Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1([C:5]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH3:15])[N:6]=2)[CH2:4][CH2:3]1.[Cl:16]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:16][C:9]1[C:5]([C:2]2([Cl:1])[CH2:4][CH2:3]2)=[N:6][N:7]([CH3:15])[C:8]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(C2(Cl)CC2)nn1C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c(C2(Cl)CC2)nn1C
Temperature: 80 °C

Procedure:
500 mg (2.19 mmol) of ethyl 3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate are dissolved in 10 ml of N,N-dimethylformamide p.a., and 438 mg (3.28 mmol)) of N-chlorosuccinimide are added. The reaction mixture is heated at 80° C. for 15. The cooled reaction solution is diluted with water and extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. The crude product is filtered through silica gel and eluted with ethyl acetate. This gives 517 mg (80%) of ethyl 4-chloro-3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate in a purity of 89%.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH3:4][C@@H:5]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=[O:7]>>[C:13]([O:12][C:10]([NH:9][C@@H:5]([C:6]([O:8][CH2:1][CH3:2])=[O:7])[CH3:4])=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCI
Product: CCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Yield: 48.8 %

Procedure:
The title compound was prepared by the method of Example 8 using ethyl iodide (2.4 mL, 30 mmol) instead of methyl iodide and BOC-D-Ala--OH (5.0 g, 26.4 mmol) instead of the product of Example 1. Concentration afforded the title compound (2.8 g) as a pale yellow oil and the structure verified by NMR.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:13]=1[N+:19]([O-:21])=[O:20].O>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[C:13]=1[N+:19]([O-:21])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1c(F)cccc1OCc1ccccc1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a suspension of sodium hydride (1.522 g, 38.06 mmol) in anhydrous DMF (150 mL) at room temperature was added benzyl alcohol (3.44 mL, 33.3 mmol) dropwise over 10 minutes, and stirring was continued for another 10 minutes. 2,6-Difluoronitrobenzene (5.046 g, 31.72 mmol) was added to the reaction mixture in one portion. The reaction mixture was stirred for an hour, and 100 mL water and 100 mL ethyl acetate were added. The layers were separated, and the aqueous layer was extracted with 75 mL ethyl acetate. The combined organic layers were washed with 100 mL water and 100 mL brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (6% to 35% ethyl acetate in hexanes) to give 6.818 g (27.6 mmol, 87%) of 1-benzyloxy-3-fluoro-2-nitro-benzene as a yellow oil. MS: 248 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42]1([C:45](Cl)=[O:46])[CH2:44][CH2:43]1.O>C(OCC)(=O)C>[CH:42]1([C:45]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])=[O:46])[CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(NC(=O)C3CC3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
4-Amino-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0940 g, 0.204 mmol) was dissolved in ethyl acetate (4.0 mL), and the solution was added with triethylamine (0.0570 mL, 0.408 mmol) and cyclopropanecarbonyl chloride (0.0280 mL, 0.306 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=85/15) to obtain 4-cyclopropylcarbonylamino-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0280 g, yield 26%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH2:12][CH2:11][NH2:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: NCCN
Product: NCCNc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 1-chloro-4-nitro-benzene (10 g, 64 mmol) and ethane-1,2-diamine (38 mL) was heated at reflux for 4 h. Excess ethane-1,2-diamine was evaporated under reduced pressure and water was added to the residue. The precipitated solid was filtered off and dried under vacuum to afford N*1*-(4-nitro-phenyl)-ethane-1,2-diamine (10.8 g, quantitative).
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH:21][C:22]([NH2:24])=[S:23]>>[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH:21][C:22]1[S:23][CH:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[C:3](=[O:5])[N:24]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: NC(=S)NC1CC2CCC1C2
Product: O=C1N=C(NC2CC3CCC2C3)SC1Cc1ccc(O)cc1

