Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6]
Reactant: C=C1CC(=O)O1
Reactant: CC(O)CN
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
19 ml (0.24 mol) 1-amino-2-propanol were added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 29.50 g (0.19 mol, 78% yield) of a colorless oil.
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]1[CH:28]=[CH:27][C:10]([NH:11][C:12]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:13]=2[C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=1.Cl>C(OCC)(=O)C>[F:6][C:7]1[CH:28]=[CH:27][C:10]([NH:11][C:12]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:13]=2[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2cccs2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2cccs2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of toluene 2.0 mL, ethanol 0.6 mL and water 0.4 mL of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added thiophene-2-boronic acid 42 mg, sodium carbonate 64 mg and tetrakis(triphenylphosphine)palladium(0) 13 mg at room temperature, and it was stirred under application of pressure at 160° C. for 5 minutes. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 0.5 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane] to give methyl 2-(4-fluoroanilino)-4-(thiophen-2-yl)benzoate. 2.0 mol/L Sodium hydroxide aqueous solution 1.0 mL was added to ethanol 7.0 mL solution of the obtained methyl 2-(4-fluoroanilino)-4-(thiophen-2-yl)benzoate, and it was stirred at room temperature for 1 hour and 30 minutes. 0.5 mol/L Hydrochloric acid and ethyl acetate were added to the reaction mixture, the organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(thiophen-2-yl)benzoic acid 3.5 mg of pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9](C)[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:28]2[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]2)[CH:13]=[CH:12][N:11]=1.[CH3:40]NC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:37]([S:34]([N:31]1[CH2:32][CH2:33][CH:28]([C:19]2[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=[C:16]([C:14]4[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH:2]([CH3:3])[CH3:40])[CH:15]=4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:29][CH2:30]1)(=[O:35])=[O:36])[CH3:38]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccnc(N(C)C)c4)cc23)CC1
Reactant: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccnc(NCC(C)C)c4)cc23)CC1
Yield: 20 %

Procedure:
The title compound was prepared according to the general procedure of 5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (1 mL) for dimethylamine to afford 11.1 mg of the title compound (20%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]2[NH:7][CH2:8][CH2:9][C@@H:4]2[CH2:3]1.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[CH3:1][N:2]1[CH2:6][C@@H:5]2[N:7]([C:21]3[C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]([NH:17][C:14]4[N:13]=[C:12]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[C:11]([Cl:10])=[CH:16][N:15]=4)=[C:19]([O:28][CH3:29])[CH:20]=3)[CH2:8][CH2:9][C@@H:4]2[CH2:3]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 49.6 %

Procedure:
(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,2-c]pyrrole (Intermediate 37, 91 mg, 0.72 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 250 mg, 0.60 mmol) and DIPEA (0.334 mL, 1.93 mmol) in 2,2,2-trifluoroethanol (3 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then absorbed onto silica. Purification by FCC, eluting with 2% 7N methnaolic ammonia in CH2Cl2 gave material that was concentrated in vacuo and dissolved in CH3OH. The resulting solution was absorbed onto an SCX column and the column was washed with CH3OH then eluted with 7N methanolic ammonia. Appropriate fractions were concentrated in vacuo to give the title compound (155 mg, 49%) as a orange/red gummy solid; 1H NMR: (CDCl3) 1.89 (1H, dd), 2.04-2.19 (1H, m), 2.24 (3H, s), 2.30-2.39 (1H, m), 2.40-2.57 (2H, m), 2.68 (1H, t), 2.98-3.11 (1H, m), 3.23 (1H, t), 3.51-3.63 (1H, m), 3.97 (3H, s), 4.36-4.48 (1H, m), 6.46 (1H, s), 6.90-7.02 (1H, m), 7.31-7.43 (2H, m), 8.38 (1H, s), 8.48 (1H, dd), 8.53-8.57 (1H, m), 8.82 (1H, s), 8.93 (1H, s); m/z: ES+ MH+ 521.45.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCC.[B:15](OC)([O:18]C)[O:16]C.Cl>CCCCCC.O1CCCC1>[Cl:8][C:4]1[C:3]([F:9])=[C:2]([B:15]([OH:18])[OH:16])[CH:7]=[CH:6][CH:5]=1
Reactant: COB(OC)OC
Reactant: Fc1c(Cl)cccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(Cl)c1F
Temperature: -80 °C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
In a 500-mL three-neck flask was put 16 g (72 mmol) of 1-bromo-3-chloro-2-fluorobenzene, and the air in the flask was replaced with nitrogen; then, 200 mL of tetrahydrofuran was added and the solution was cooled down to −80° C. under a nitrogen stream. To this solution, 48 mL (76 mmol) of n-butyl lithium (a 1.6 mol/L hexane solution) was added dropwise with a syringe, and then the mixture was stirred for 1.5 hours at the same temperature. After stirring, 9.0 mL (80 mmol) of trimethyl borate was added to this mixture. While the temperature was raised to room temperature, the mixture was stirred for about 19 hours. After stirring, about 100 mL of a 1 mol/L hydrochloric acid was added to the resulting solution and the mixture was stirred. The organic layer of this mixture was washed with water and the aqueous layer was subjected to extraction with toluene twice. The solution of the extract and the organic layer were combined and washed with a saturated aqueous solution of sodium chloride. The resulting organic layer was dried over magnesium sulfate, and this mixture was gravity-filtered. The resulting filtrate was concentrated to give 4.5 g of a pale yellow solid of a target substance, in a yield of 35%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].CC(C)([O-])C.[K+].[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>[Pd](Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: OCC(F)(F)F
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1c(OCC(F)(F)F)cc[n+]([O-])c1C
Temperature: 85.5 °C
Yield: 95 %

