Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:6][C:4]1([CH2:3][CH2:2][C:1]([O:8][CH2:9][CH3:10])=[O:7])[O:13][CH2:12][CH2:11][O:5]1
Reactant: CCOC(=O)CCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCC1(C)OCCO1

Procedure:
In a flask equipped by a Dean-Stark trap, a mixture of ethyl levulinate (28.83 g; 200 mmol), ethylene glycol (37.24 g; 600 mmol) and a catalytic amount of pyridinium para-toluenesulfonic acid in toluene (200 mL) was heated at reflux until the theoretical amount of water was distilled off. After cooling, the mixture was washed with a saturated solution of sodium hydrogenocarbonate. The basic layer was extracted with diethylether and the organics were combined, then washed with brine and water. The organic layer was dried over sodium sulphatesulphate and concentrated under reduced pressure to afford the ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate as a colorless oil.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH2:44][C@@:42]2([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]2[OH:45])[C@@:37]2([CH:46]=[O:47])[C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([O:48][CH3:49])=[CH:33][C:34]=1[CH2:35][CH2:36]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH2:44][C@@:42]2([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]2[O:45][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[C@@:37]2([CH:46]=[O:47])[C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([O:48][CH3:49])=[CH:33][C:34]=1[CH2:35][CH2:36]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc2c(c1)CC[C@]1(C=O)C2=C(CCCCCOCc2ccccc2)C[C@@]2(C)[C@H]1CC[C@@H]2O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CC[C@]1(C=O)C2=C(CCCCCOCc2ccccc2)C[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]21
Temperature: 25 °C
Yield: 93.2 %

Procedure:
4.46 g of imidazole and 9.66 g of tert-butyldimethylsilyl chloride are added in succession at 0° C. to a solution of 12.49 g of alcohol 5 in 160 ml of N,N-dimethylformamide and stirred at room temperature until the reaction is completed. For working-up, the aqueous phase is mixed with water and extracted several times with diethyl ether. The combined organic phases are washed with water and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. The residue is purified by column chromatography (cyclohexane/ethyl acetate) and yields 14.36 g of silyl ether 6 as a yellow, viscous mass (GC-MS: m/z theor.: 602, pract.: 602).
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH3:20])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].Br[CH2:30][CH:31]1[CH2:34][CH2:33][CH2:32]1>>[C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)=[CH:23][CH:22]=3)[CH3:20])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: BrCC1CCC1
Reactant: CC(=O)CNC1CCN(c2ccc(NC(=O)C(C)c3ccc(O)cc3)cc2)C1
Product: CC(=O)CNC1CCN(c2ccc(NC(=O)C(C)c3ccc(OCC4CCC4)cc3)cc2)C1

Procedure:
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide was reacted with bromomethylcyclobutane by method H. This resulted in a product with the molecular weight 449.60 (C27H35N3O3); MS (ESI): 450 (M+H+).
Reaction SMILES: [C:1]12([CH:11]([OH:18])[CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41]>O>[C:1]12([CH:11]([O:18][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=3[Cl:41])[CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OC(Cn1ccnc1)C12CC3CC(CC(C3)C1)C2
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Clc1ccc(COC(Cn2ccnc2)C23CC4CC(CC(C4)C2)C3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 500 mg. of 1-[2-(1-adamantyl)-2-hydroxyethyl]imidazole in 3 ml. of hexamethylphosphoramide is added 96 mg. of a 56% dispersion of sodium hydride in mineral oil. The addition of base is carried out under a nitrogen atmosphere with continuous stirring. The reaction temperature is then maintained at 25° C. for 1 hour and thereafter at 50° C. After 11/2 hours at 50° C., the reaction mixture is cooled in ice and 450 mg. α,2,4-trichlorotoluene in 3 ml. hexamethylphosphoramide is added dropwise. The temperature is then held at 5° C. for a 1 hour, then raised to 25° C. for 1 hour, and finally held at 50° C. for 2 hours. Thereafter, the resulting solution is poured into 200 ml. water. The aqueous phase is extracted with ether and the extracts washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting residue is chromatographed on silica gel to effect purification. Elution with 5% acetone in dichloromethane yields 1-[2-(1-adamantyl)-2-(2,4-dichlorobenzyloxy)ethyl]imidazole which is then further characterized as the oxalate salt, decomp. 203.5°-205.5° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl.O>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:17]
Reactant: O=C(Cl)CCCCl
Reactant: NCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCl)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a solution of phenethylamine (2.42 g, 20 mmol) and NaOH (0.88 g, 22 mmol) in DCM/H2O (20 mL/20 mL) was added 4-chloro-butyryl chloride (2.82 g, 20 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 20 min. The mixture was partitioned between DCM (20 mL) and H2O (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a white solid. This residue was purified with silica gel column (Hexane/EtOAc=3/1 to 1/1) to obtain HJC-1-48 (4.2 g, 93%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 7.32 (t, 2H, J=7.8 Hz), 7.23-7.26 (m, 1H), 7.20 (d, 2H, J=7.8 Hz), 5.46-5.47 (m, 1H), 3.52-3.58 (m, 4H), 2.82 (t, 2H, J=7.2 Hz), 2.31 (t, 2H, J=7.2 Hz), 2.07-2.11 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:3]1.CO.[OH-].[Na+].Cl>O>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)=[N:3]1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O

