Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Cn1cnc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cnc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)cc21
Yield: 91 %

Procedure:
The title compound is prepared from 3-methyl-3H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 91% of theory; LC (method 4): tR=1.65 min; Mass spectrum (ESI+): m/z=346 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N+:23]([O-:25])=[O:24])[C:16]=2[CH3:26])[CH2:12][C:11](=[O:27])[C:10]=1[C:28](=O)[CH2:29][CH3:30]>C(O)C>[CH2:2]([O:4][N:5]=[C:28]([C:10]1[C:11](=[O:27])[CH2:12][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N+:23]([O-:25])=[O:24])[C:16]=2[CH3:26])[CH2:14][C:9]=1[OH:8])[CH2:29][CH3:30])[CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
Ethoxyamine hydrochloride (0.26 g; 2.7 mmole) and then sodium hydroxide (0.11 g; 2.7 mmole) were added to a solution of 3-hydroxy-5-(2,4,6-trimethyl-3-nitrophenyl)-2-propionylcyclohex-2-en-1-one (0.6 g; 1.8 mmole) in absolute ethanol (150 ml). The mixture was stirred at room temperature for a period of 18 hours and then the ethanol was removed by evaporation under reduced pressure. The residue was treated with dichloromethane and the organic phase was washed twice with water and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethyl-3-nitrophenyl)cyclohex-2-en-1one (0.56 g; 83.2%) as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 5, Example 37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 0 °C
Yield: 45.5 %

Procedure:
Methyl 4-(4′-methoxyphenyl)benzoate (3.0 g, 12.3 mmol) was added in portions to a suspension of lithium aluminum hydride (0.94 g, 25.0 mmol) in tetrahydrofuran (40 ml) at room temperature for 20 minutes with stirring. The reaction solution was refluxed for 2 hours under heating and cooled to 0° C. To the residue was added water (1 ml) and 1 N aqueous sodium hydroxide (3 ml), the insoluble matter was filtered out and the filtrate was concentrated under reduced pressure. The object compound (1.2 g) was obtained from the residue as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[C:10](O)(=[O:15])[CH2:11][C:12](O)=[O:13].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Zn+2].[Cl-].O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[O:9][C:12](=[O:13])[CH:11]=[C:10]2[OH:15])[CH3:2]
Reactant: O=C(O)CC(=O)O
Reactant: CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cccc2c(O)cc(=O)oc12
Reaction time: 24 h
Yield: 24.1 %

Procedure:
A mixture of 2-ethylphenol (Aldrich) (6.1 g; 50 mmole), malonic acid (Aldrich) (5.2 g; 50 mmole), zinc chloride (20.4 g, 150 mmole) and phosphorous oxychloride (Merck) (14 mL; 150 mmole) was heated under stirring for 24 hours at 70–75° C., whereupon the reaction was stopped and a mixture of water and ice was added. The reaction mixture was stirred for further 2 hours at room temperature and then 10% sodium carbonate (150 mL) was added to the filtered brown precipitate while stirring. The insoluble part was filtered and the filtrate was acidified with concentrated hydrochloric acid, whereat a brown precipitate was precipitated, which was then filtered and washed with cold water. By recrystallization from 50% ethanol there were obtained 2.29 g (24%) of brown powdery 8-ethyl-4-hydroxycoumarin.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:30][Si](C)(C)C>CC(CC)=O>[ClH:30].[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCCCc2ccccc2)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1.5 h

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexyl)-N-(4-phenylbutyl)acetamide (194 mg, 0.49 mmol) was dissolved in ethyl methyl ketone, and chlorotrimethylsilane (0.093 ml, 0.74 mmol) was added. After 1.5 h it was possible to filter off the product with suction as a colourless, hygroscopic solid in a yield of 30% (63 mg).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([C:31]#[CH:32])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+:37]([CH2:40][CH2:41][O:42]C1CCCCO1)([O-])=[O:38].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:33])([CH3:34])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([C:31]3[O:38][N:37]=[C:40]([CH2:41][OH:42])[CH:32]=3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:8]=1
Reactant: C#Cc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: O=[N+]([O-])CCOC1CCCCO1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1-c1cc(-c2cc(CO)no2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 15.3 %