Procedure:
13.5 ml of 2,2,2-trifluoroethanol were added to the solution of 2,3-dimethyl-4-nitropyridine N-oxide (60 ml, 0.080 mole) obtained in the previous step. Then methylene chloride was distilled off. The resulting concentrated solution was added to a solution of 14.85 g (0.133 mole) potassium tert-butoxide in 54 ml of 2,2,2-trifluoroethanol and 0.034 g of palladium(II) chloride. The reaction mixture was heated to 83-88° C. for 6-8 hours. After cooling to 30° C., potassium nitrite was filtered off, following by distillation of 2,2,2-trifluoroethanol. To this residue 17 ml of a saturated solution of sodium chloride were added and the pH was adjusted by the addition of conc. hydrochloric acid to 6.6. The product was extracted with methylene chloride and 100 ml of a saturated solution of sodium chloride. The organic phases were dried with sodium sulphate and concentrated to a volume of 40 ml. The yield was 95-97%, determined by HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].C([O:18][C:19](=[O:22])[CH:20]=[CH2:21])C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:7]([C:6]1[CH:9]=[C:2](/[CH:21]=[CH:20]/[C:19]([OH:22])=[O:18])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)#[N:8]
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(/C=C/C(=O)O)cc2C#N)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a DMF (10 mL) solution of 5-bromo-2-(4-methyl-1H-imidazol-1-yl)benzonitrile (700 mg) and acrylic acid ethyl ester (362 mg), palladium acetate (31 mg), tri-ortho-tolylphosphine (85 mg) and TEA (2 mL) were added, and the reaction solution was agitated at 80° C. under nitrogen-atmosphere overnight. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system), fractions of the object substance were combined, and concentrated under reduced pressure. The obtained substance was dissolved by SN sodium hydroxide solution (5 mL) and ethanol (30 mL), and the reaction mixture was agitated at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and was made neutral with 5N hydrochloric acid. Insoluble matter consequently deposited was separated by filtering, washed with ether, and 498 mg of the title compound was obtained.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:48]([C:49](=O)[CH3:50])=[C:47]([CH3:52])[O:46][N:45]=2)=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:48]([C:49]3[CH:50]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)=[C:47]([CH3:52])[O:46][N:45]=2)=[CH:40][CH:39]=1
Reactant: CC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2ccc(Cl)cc2)c1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 12 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-yl]-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (16 mg, 12% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH2:7][C:6]1=[O:17])=[O:4].[Li+].[CH3:19][CH:20]([N-]C(C)C)[CH3:21].C(Br)C=C>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH:7]([CH2:21][CH:20]=[CH2:19])[C:6]1=[O:17])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1C(=O)CCc2cccc(OC)c21
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1Cc2cccc(OC)c2C(C(=O)OC)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 10.2 g (43.5 mmol) 1,2,3,4-tetrahydro-8-methoxy-2-oxo-1-naphthalene carboxylic acid methyl ester in 108 mL of THF in a three-neck, round-bottomed flask, equipped with a dropping funnel, was added dropwise 63.8 mL (95.7 mmol) of LDA (1.5M in cyclohexane) at -30° C. to -40° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. and 6.0 mL (69.6 mmol) of allylbromide was added. After stirring the mixture for one hour at room temperature, TLC analysis showed no starting material remaining. The reaction was quenched with 3N hydrochloric acid to pH 2-3 and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by liquid chromatography on 800 g silica gel 60 (230-400 m), eluting with hexane-acetone (3:1), and collecting 40 mL fractions. Fractions 36-63 gave 10.3 g (87%) of pure title compound as a yellow oil.
Reaction SMILES: [NH2:1][OH:2].CO.[C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1)#[N:6]>O1CCCC1>[NH2:6][C:5](=[N:1][OH:2])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(C#N)cn2)cc1
Reactant: NO
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(N)=NO)cn2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
50% Aqueous hydroxylamine solution (40 g) was added to a methanol (100 mL) and tetrahydrofuran (100 mL) solution containing methyl 3-[4-(5-cyanopyridin-2-yl)-phenoxy]-2,2-dimethylpropanoate (6.0 g), and the mixture was stirred at 80° C. for 4 hours. After cooling the reaction mixture to room temperature, the mixture was concentrated under reduced pressure. To the obtained residue were added ethyl acetate and water, and the liquids were separated. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. Ether was added to the solid residue obtained by concentrating the mixture under reduced pressure to pulverize the same, and the solid was collected by filtration and dried to obtain methyl 3-(4-{5-[amino(hydroxyimino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate (5.8 g).
Reaction SMILES: C(N)C1C=CC=CC=1.C(O[C:17]([N:19](C)[C@H:20]([C:24]([NH:26][C@H:27]([C:31]([NH:33][C@H:34]([C:38]([NH:40][C@H:41]([P:43](=[O:46])([OH:45])[OH:44])[CH3:42])=[O:39])[CH2:35][CH2:36][CH3:37])=[O:32])[CH2:28][CH2:29][CH3:30])=[O:25])[CH:21]([CH3:23])[CH3:22])=O)C1C=CC=CC=1>>[CH3:17][NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:31]([NH:33][C@H:34]([C:38]([NH:40][C@H:41]([P:43](=[O:44])([OH:46])[OH:45])[CH3:42])=[O:39])[CH2:35][CH2:36][CH3:37])=[O:32])[CH2:28][CH2:29][CH3:30])=[O:25])[CH:21]([CH3:22])[CH3:23]
Reactant: CCC[C@H](NC(=O)[C@H](CCC)NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](NC(=O)[C@H](CCC)NC(=O)[C@@H](NC)C(C)C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 5(A) (iii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-N-methyl-L-valyl-L-norvalyl-L-norvalyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(N-methyl-L-valyl-L-norvalyl-L-norvalylamino)-ethylphosphonic acid of melting point 300°-302° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[C:13](C(O)=O)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]3)[C:3]=1[Cl:22]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[CH:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]3)[C:3]=1[Cl:22]
Reactant: O=C(O)c1c2nc3ccc(Br)c(Cl)c3c-2[nH]c2ccccc12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1c(Br)ccc2nc3cc4ccccc4[nH]c-3c12
Yield: 95.8 %