Procedure:
Still following the procedure of Example 1, 6.8 g. of methyl 1-methyl-3-(4-trifluoromethylphenyl)pyrazole-5-carboxylate dissolved in 100 ml. of methanol was heated for about one hour with a solution of 1 g. of sodium hydroxide in 75 ml. of water. The reaction mixture was cooled and then acidified with 1N aqueous hydrochloric acid. The free acid, being insoluble in the acidic solution, separated and was collected by filtration. Recrystallization from benzene yielded 1-methyl-3-(4-trifluoromethylphenyl)pyrazole-5-carboxylic acid melting at 230°-2° C.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:11](Cl)([CH3:14])([CH3:13])[CH3:12].[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: CC(C)(C)Cl
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
In a 200 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.05 g (0.0005 mol (corresponding to 1% by mol)) of copper(I) chloride and 20 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 6.0 g (0.065. mol) of tert-butyl chloride and 1.9 g (0.078 mol) of metallic magnesium in 50 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 20° C. to 25° C. After the dropwise addition was completed, stirring was conducted at a temperature of 35° C. to 40° C. for 3 hours. Then, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 20 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 111° C. to 113° C. under reduced pressure of 15 Torr were collected. As a result, 9.2 g (purity: 99.0%) of the aimed tri-tert-butylphosphine was obtained as an oily substance. The yield was 90.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[CH2:10][C@H:9]([CH2:11][NH:12]C(=O)OC(C)(C)C)[CH2:8]2)=[CH:4][CH:3]=1.Cl.C(OCC)C>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[CH2:10][C@H:9]([CH2:11][NH2:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](Oc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC[C@H]1C[C@H](Oc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution in 1,4-dioxane (30 mL) of the compound (0.98 g) obtained in step (5) above, a solution (25 mL) of 4 mol/L hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at room temperature for 5 hours. After adding diethyl ether (120 mL), the mixture was stirred for another two hours and thereafter the precipitate was recovered by filtration. The recovered precipitate was dissolved in an aqueous solution of 1 mol/L sodium hydroxide and chloroform and two extractions were conducted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the titled compound as a colorless oil (660 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8]CC)=O)=[CH:2]1.[NH2:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH3:22]>>[CH3:22][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][CH2:14][C:13]1[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=1[NH:11][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: CCOC(=O)c1ccoc1
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccoc1