Procedure:
To a solution of 200 mg (0.396 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-ethynyl-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide (Example 66), 0.182 ml (1.19 mmol) 2-(2-nitroethoxy)tetrahydropyran and 5 mg (0.04 mmol) 4-N,N-dimethylaminopyridine in 3 ml acetonitrile a solution of 260 mg (1.19 mmol) di-tert-butyl dicarbonate in 2 ml toluene was added, and the mixture was stirred at room temperature for 70 h. Quenching with water was followed by extraction with two portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. The residue was dissolved in 1.5 ml methanol and treated with 4 mg (0.02 mmol) 4-toluenesulfonic acid monohydrate. After stirring for 1.5 h at room temperature the solvent was evaporated. The residue was dissolved in ethyl acetate. Washing with saturated sodium bicarbonate solution was followed by drying with sodium sulfate and concentration. Column chromatography afforded 35 mg (15%) of the title compound as a viscous orange oil.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:15][C:16]1[CH:40]=[CH:39][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:25]([C:35]([F:38])([F:37])[F:36])[CH:24]=3)[S:22][C:18]=2[CH:17]=1>CN(C=O)C.CCOC(C)=O>[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][CH2:15][C:16]1[CH:40]=[CH:39][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[C:25]([C:35]([F:36])([F:37])[F:38])[CH:24]=3)[S:22][C:18]=2[CH:17]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: FC(F)(F)c1cc(-c2nc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
To a solution of β-alanine tert-butyl ester hydrochloride (47 mg, 1.1 eq.) in DMF (2 ml) is added NaH (60% in mineral oil) (28 mg, 3 eq.) at room temperature. The mixture is stirred at room temperature for 15 minutes before a solution of 6-bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole (105 mg, 0.234 mmol) in DMF (1 ml) is added. The mixture is stirred at room temperature overnight, diluted with EtOAc, washed with 10% Na2S2O3, brine, dried over MgSO4, filtered and concentrated. Column chromatography (CH2Cl2/CH3OH, 95/5) gave 31 mg (26%) of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino}-propionic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11](=O)[C:10]2[CH:9]=[C:8]([CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:6][C:5]=2[CH2:4]1)[CH3:2].[H][H].Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[CH2:1]([CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:6][C:5]=2[CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCC1CC(=O)c2cc(CC(=O)O)ccc2C1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCC1CCc2cc(CC(=O)O)ccc2C1

Procedure:
5.4 g of 6-ethyl-5,6,7,8-tetrahydro-8-oxo-naphthalene-2-acetic acid are dissolved in 150 cc of acetic acid and hydrogenation is effected at 4 atmospheres of hydrogen pressure and 45° with the addition of 1 g of palladium/charcoal (10%) and 2 cc of 70% aqueous perchloric acid. After the take up of the calculated amount of hydrogen, filtration is effected, 2 g of sodium acetate are added and the solution is concentrated. The residue is divided between ether and water, the ether extract is dried over sodium sulphate and concentrated by evaporation. The resulting 6-ethyl-5,6,7,8-tetrahydronaphthalene-2-acetic acid is recrystallized from hexane and has a M.P. of 64°-66°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH2:14].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(N)c1N

Procedure:
A slurry of 2-amino-5-chloro-3-nitro-benzoic acid methyl ester (1.8 g, 8.40 mmol) and 10% Pd/C (0.5 g) in methanol (50 mL) was hydrogenated with a hydrogen balloon for 2 h. After completion of reaction, the reaction mixture was filtered over a celite bed and concentrated to dryness. The resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as off white solid.
Reaction SMILES: C([O:8][C:9](=[O:40])[CH:10]([CH:21]([C:26](=[O:39])[NH:27][CH:28]([C:33](=[O:38])[NH:34][CH:35]1[CH2:37][CH2:36]1)[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:11](OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[H][H].N1CCCCC1.C=O>C(O)C.[Pd]>[CH:35]1([NH:34][C:33]([CH:28]([NH:27][C:26]([CH:21]([C:10](=[CH2:11])[C:9]([OH:40])=[O:8])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:39])[C:29]([CH3:30])([CH3:32])[CH3:31])=[O:38])[CH2:37][CH2:36]1
Reactant: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C(C(=O)O)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Temperature: 25 °C

