCN to give tribromo intermediate; which was subjected to a cyanation condition CuCN/NMP similar to that of Example 105(a) to give the C-7 CN intermediate; which was further subjected to a reductive debromination condition (ammonium formate, Pd/C in refluxing EtOAc) similar to that of Example 6(a) to give the desired title compound. The title compound, ESI MS (m/z): 340 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.Cl.[O:19]([NH2:21])[CH3:20]>O>[CH3:20][O:19][N:21]=[CH:10][C:5]1[C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
To an amount of 1H-Indole-4-carbaldehyde (50 mg, 0.34 mmol) is added pyridine (10 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (31.6 mg, 0.38 mmol). The mixture is stirred at ambient temperature for 24 h, and 2 mL of water is added. After the solvents were evaporated, the residue is dissolved 2 mL of anhydrous ether, washed successively with 2 mL of aqueous sodium bicarbonate, 2 mL of sodium bisulfite, and 2 mL of brine. Dried over magnesium sulfate, evaporated to give a white solid (35 mg). MS (ESI) m/z 175.2 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:30]1[CH:29]=[N:28][CH:27]=[C:26]([F:25])[CH:31]=1
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2ccccc21
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(-c3cncc(F)c3)c2)c2ccccc21
Yield: 31 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #11, G) as described in Example 67 (Scheme #10, D) in 31% yield using 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. 1H NMR (DMSO-d6) δ 8.63 (d, J=2.78 Hz, 1 H), 8.57-8.51 (m, 1 H), 8.50-8.42 (m, 2 H), 7.95-7.86 (m, 2 H), 7.85-7.78 (m, 1 H), 7.56-7.46 (m, 4 H), 7.36-7.27 (m, 3 H), 6.96 (br s, 2 H), 1.91 (s, 2.5 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C:15]([NH:19]C(OC(C)(C)C)=O)([CH3:18])[CH2:14]2)[C:9]([CH3:27])=[C:8]2[C:3]=1[C:4](=[O:34])[C:5]([C:31]([OH:33])=[O:32])=[CH:6][N:7]2[CH:28]1[CH2:30][CH2:29]1.Cl.[OH-].[K+]>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C:15]([NH2:19])([CH3:18])[CH2:14]2)[C:9]([CH3:27])=[C:8]2[C:3]=1[C:4](=[O:34])[C:5]([C:31]([OH:33])=[O:32])=[CH:6][N:7]2[CH:28]1[CH2:29][CH2:30]1
Reactant: Cc1c(N2CCC(C)(NC(=O)OC(C)(C)C)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N2CCC(C)(N)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To 0.76 g of 5-Amino-7-(3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, 1.1 ml of hydrochloric acid was added and then stirred at room temperature for 2 hours. To the reaction mixture, a solution of 0.89 g of potassium hydroxide in 1.8 ml of water was added under ice cooling and resulting mixture was neutralized with 10% hydrochloric acid to pH 8. The deposited crystals were collected by filtration and washed with water to give 0.33 g of the desired compound as yellow crystals. The crystals were subsequently recrystallized from a mixture of methylene chloride and methanol to afford 0.30 g of yellow crystals, m.p. 217°-221° C. were obtained.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([NH:18][C@H:19]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36][F:37])[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([NH:18][C@H:19]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36][F:37])[CH2:27][C:28]([OH:30])=[O:29])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)O)C(=O)CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A solution of N-[(1-phenylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester (154 mg) in anisole (0.2 mL) and methylene chloride (2 mL) was treat d with TFA (1 mL), and the resultant reaction mixture was stirred for one hour under nitrogen atmosphere at room temperature. The reaction mixture was concentrated and chased with methylene chloride, then triturated with ether to yield the title product as white powder (100 mg). TLC (methylene chloride/methanol/acetic acid, 20:1:1): Rf=0.38, MS for C25H26FN3O5: MH+=468; (M−H)+=466.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH2:26]([O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1)[CH3:27]>CN(C=O)C>[CH2:26]([O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:32][CH:31]=1)[CH3:27]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (800 mg) in DMF (10 mL) was added to a suspension of NaH (60% in mineral oil, 204 mg) in DMF (8 mL) over a period of 20 minutes. Stirring was continued for 30 minutes at r.t. The mixture was cooled to 0° C. and ethyl-4-(bromomethyl)-benzoate (591 mg, [CAS Reg. No. 26496-94-6]) dissolved in DMF (7 mL) was added dropwise over a period of 15 minutes. Stirring was continued for 1 hour at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (625 mg, 53%). MS (m/e)=508.0 [MH+].
Reaction SMILES: O.[OH-].[Li+].C[C:5]1([C:22]([O-:24])=[O:23])[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:7][CH2:6]1>O.CO>[C:18]([O:17][C:15]([N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([C:22]([OH:24])=[O:23])=[CH:6][CH:7]=2)[CH2:12]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC2=CCC(C)(C(=O)[O-])C=C2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Reaction time: 4 h

Procedure:
Lithium hydroxide monohydrate (5.8 g, 0.136 mol) dissolved in water (73 ml) was added to a solution of 2-tert-butyl 7-methyl-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (7.9 g, 0.027 mol) in methanol (110 ml), and the mixture was stirred for 4 h. The solvent was removed in vacuo. Water and diethyl ether were added to the residue, and the phases were separated. The aqueous phase was adjusted to an acidic pH with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was used directly in the following stage. Yield: 5.8 g (76%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C@H:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH3:12])C.[H-].Cl>CCOCC>[F:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C@H:11]([CH3:12])[CH2:10][OH:9])=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@@H](C)Oc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C[C@H](CO)Oc1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 17 h
Yield: 107.4 %

