Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].OC1C2C3C(=CC=CC=3)NC=2C=CC=1.BrC(C)(C)C(OCC)=O.[OH-].[Na+].[CH:32]1[C:44]2[NH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[C:35]([O:45][C:46]([CH3:53])([CH3:52])[C:47]([O:49]CC)=[O:48])=[CH:34][CH:33]=1.Cl>C(O)C.CN(C)C=O>[CH:32]1[C:44]2[NH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[C:35]([O:45][C:46]([CH3:53])([CH3:52])[C:47]([OH:49])=[O:48])=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc2[nH]c3ccccc3c12
Agent: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
4.35 g of potassium carbonate was added to N,N-dimethylformamide (15 mL) solution of 1 g of 4-hydroxycarbazole and 4.72 g of ethyl 2-bromo-2-methylpropionate, and stirred at 90° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, ice water was added thereto thereafter, and extracted twice with ethyl acetate. The combined extract was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by NH silica gel chromatography (ethyl acetate:n-hexane=1:2), and ethyl 2-(9H-carbazole-4-yloxy)-2-methylpropionate was prepared. 5 N sodium hydroxide solution was added to the prepared ethanol 30 mL solution of ethyl 2-(9H-carbazole-4-yloxy)-2-methylpropionate, and stirred at 70° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, 1 N hydrochloric acid was added thereafter to be acidified, and extracted twice with ethyl acetate. The combined extract was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The filtrate was crystallized from diisopropylether, and isolated by filtration, washed with n-hexane, dried under reduced pressure, and 1.18 g of the subject compound was prepared as yellow crystal.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)C1C=CC=C(N(CC)CC)C=1)C.C(OC(=O)C)(=O)C>CO>[C:1]1([C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][O:9]1)=[O:8]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: O=C(O)c1ccccc1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: O=C1OCc2ccccc21
Temperature: 52 °C
Yield: 247.1 %

Procedure:
A mixture of 2-(4-dimethylamino)benzoyl)benzoic acid (8.07 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (7.26 g.) and acetic anhydride (5 ml.) was heated (at 52° C.) during one and one-half hours. Addition of methanol (10 ml., then 15 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-dimethylamino)phenyl)phthalide (I: X = (CH3CH2)2N, Y2 = Z4 = Z5 = Z6 = Z7 = H, Y4 = (CH3)2N) (10.92 g., m.p. 117°-119° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([CH3:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.C(O)C>C1(=O)OC(C)CO1>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[CH3:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(C)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC1COC(=O)O1
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 24 h

Procedure:
To a suspension of potassium carbonate (0.71 g, 10 mmol, 1.3 equiv) and 2-amino-3-methyl-5-chloro-N-(diethyl-λ4-sulfanylidene)benzamide (1.42 g, 3.96 mmol) in propylene carbonate (20 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (1.35 g, 4.35 mmol, 1.10 equiv.) in propylene carbonate (10 mL) at room temperature. After 24 h at this temperature, the mixture was poured onto water and spiked with ethanol under vigorous stirring. The resulting solids were collected by filtration and contained pure title compound (1.57 g, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13]CC(C)(C)N=2)=[CH:8][CH:7]=1)=[O:5].Cl.[OH2:24]>>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:13])=[O:24])=[CH:10][CH:11]=1)=[O:5]
Reactant: O
Reactant: Cc1ccccc1C(=O)c1ccc(C2=NC(C)(C)CO2)cc1
Agent: Cl
Product: Cc1ccccc1C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
2-[4-(2-Methylbenzoyl)phenyl]-4,4-dimethyl-2-oxazoline (2.86 g) and 4.5M hydrochloric acid (150 ml) are refluxed for 8 hours. The mixture is cooled to room temperature, and thereto is added water. The precipitates are collected by filtration to give 4-(2-methylbenzoyl)benzoic acid (2.23 g) as white powder.
Reaction SMILES: C([SiH2]CCOC[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:33]=[CH:32][C:22]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:21][CH:20]=3)[CH:17]=2)[C:12]([C:34]2[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=2)=[N:11]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:39][N:37]1[CH:38]=[C:34]([C:12]2[C:13]3[C:18](=[CH:17][C:16]([C:19]4[CH:33]=[CH:32][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[NH:10][N:11]=2)[CH:35]=[N:36]1
Reactant: Cn1cc(-c2nn(COCC[SiH2]C(C)(C)C)c3cc(-c4ccc(CNC(=O)OC(C)(C)C)cc4)ccc23)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2n[nH]c3cc(-c4ccc(CN)cc4)ccc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 31A (0.17 g, 0.319 mmol) in CH2Cl2 (4 mL) under argon was treated with trifluoroacetic acid (1 ml, 12.98 mmol), stirred at room temperature for 1 hour, then partitioned between dilute Na2CO3 solution and ethyl acetate (2×). The combined organics were dried (MgSO4), then concentrated to afford the title compound which was used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:24][CH2:23][CH:22]3[CH:18]([CH2:19][NH:20][CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:24][CH2:23][CH:22]3[CH:18]([CH2:19][N:20]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4CNCC4C3)n2)cn1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4CN(C(=O)CC#N)CC4C3)n2)cn1
Temperature: 45 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydro-1H-isoindol-5-yl)pyrimidine-2,4-diamine (470 mg, 1.35 mmol), 2-cyanoacetic acid (246.7 mg, 2.90 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added EDCI (505.2 mg, 2.64 mmol) and HOAT (325.4 mg, 0.30 mmol). After addition, the reaction mixture was stirred at 45° C. for 3 h, quenched with H2O (30 mL) and extracted with DCM (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as beige solid (228.4 mg, 40.8%).
Reaction SMILES: O[C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>P(Cl)(Cl)(Cl)=O>[Cl:18][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1Cc1n[nH]c(O)n1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1Cc1n[nH]c(Cl)n1
Reaction time: 11 h