Procedure:
2-[1-(1-Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-3-methyl-butyl]-malonic acid dibenzyl ester (14.53 g, 25.7 mmol) was dissolved in ethanol (200 ml) and the solution was placed under a blanket of argon. 10% Palladium on charcoal (3.2 g) was added and a fine stream of hydrogen gas was passed through the suspension for 3h with stirring. TLC showed that all the starting material had been consumed. The system was purged with argon and the catalyst was removed by filtration. The filtrate was cooled and stirred in an ice bath and treated with piperidine (2.39 g, 28.1 mmol) which was added dropwise, followed by 37% formaldehyde solution (22.6 ml, ca. 257 mmol). The reaction mixture was allowed to warm slowly to room temperature, then stirred overnight. The solvents were removed under reduced pressure and the residual oil was partitioned between ethyl acetate (300 ml) and 1 M hydrochloric acid (300 ml). The organic layer was separated, washed with 1M HCl and brine, dried over MgSO4, filtered and evaporated to dryness. The remaining pale brown foam (4.40 g, crude) contained a number of minor impurities but was used in Step C without purification. 1H-NMR; δ (CDCl3), 8.34 (1H, d, J=10.0 Hz), 7.37 (1H, m), 6.47 (1H, s), 5.99 (1H, s), 4.50 (1H, d, J=9.9 Hz), 4.07 (1H, m), 2.73 (1H, m), 1.79 (1H, m), 1.52 (2H, m), 1.00-0.82 (1 5H, br m), 0.78 (2H, m) and 0.55 (2H, m).
Reaction SMILES: [Li+].[Cl-].C([Sn](CCCC)(CCCC)[CH:8]=[CH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]#[N:21])[CH:14]=[CH:13]2)CCC.[CH3:30][N:31]([CH:33]=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]([C:30]1[C:11]2[C:10](=[CH:19][CH:18]=[C:17]([CH:8]=[CH:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:20]#[N:21])[CH:14]=[CH:13]4)[CH:12]=2)[CH2:9][CH2:33][N:31]=1)([CH3:15])[CH3:13]
Reactant: CCCC[Sn](C=Cc1ccc2cc(C#N)ccc2c1)(CCCC)CCCC
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(C)C1=NCCc2ccc(C=Cc3ccc4cc(C#N)ccc4c3)cc21
Temperature: 80 °C
Reaction time: 1.75 h

Procedure:
A solution of Example 13I (70 mg, 0.23 mmol), dichlorobis(triphenylphosphine)palladium (II) (7.0 mg, 0.01 mmol), and LiCl (31 mg, 0.73 mmol) in DMF (1.7 mL) was treated dropwise with a solution of Example 13E (120 mg, 0.26 mmol) in DMF (0.2 mL). The mixture was heated to 80° C., stirred for 1.75 hours, cooled to room temperature, diluted with ethyl acetate, washed with H2O and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetatehexanes to provide the desired product.
Reaction SMILES: [C:1](=[O:28])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[CH:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:33][CH:34]=1.CCN(CC)CC>CN(C=O)C>[C:32]1([N:35]2[CH2:40][CH2:39][N:38]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10]3)=[O:28])[CH2:37][CH2:36]2)[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCOC(=O)N2CCN(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
2-(4-(tert-Butoxycarbonyl)piperazin-1-yl)ethyl 4-nitrophenyl carbonate (7.01 g, 17.7 mmol) was dissolved in DMF (150 mL). Phenylpiperazine (2.8 mL, 18.3 mmol) and NEt3 (3.0 mL, 21.5 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (250 mL), washed with 1M aq Na2CO3 solution (5×250 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, 0-100%) to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl 4-phenyl-piperazine-1-carboxylate (5.68 g, 77%) as a yellow oil. 2-(4-(tert-Butoxycarbonyl)-piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate (0.45 g, 1.07 mmol) was dissolved in a mixture of DCM (30 mL) and 2M HCl in Et2O (4 mL, 8 mmol) and stirred overnight. The supernatant was discarded. The residue washed with DCM (3×15 mL) and dried in vacuo to give 2-(piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate trihydrochloride (0.42 g, 98%) as a pale brown glass.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3].[CH:15]([O-])=[O:16].[Na+].C(OC(=O)C)(=O)C>C(O)=O>[CH2:2]([O:4][C:5](=[O:14])[CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:15]=[O:16])[CH3:3]
Reactant: O=C[O-]
Reactant: CCOC(=O)CNc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CN(C=O)c1ccccc1
Reaction time: 2 h