Procedure:
7-Bromo-6-chloroquindoline-11-carboxylic acid from Example 77 (1.75 g, 4.66 mmol) was refluxed at 252° C. in diphenyl ether (30 mL) for 4 hours in an oversize flask. The mixture was cooled, diluted with petroleum ether (30 mL), and filtered. The filter cake was washed with petroleum ether (100 mL) and dried to yield 1.48 g (96%) of the title compound as a brown solid; 1H NMR (DMSO-d6) δ 11.92 (s, 1H), 8.39 (s, 1H), 8.21 (d, J=8.4, 1H), 8.13 (d, J=7.6, 1H), 7.90 (d, J=8.4, 1H), 7.69 (t, J=7.6, 1H), 7.60 (td, J=7.6, J=1.6, 1H), 7.52 (d, J=8.8, 1H); 13C NMR (DMSO-d6) δ 143.88, 143.64, 143.59, 133.31, 132.56, 129.23, 127.82, 127.53, 126.62, 125.62, 119.09, 118.6, 113.96, 112.14, 111.89.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:32])[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28](SC)=[NH:29])=[CH:23][CH:22]=2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:37].[Cl-].[NH4+]>CO.C(Cl)Cl>[NH2:29][C:28](=[NH:37])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]2[C:12](=[O:32])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[C:14]2=[O:19])=[CH:22][CH:23]=1
Reactant: CSC(=N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: N=C(N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
320 mg (0.661 mmol) of methyl 2-{4-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}ethaneimidothioate are suspended in 40 ml of methanol, and 153 mg (1.98 mmol) of ammonium acetate and 106 mg (1.98 mmol) of ammonium chloride are added. The mixture is stirred at room temperature overnight, diluted with methanol and methylene chloride until a clear solution is formed and adsorbed on silica gel. Chromatography on silica gel (CH2Cl2/EtOH=10/1 to 3/1) gives the desired compound. The product is dissolved in methanol and methylene chloride, and trifluoroacetic acid is added. Removal of the solvent under reduced pressure gives 298 mg (80% of theory) of the desired product as trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH:13][C:14]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15].[CH:22]([C:24]1[CH:33]=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1)=[CH2:23].C(O)(=O)C.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH:13][C:14]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:22][C:24]2[CH:33]=[N:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH2:18][CH2:17]1)=[O:15]
Reactant: C=Cc1cnc2ccccc2n1
Reactant: COc1ccc2nccc(NC(=O)C3CCNCC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2nccc(NC(=O)C3CCN(CCc4cnc5ccccc5n4)CC3)c2n1
Yield: 12.9 %