Procedure:
A mixture of 1 g of 5-hydroxy-3-(o-nitrobenzyl)-1,2,4-triazole, 10 ml of phosphorus oxychloride and 1.89 g of phosphorus pentachloride is stirred at 70° for 11 hours, then at room temperature over the weekend and evaporated to dryness. The residue is dissolved in water, the solution is basified with 10% aqueous potassium carbonate and extracted 3 times with ethyl acetate. The combined extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness. The residue is chromatographed with 50 g of silica gel using methylene chloride-ethyl acetate (1:1) as eluent to give 5-chloro-3-(o-nitrobenzyl)-1,2,4-triazole, m.p. 160°-163°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH:11]=[CH:10]2)=[O:4].[OH-].[Na+]>C(O)C>[S:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])[CH:10]=[CH:11][CH2:12]1
Reactant: COC(=O)c1cccc2c1SCC=C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc2c1SCC=C2
Reaction time: 5 h
Yield: 69.5 %

Procedure:
Methyl-2H-thiochromene-8-carboxylate (0.300 g, 1.46 mmol) was dissolved in ethanol (5 ml) and treated with 10% sodium hydroxide solution (10 ml). The mixture was then heated to reflux with stirring. After 5 h, the reaction mixture was allowed to cool The ethanol present was then removed by evaporation under reduced pressure. The aqueous residue was then washed with CH2Cl2 (2x) before being acidified to pH1 using 5M HCl. The resultant pale yellow precipitate was then filtered off and dried in vacuo to give the title compound (0.195 g, 69%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].[Cl-].[Li+].Cl>CO.O.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:7]=1[CH:8]([OH:9])[C:10]1[CH:11]=[CH:12][C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CC(=O)O)c2)c(OCC(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)COc1ccc(C(O)c2ccc(OCC(C)C)c(CC(=O)O)c2)c(OCC(C)C)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
In 2 ml of methanol is dissolved 100 mg of 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]acetic acid. After adding 18 mg of sodium borohydride at 5-10° C., the mixture thus obtained is stirred at 50-60° C. for one hour. Then, 40 mg of sodium borohydride and 40 mg of lithium chloride are further added at ambient temperature, and the mixture thus obtained is stirred at 50-60° C. for two hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 50 mg of 2-{5-[(2,4-diisobutoxyphenyl)(hydroxy)methyl]-2-isobutoxyphenyl}-acetic acid is obtained as a colorless oily product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C[Si]([N:33]=[C:34]=[O:35])(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:33][C:34]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[O:35]
Reactant: C[Si](C)(C)N=C=O
Reactant: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCN)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCNC(N)=O)c1ccccc1
Reaction time: 12 h

Procedure:
To 20 mg (0.05 mmol) of amine 20-2 in CH2Cl2 was added a large excess of trimethylsilyl isocyanate and triethylamine. After stirring for 12 h, the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with MeOH/CHCl3 to provide 23-1 as a white solid. Data for 23-1: 1HNMR (500 MHz, d6-DMSO) δ 7.6 (m, 1H), 7.5-7.1 (m, 7H), 6.2 (s, 1H), 5.95 (m, 1H), 5.3 (s, 2H), 4.95 (m, 1H), 4.7 (m, 1H), 3.0 (m, 2H), 2.7 (s, 6H), 2.1 (m, 1H), 1.3 (m, 3H) ppm. HRMS (ES) calc'd M+H for C23H26ClFN4O2: 445.1801. Found: 445.1805.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[CH3:22]>CC(C)=O>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH:27][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:22]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)CCNS(=O)(=O)c1cccc(OC)c1
Reaction time: 96 h