Procedure:
Reaction of ethyl furan-3-carboxylate prepared by the method of Boyd et al, Synthesis, 545, (Oct. 1971) with 2-(2-amino-phenethyl)-1-methylpiperidine according to the procedure of Example 115 provides 2'-[2-(1-methyl-2-piperidyl)ethyl]-3-furancarboxanilide, m.p. 114.5° - 115.5° C. (corr.), from isopropyl ether and then ethyl acetate.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[CH2:19][C:20](=[O:22])[CH3:21].Cl>CN(C)C=O>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:19][C:20](=[O:22])[CH3:21])=[O:4]
Reactant: CC(=O)CCl
Reactant: CCCCCC(Br)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(Br)C(=O)OCC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
2-Bromoheptanoic acid (86.0 g, 411.3 mmol) is placed in 600 ml of dimethylformamide, 49.95 g (493.6 mmol) of triethylamine are added dropwise thereto within 5 minutes at 20° C. and the pale yellow solution is stirred at room temperature for 15 minutes. Chloroacetone (57.07 g, 617 mmol) is added dropwise during 30 minutes and the yellow-brown suspension is stirred at room temperature for 90 minutes. The reaction mixture is poured on to 1 l of 1N HCl and ice and extracted in a separating funnel with 3×500 ml of ether. The organic phases are washed with 2×200 ml of water, dried over MgSO4 and concentrated on a rotary evaporator. Distillation at 86°-88° C./0.05 mbar yields 80.56 g (73.9%) of acetylmethyl 2-bromoheptanoate.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]([NH2:38])(=[O:37])[CH2:35]O>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([O:16][CH2:35][C:34](=[O:37])[NH2:38])=[O:15])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: NC(=O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)OCC(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 15.5 g (0.05 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 8.50 g (0.052 mol) of 1,1'-carbonyldiimidazole in 350 ml of tetrahydrofuran is stirred at room temperature for 2 hours and 4.00 g (0.052 mol) of glycolamide are added thereto. After stirring at room temperature overnight, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with methylene chloride-methanol (20:1) and crystallization from ethyl acetate/ether gives carbamoylmethyl 2-(4-acetamidobutyryl)-5-chlorohydrocinnamate as white crystals with melting point 114°-116°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([F:14])[C:3]=1[NH2:15].[CH:16]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[CH:16]1([CH2:21][C:22]([NH:15][C:3]2[C:2]([F:1])=[CH:7][C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:5][C:4]=2[F:14])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1c(F)cc(N2CCOCC2)cc1F
Reactant: O=C(Cl)CC1CCCC1
Solvent: CC#N
Product: O=C(CC1CCCC1)Nc1c(F)cc(N2CCOCC2)cc1F
Temperature: 150 °C
Yield: 75 %

Procedure:
2,6-Difluoro-4-morpholin-4-yl-phenylamine (0.20 g) and cyclopentylacetyl chloride (149 μL) were dissolved in acetonitrile (4 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo and purified by flash chromatography to furnish 228 mg (75%) of the title compound as a white solid. LC-MS (m/z) 325 (MH+); tR=2.61, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.19 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.74 (m, 2H), 2.19 (m, 1H), 2.26 (d, 2H), 3.14 (m, 4H), 3.70 (m, 4H), 6.68 (d, 2H), 9.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][NH:14][CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][N:14]([CH3:15])[CH3:13]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Yield: 81.2 %

Procedure:
2-chloro-5-nitrobenzaldehyde (1 g, 5.39 mmol) was dissolved in THF (10 mL), and added with dimethylamine (2 M THF solution, 2.7 mL, 5.39 mmol). The reaction solution was cooled to 0° C., and NaBH(OAc)3 (1.6 g, 7.55 mmol) was slowly added thereto, followed by stirring for 12 hours or more at room temperature. The reaction mixture was added with water, and subjected to extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (940 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([OH:18])=[CH:12][CH:11]=3)=[O:4].Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1)=[CH:12][CH:11]=3)=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccc(O)cc12
Product: COC(=O)c1cc2c(cn1)[nH]c1ccc(Oc3ccc([N+](=O)[O-])cn3)cc12