Procedure:
A mixture of amine (1f) (0.403 g, 1.4 mmol), 2-vinyl-quinoxaline (b), (0.22 g, 1.4 mmol), acetic acid (0.1 ml) and ethanol (5.2 ml) was heated under reflux for 6 hours. The mixture was then made basic with aqueous sodium hydroxide and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with dichloromethane-methanol (99-1). After evaporation the residue was triturated with a small amount of ethyl acetate and crystallised. The solid was collected by filtration and dried to give the title compound (80 mg) mp.: 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:5]2=1>CO>[NH2:15][C:13]1[CH:14]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:5]2=1
Reactant: O=C(Nc1cncc2[nH]c3c([N+](=O)[O-])cc(Cl)cc3c12)C(F)(F)F
Solvent: CO
Product: Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12
Reaction time: 8 h
Yield: 94.7 %

Procedure:
The crude N-(6-chloro-8-nitro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (130 mg, 0.36 mmol) was dissolved in 7 ml of MeOH and the reaction vessel was vacuum purged 3× with N2. Platinum (20 mg, 20% wt. on activated carbon) was added quickly, and the reaction vessel was again vacuum purged 3× with N2, followed by 3 additional vacuum purge cycles with H2. The reaction was allowed to stir under H2 at 1 atm overnight. Upon completion, the reaction vessel was purged of H2 and filtered over celite. The celite was washed several times with methanol until the filtrates were clear. The combined filtrates were concentrated to give N-(8-amino-6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide as a yellow solid (112 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.Cl.[NH2:13][OH:14]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[N:13][OH:14])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: NO
Reactant: Cn1nc(Cl)cc(C=O)c1=O
Agent: Cl
Solvent: CO
Solvent: O
Product: Cn1nc(Cl)cc(C=NO)c1=O
Temperature: 70 °C
Yield: 73.6 %

Procedure:
To a solution of 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde (2 g, 11.59 mmol, Preparation #30) in MeOH (30 mL) was added a solution of hydroxylamine hydrochloride (0.966 g, 13.91 mmol) in water (5 mL) and heated to about 70° C. for 1 h. The mixture was cooled to RT and solids obtained were collected by filtration to afford the 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde oxime 1.6 g, (73.6%) as an off white solid. 1H NMR (400 MHz, DMSO) δ 12.316 (s, 1H), 8.092 (s, 1H), 7.675 (s, 1H), 3.651 (s, 3H); MS m/z: 185.7 (M−H)−
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1C(O)=O>C1(C)C=CC=CC=1>[N:13]12[CH2:20][CH2:19][CH2:18][CH:14]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3CCCN3C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight with 5.8 g (50 mmol) of proline in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]#[N:13])=[CH:5][NH:6]2.[H-].[Na+].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>O1CCCC1>[CH3:16][N:17]([CH3:21])[C:18]([N:6]1[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:11][C:12]#[N:13])=[CH:5]1)=[O:19]
Reactant: N#CCc1c[nH]c2cccc(Cl)c12
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)n1cc(CC#N)c2c(Cl)cccc21
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of (4-chloro-1H-indol-3-yl)-acetonitrile (200 mg, 1.05 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) at 0° C. was added sodium hydride (63 mg, 1.57 mmol, 60% dispersion in mineral oil). After 20 minutes at 0° C., the ice bath was removed and dimethyl carbamyl chloride (0.12 mL, 1.26 mmol) was slowly added. After one hour, the reaction was partitioned between ethyl acetate (100 mL) and saturated sodium chloride solution (2.5 mL). The ethyl acetate extract was dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. The resulting material was purified by flash column chromatography over silica gel eluting with 40% ethyl acetate in hexane to give 4-Chloro-3-cyanomethyl-indole-1-carboxylic acid dimethylamide as a white solid (239 mg, 87%).