Procedure:
To a solution of 3-methoxybenzenesulfonyl chloride (3.53 g, 12.1 mmol) and triethylamine (3.45 g, 17.1 mmol) in acetone at 0° C. was added β-alanine ethyl ester hydrochloride (2.00 g, 17.1 mmol) under a nitrogen atmosphere. After 4 days, the reaction was concentrated in vacuo. The residue was partitioned between 0.1 N HCl solution and EtOAc, the organic layer separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the crude product which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]1[N:16]([CH3:17])[N:15]=[N:14][N:13]=1.[CH2:18](I)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[C:3]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)=[CH:4]1)[CH3:19]
Reactant: CCI
Reactant: Cn1nnnc1-c1cnc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2nnnn2C)c(=O)c2ccccc21

Procedure:
A mixture of 4-hydroxy-3-(1-methyl-1H-tetrazol-5-yl)quinoline (2 g), ethyl iodide (1.1 ml), anhydrous potassium carbonate (1.83 g) and dimethylformamide (100 ml) was stirred and heated on a steam bath for 18 hours. The mixture was evaporated under reduced pressure and the residue dissolved in industrial methylated spirit (100 ml). Dilution with diethyl ether (100 ml) gave a white precipitate which was collected and extracted with hot dichloromethane (100 ml). The extract was evaporated to give the novel compound 1-ethyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 170°-176°.
Reaction SMILES: [N+]([O-])(O)=O.C([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[O:13][C:12](=[O:18])[CH:11]=[C:10]2[OH:19])C.[CH:20](Cl)(Cl)Cl>>[CH3:17][C:16]1[C:15]([CH3:20])=[C:14]2[C:9]([C:10]([OH:19])=[CH:11][C:12](=[O:18])[O:13]2)=[CH:8][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: CCc1cc2c(O)cc(=O)oc2cc1C
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c(O)cc(=O)oc2c1C