Procedure:
In analogy to Example 8 from 6-hydroxy-β-carboline-3-carboxylic acid methyl ester and 2-chloro-5-nitropyridine, mp 150°-155° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][OH:14])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N@:23]1([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25][CH:24]1[C:26]([O:28][CH3:29])=[O:27].B(F)(F)F.O(CC)CC>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:23][C@@H:24]([CH2:25][O:14][CH2:13][C@H:12]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][OH:11])[C:26]([O:28][CH3:29])=[O:27])=[O:31])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Reactant: OC[C@H](OCc1ccccc1)[C@H](CO)OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@H](CO)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of (2S,3S)-2,3-bis(benzyloxy)butane-1,4-diol (283 mg, 0.935 mmol), prepared as disclosed in Journal of Organic Chemistry 1991, 56(3), 1321-1322, and (S)-1-benzyl 2-methyl aziridine-1,2-dicarboxylate (110 mg, 0.468 mmol) in CH2Cl2 (1.5 mL) at −78° C. was added BF3-OEt2 (10 μL, 0.081 mmol), and the reaction mixture was stirred at −78° C. for 1 h, slowly warmed to 0° C., and then stirred at 0° C. for 3 h. The reaction mixture was directly purified by flash chromatography (SiO2) to afford the title compound as a colorless oil (208 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 7.45-7.20 (m, 16H), 5.70 (d, J=8.5 Hz, 1H), 4.70-4.54 (m, 6H), 4.53-4.46 (m, 1H), 3.93 (dd, J=9.5, 3.2 Hz, 1H), 3.80-3.53 (m, 9H), 2.09-1.96 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 170.72, 156.04, 138.16, 138.08, 136.24, 128.54, 128.49, 128.47, 128.20, 128.13, 127.99, 127.91, 127.89, 127.86, 79.03, 78.10, 73.09, 72.88, 71.40, 71.08, 67.08, 61.40, 54.46, 52.60; ESIMS m/z 538.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].Cl[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[F:9]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)c(F)c1
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
TEA (2.28 g, 0.023 mol) was added at once to a solution of 3 g (0.0206 mol) 4-chloro-3-fluoroaniline in 50 ml of DCM and then ethyl 2-chloro-2-oxoacetate (2.81 g, 0.0206 mol) was added dropwise at 0° C. Reaction mixture was stirred at 0° C. for 1 h and then continued at room temperature (RT) for 6 h. The mixture was washed with 25% aqueous solution of K2CO3 (2×50 ml) and water (50 ml). The product was dried over Na2SO4 and evaporated. The residue was washed with ether and dried on the air to give ethyl 2-(4-chloro-3-fluorophenylamino)-2-oxoacetate (2′) (3.97 g, 78.6%) as a white powder; LC-MS (APCI+) m/z: calcd for C18H8CIFNO3: 245.03. found: 245 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1nccnc1Cl
Reaction time: 48 h

Procedure:
To a suspension of 3-chloropyrazine-2-carboxylic acid (10 g, 63 mmol) and cesium carbonate (31 g, 95 mmol) in DMF was added iodomethane (5.9 ml, 95 mmol). The solution was stirred for 48 hours. After that time, the reaction was removed from stirring, acidified to pH 5 with 1.0 N HCl and extracted five times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated, affording to target material as an orange oil. MS (ESI, pos. ion) m/z: 173.0 (M+1).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].ClC1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.[CH3:70][O:71][CH2:72]CN>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH2:30][CH2:70][O:71][CH3:72])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: COCCN
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Agent: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Product: COCCNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Yield: 40 %

Procedure:
Preparation analogous to 96a by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.061 mmol, 30 mg) and 2-aminoethyl methyl ether (1.531 mmol, 133 μL) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(2-methoxyethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96g (13 mg, 40%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.24 (s, 3H), 3.30 (s, 3H), 3.54 (m, 4H), 7.28 (d, J=8.6 Hz, 1H), 7.61 (m, 2H), 7.76 (m, 1H), 7.83 (m, 1H), 7.94 (m, 1H), 7.96 (s, 1H), 8.05 (s, 1H), 8.18 (s, 1H), 8.25 (s, 1H), 10.09 (s, 1H), 10.34 (s, 1H). (m/z)=530 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[CH:62]=[CH:61][C:54]([O:55][C:56]([CH3:60])([CH3:59])[CH2:57][NH2:58])=[CH:53][CH:52]=1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:58][CH2:57][C:56]([O:55][C:54]2[CH:53]=[CH:52][C:51]([F:50])=[CH:62][CH:61]=2)([CH3:60])[CH3:59])=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC(C)(CN)Oc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)c1ccc(N)c(F)c1)Oc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-amino-3-fluorobenzoic acid (200.0 mg, 1.289 mmol) and HBTU (490 mg, 1.3 mmol) in DMF (2 mL, 20 mmol) at 0° C. were added N,N-diisopropylethylamine (0.67 mL, 3.9 mmol) and 2-(4-fluorophenoxy)-2-methylpropan-1-amine (Preparation 91, 280 mg, 1.5 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (120 g cartridge, chloroform to 12% MeOH in chloroform).