Procedure:
Phenylglycine ethyl ester hydrochloride (21.5 g; 0.1 mol) was dissolved in 200 ml of formic acid, whereto sodium formate (8.16 g; 1.2 eq.) was added, followed by adding dropwise acetic anhydride (20 ml; 2.1 eq.). After two hours' stirring, 10 ml of acetic anhydride was added dropwise, and the mixture was stirred at 50°-60° C. for 1.5 hours. After the solvent was distilled off, the residue was neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to afford an oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethylamine. The title compound, ESI MS (m/z): 394 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21](O)=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC[N:27](C(C)C)C(C)C.N.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([NH2:27])=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)n[nH]3)c2nc1NC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc(C(N)=O)n[nH]3)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a 10-mL reaction vial was added ethyl 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylate (467a) (94 mg, 0.27 mmol), LiOH hydrated (56 mg, 1.33 mmol), dioxane (4 mL), and water (1 mL). The reaction mixture was heated at 50° C. for 1 h and at 100° C. for 2 h and then cooled to RT. The solvent was removed under vacuum and HCl (1N, 3 mL) was added, the yellow precipitate obtained was filtered off, washed with water, and dried. 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) was obtained as a yellow solid and used without further purification. To a 50-mL round-bottomed flask was added 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) (77 mg, 0.24 mmol), DCM (3 mL), DMF (1 mL), DIPEA (82 μL, 0.47 mmol), ammonia (0.95 mL, 0.47 mmol, 0.5 M in dioxane), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (123 mg, 0.24 mmol) (Sigma-Aldrich). The reaction mixture was stirred at RT for 30 min, concentrated to half of its volume, and diluted with EtOAc (20 mL). The organic extract was washed with sat NaHCO3 (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 40% EtOAc in hexanes to give 5-(3-(tert-butylamino)-2-methyl-quinoxalin-5-yl)-1H-pyrazole-3-carboxamide (467) (65 mg, 85% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br. s, 1H), 7.85 (dd, J=1.08, 7.34 Hz, 1H), 7.76 (d, J=7.63 Hz, 1H), 7.53 (br. s., 1H), 7.41 (t, J=7.73 Hz, 1H), 7.30 (s, 1H), 7.18 (br. s, 1H), 6.06 (br. s., 1H), 2.58 (s, 3H), 1.52 (s, 9H). m/z (ESI, +ve) 325.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O-])=O>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C:13]1[N:14]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[NH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1-c1nc(C(F)(F)F)c[nH]1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1-c1nc(C(F)(F)F)c[nH]1
Yield: 94.4 %

Procedure:
2-(2-Nitro-phenyl)-4-trifluoromethyl-1H-imidazole (1.50 g, 5.83 mmol) was dissolved in Methanol (35 mL) and solution was carefully added to 10% Palladium on Carbon (90:10, carbon black:Palladium, 0.500 g) under nitrogen. The reaction was then hydrogenated at 55 psi until HPLC showed consumption of starting material (˜4 hours). Catalyst was removed via filtration and the filtrate was reduced en vacuo to afford 1.25 grams (94%) of the desired product. LC/MS (ESI): 288.09.