Procedure:
Fuming nitric acid (16 ml) was added to a stirred suspension of 6-ethyl-4-hydroxy-7-methylcoumarin (m.p. 234°-7° ; 3.17g) in chloroform (250 ml) at room temperature over 1 hour. After standing for a further hour, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (60 ml) added to the residue. Filtration gave the product, m.p. 170°-2°(d), (C12H11NO5 requires C, 57.83; H, 4.45; N, 5.62. Found: C, 58.07; H, 4.54; N, 5.76).
Reaction SMILES: [C:1]([O:7]C)(=O)[C:2]([O:4][CH3:5])=[O:3].C[O-].[Na+].[I:12][C:13]1[CH:14]=[C:15]([N+:24]([O-:26])=[O:25])[C:16]([CH3:23])=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.Cl>CO>[N+:24]([C:15]1[CH:14]=[C:13]([I:12])[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[C:16]=1[CH2:23][C:1](=[O:7])[C:2]([O:4][CH3:5])=[O:3])([O-:26])=[O:25]
Reactant: Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dimethyl oxalate (127.79 g, 5.0 eq) was added to sodium methylate (216.4 mL, 28%, 5.0 eq). The resulting mixture was stirred at room temperature for 1.5 hours. To the mixture was then added 5-iodo-2-methyl-3-nitrobenzotrifluoride (71.64 g, 216.4 mmol), dissolved in MeOH (216 mL). The dark red mixture was then stirred at room temperature for 6 hours and left over night. The solvent was removed in vacuo to give a red solid which was subsequently added to aqueous 2.5N HCl (800 mL). The mixture was extracted with EtOAc (500 mL and 2×300 mL). The extracts were combined and dried (anhydrous MgSO4). After filtration, the solvent was removed in vacuo to give a yellow solid of the crude product (161.41 g). A fraction of this was purified by column chromatography (silica gel, eluting 15:1 to 10:1 hexane:EtOAc) to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:60][CH:61]1[CH2:66][CH2:65][N:64](C(OC(C)(C)C)=O)[CH2:63][CH2:62]1>FC(F)(F)C(O)=O.O1CCCC1.ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([C:22]([NH:60][CH:61]5[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]5)=[O:24])=[CH:25][CH:26]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(Nc2nc3cccc(-c4cccc(Cl)c4)n3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NC1CCNCC1)c1ccc(Nc2nc3cccc(-c4cccc(Cl)c4)n3n2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 4-{[5-(3-chlorophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}benzoic acid (182 mg, 0.499 mmol, 1 equiv), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (228 mg, 0.600 mmol, 1.20 equiv), and diisopropylethylamine (97 mg, 0.75 mmol, 1.5 equiv) in 1:2 dichloromethane/tetrahydrofuran (5 mL) was added tert-butyl 4-amino-1-piperidine carboxylate (120 mg, 0.60 mmol, 1.2 equiv). The resulting mixture was stirred at 30° C. overnight, filtered, concentrated to give crude product. The crude product was dissolved in 1:1 trifluoroacetic acid/tetrahydrofuran (10 ml) and stirred at room temperature for 2 h. After removal of the solvent, the resulting residue was purified by preparative HPLC to give the desired product (39.5 mg, 17%). 1H NMR (400 MHz, DMSO-d6), δ: 9.98 (s, 1H), 8.24 (s, 1H), 7.94-7.97 (m, 1H), 7.86 (s, 3H), 7.61-7.75 (m, 6H), 7.29-7.32 (m, 3H), 3.30-3.40 (m, 3H), 3.00 (m, 2H), 1.89 (m, 2H), 1.40 (m, 2H). LCMS (ESI) m/z: 447.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:43][C:44]([F:56])([F:55])[O:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](O)=[O:50]>ClCCl.O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:49](=[O:50])[C:48]2[CH:52]=[CH:53][CH:54]=[C:46]([O:45][C:44]([F:43])([F:55])[F:56])[CH:47]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(OC(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 203 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 230 mg of 3-trifluoromethoxy benzoic acid is added and agitation is carried out for 4 hours and 30 minutes at ambient temperature. Water is added, followed by extracting with methylene chloride, drying, evaporating the solvents, recrystallizing from ether, separating, drying and 326 mg of expected product is collected.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30]C(=O)C(F)(F)F)[CH:25]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:30][C:26]1[CH:25]=[C:24]([C:23]#[C:22][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(C2(C#Cc3cccc(NC(=O)C(F)(F)F)c3)CCCC(=O)C2)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2(C#Cc3cccc(N)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To a solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-trifluoroacetamidophenylethynyl)cyclohexan-1-one (0.62 g, 1.24 mmol) in 95:5 methanol/water (10 mL) under an argon atmosphere was added potassium carbonate (0.86 g, 6.2 mmol). The mixture was refluxed for 6 h and was stirred for 18 h at room temperature. The solid precipitate was collected and purified by trituration from ethyl acetate/hexanes to provide the title compound as a white solid (0.39 g, 77%), m.p. 100-102° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[B-]C#[N:36].[Na+]>CO>[NH2:36][CH:13]([C:12]1[CH:27]=[CH:28][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: [B-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)c1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 40.4 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(benzyloxy)benzoyl)pyrrolidine-1-carboxylate (247 mg, 0.648 mmol) and dry ammonium acetate (399 mg, 5.18 mmol) in methanol (13.0 mL) was stirred at room temperature for 30 min. To this was added sodium cyanotrihydroborate (81 mg, 1.295 mmol) and the reaction mixture heated to 60° C. for 24 h. An additional portion of sodium cyanotrihydroborate (81 mg, 1.30 mmol) was added and the heating continued at 60° C. for 48 h. The reaction solution was cooled to room temperature, quenched with water and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (5%→60% ethyl acetate in hexanes). Obtained (R)-tert-butyl 2-(amino(4-(benzyloxy)phenyl)methyl)pyrrolidine-1-carboxylate (100 mg, 0.262 mmol, 100% yield) as a slightly yellow oil that was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 7.27-7.46 (m, 5H), 6.90-7.15 (m, 4H), 4.97-5.14 (m, 2H), 4.10-4.53 (m, 1H), 3.27-3.64 (m, 1H), 2.55-2.78 (m, 1H), 2.26-2.45 (m, 1H), 1.54-2.11 (m, 4H), 1.45-1.54 (m, 9H); LRMS (ESI) m/e 383.13, 404.11 [(M+H)+, calcd for C23H31N2O3 383.23].
Reaction SMILES: COC1C=C2C(CCCC2=O)=CC=1.C[Si](C#N)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:26][CH2:27][C:28]1(O)[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=2)[CH2:31][CH2:30][CH2:29]1.[ClH:41]>C(O)C>[ClH:41].[NH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=2)[CH2:31][CH2:30][CH:29]=1
Reactant: COc1ccc2c(c1)C(O)(CN)CCC2
Agent: COc1ccc2c(c1)C(=O)CCC2
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)C(CN)=CCC2

Procedure:
25 g. of 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenone is reacted with trimethylsilylcyanide and then with lithium aluminum hydride as described in Example 1 to yield 28 g. of 1-aminomethyl-1-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalene. This compound is treated with HCl in ethanol as described in Example 3 to give 1-aminomethyl-7-methoxy-3,4-dihydronaphthalene HCl; m.p. 174°-175° C.