Procedure:
Under argon (Ar), lithium aluminum hydride (LiAlH4) (35.21 g, 0.98 mol) in 2.2 L of dry ether was placed in a 5-liter three-necked flask equipped with reflux condenser, dropping funnel, and mechanical stirrer under dry Ar. The mixture was cooled to 0-5° C., and a solution of 3 (185 g, 0.87 mol) in 1 L of ether was added dropwise. After the addition, the stirred mixture was allowed to slowly come to room temperature and stirred for 16-18 hr until no starting material could be detected by HPLC. The mixture was again cooled in an ice bath and excess hydride was carefully decomposed by addition of 6N HCl (750 mL). Stirring was continued overnight until the solution became a clear, light yellow color. The reaction mixture was extracted with 2×500 mL ethyl ether, and the combined ether layers were then washed with 2×700 mL of water and 500 mL of brine. The ether was evaporated, and the residue was dissolved in 700 mL of CH2Cl2 and dried over MgSO4. After filtration, the organic solvent was removed in vacuo to yield 159 g of a yellow oil in 95% yield. HPLC retention time 4.1 min, Bp 70° C. at 0.7 mm Hg. The reaction is shown as follows:
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH:26]=[CH2:27].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH:26]=[CH2:27])=[O:11]
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO200687543, 2.27 g, 11.8 mmol) and Ethyl (3S,4R)-4-amino-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 18, 2.7 g, 11.8 mmol) in dichloromethane (180 mL) was added HOBt (1.85 g, 11.8 mM) and N-methylmorpholine (3.8 mL, 35.43 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (4.07 g, 21.3 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight, treated by the addition of 2 N HCl (120 mL) and the resulting layers were evaporated. The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica gel, 35% ethylacetate in pet ether) to afforded 3.5 g (73.6%) as brown solid. NMR (400 MHz, DMSO-d6): δ 1.24 (t, 3H), 1.62 (m, 2H), 2.16 (s, 3H), 2.97 (m, 2H), 3.53 (m, 2H), 3.97 (m, 4H), 4.15 (q, 2H), 4.21 (m, 1H), 5.13 (d, 1H), 5.23 (d, 1H), 5.87 (m, 1H), 7.10 (d, 1H), 12.10 (s, 1H).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH2:10]C)[CH2:6][C@H:5]1[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)[CH:17]=[CH:16]2)([CH3:3])[CH3:2].C1([C@@H]2CC[C@H](OC3C=C4C(=CC=3)C=C(CN3CCC(C(OCC)=O)CC3)C=C4)CC2)C=CC=CC=1>>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]1)[CH:17]=[CH:16]2)([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@@H]4C[C@H](CC)CC[C@H]4C(C)C)ccc3c2)CC1
Agent: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)CC1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@@H]4C[C@H](C)CC[C@H]4C(C)C)ccc3c2)CC1
Yield: 38 %

Procedure:
The preparation of ethyl 1-((6-(((1R,2S,5R)-2-isopropyl-5-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate was the same as that of ethyl 1-((6-((cis-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate. 82 mg, slight yellow oil, yield: 38%. ESI-MS (M+1)+: 452.2. 1H NMR (400 MHz, CDCl3) δ: 7.66-7.63 (m, 3H), 7.40-7.39 (m, 1H), 7.08-7.05 (m, 2H), 4.12-4.03 (m, 3H), 3.54 (s, 2H), 2.84-2.80 (m, 1H), 2.25-2.15 (m, 2H), 1.81-1.69 (m, 1H), 1.70-1.66 (m, 2H), 1.25-1.15 (m, 11H), 1.10-0.91 (m, 4H), 0.87 (d, J=6.8 Hz, 6H), 0.71 (d, J=6.8 Hz, 3H).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:13])[C:3]=1[CH3:14].COCCO.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O.C(N(CC)CC)C>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([F:8])=[C:6]([CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:13])[C:3]=2[CH3:14])[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: Cc1c(F)c(F)c(C)c([N+](=O)[O-])c1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCO
Product: Cc1c(F)c([N+](=O)[O-])c(C)c(F)c1N1CCN(C)CC1

Procedure:
To 2,3,6-trifluoro-4-methyl-5-nitrotoluene (1.9 g) are added 2-methoxyethanol (9.9 ml), water (1.1 ml), N-methylpiperazine (4.1 ml) and triethylamine (5.2 ml) and the mixture is refluxed for 25 hours. After the reaction is completed, water is added and the resultant is extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane : methanol=40 : 1) to give 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-methyl-5 -nitrotoluene (1.73 g).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Br)=[C:17]([CH3:24])[CH:16]=1>>[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)=[C:17]([CH3:24])[CH:16]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Cc1cc(F)ccc1C[Mg]Br
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)cc1C

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate was reacted with (4-fluoro-2-methylbenzyl)magnesium bromide) according to General Procedure 3. The resulting product was then converted to the title compound by hydrogenation according to General Procedure 6.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:24][C:17]1[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[N:7][CH:6]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)cc1C
Yield: 79 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(2,4,5-trimethylphenyl)piperazin-1-yl]methanone (430 mg) described in Preparation Example 143 and oxazolidin-2-one (128 mg), the title compound (345 mg) was obtained.