Procedure:
Synthesis was performed from (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid and N-bicyclo[2.2.1]hept-2-ylthiourea according to Method E and C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:16]=2[C:17]([NH:19][CH2:20][C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N+:34]([C:31]1[CH:32]=[CH:33][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:16]([CH:30]=1)[C:17]([NH:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1)=[O:18])([O-:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a solution of 2-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(469 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (1.07 g), and the mixture was stirred for 4 hours at ambient temperature. The reaction mixture was washed with 1N-sodium hydroxide solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (335 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([N:15]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CCNC(=O)CCNC1CCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)CCN(c1nc(Cl)ncc1Br)C1CCCC1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (Aldrich; 1.825 g, 8.00 mmol), 3-(cyclopentylamino)-N-ethyl-propanamide (Intermediate 141; 1.48 g, 8.00 mmol) and triethylamine (1.2 mL, 8.16 mmol) were combined in acetonitrile (50 mL) and heated at 100° C. for 4 hours. The solvent was removed under reduced pressure and the residue taken up in Ethyl Acetate, washed with water and purified by flash silica chromatography (companion, 40 g, 0-10% Methanol/DCM) to give the title compound as a brown oil, (2.14 g, 71%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[CH:43]=[CH:42][NH:41][C:38]3=[N:39][CH:40]=2)O1>C([O-])([O-])=O.[Na+].[Na+].C(#N)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>[O:15]1[CH2:16][CH2:17][N:12]([C:4]2[C:5]3[S:10][C:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:8][C:6]=3[N:7]=[C:2]([C:35]3[CH:36]=[C:37]4[CH:43]=[CH:42][NH:41][C:38]4=[N:39][CH:40]=3)[N:3]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(-c2cc3nc(-c4cnc5[nH]ccc5c4)nc(N4CCOCC4)c3s2)cc1
Temperature: 150 °C

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 from Example 12 (0.2 g, 0.6 mmol), phenylboronic acid (70 mg, 0.6 mmol), and bis(triphenylphosphine)palladium(II) dichloride (20 mg, 30 μmol) in 1 M aqueous Na2CO3 (1 mL) and acetonitrile (1 mL) were heated to 100° C. in a sealed microwave reactor for 10 min. Upon completion, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (210 mg, 0.87 mmol) and bis(triphenylphosphine)palladium(II) dichloride (20 mg, 30 μmol) were added and the mixture was heated to 150° C. in a sealed microwave reactor for 20 min. The mixture was extracted with EtOAc and CH2Cl2. The combined organics were concentrated to yield 419 after reverse phase HPLC purification (45 mg). MS (Q1) 414 (M)+
Reaction SMILES: [Cl:1][C:2]([O:4][CH:5](Cl)[CH3:6])=O.CO[CH:10]1[C:16]2[CH:17]=CC=[CH:20][C:15]=2[CH2:14][CH2:13][N:12](C)[CH2:11]1>ClCCCl>[ClH:1].[CH3:2][O:4][C:5]1[CH:6]=[CH:17][C:16]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]=2[CH:20]=1
Reactant: COC1CN(C)CCc2ccccc21
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COc1ccc2c(c1)CCNCC2
Product: Cl
Reaction time: 16 h
Yield: 179 %

Procedure:
The reactions are set up in a 22 L flask, each equipped with a mechanical stirrer, heating mantle, condenser and nitrogen bubbler. Add 1-chloroethyl chloroformate (620 mL, 5.750 mol, 10.0 eq) over 1 hour to methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (110 g, 575 mmol, 1.0 eq) dissolved in 1,2-dichloroethane (8.0 L) at 60° C. under nitrogen, in a 22 L flask. The solution turns dark purple over the next 2 hours. Heat the mixture to reflux and stir for 16 hours under nitrogen. The reaction is determined to be complete by TLC. Cool the reaction flask and concentrate under vacuum to an oil. Dissolve the oil in methanol (4 L) and add to a 22 L reaction flask and stir for 16 hours at room temperature under nitrogen. Concentrate the resulting solution under vacuum to an off-white solid 220 g, 90% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][N:5]2[C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH2:37][CH2:38][C:39]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42].C(N(CC)CC)C>CN(C=O)C>[F:49][C:46]1[CH:47]=[CH:48][C:39]([CH2:38][NH:37][C:19]([C:3]2[C:2]([OH:1])=[C:6]3[C:7](=[O:18])[N:8]([CH3:17])[CH2:9][C@H:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:5]3[N:4]=2)=[O:21])=[C:40]([CH:45]=1)[C:41]([O:43][CH3:44])=[O:42]
Reactant: CN1C[C@H](c2ccccc2)n2nc(C(=O)O)c(O)c2C1=O
Reactant: COC(=O)c1cc(F)ccc1CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(F)ccc1CNC(=O)c1nn2c(c1O)C(=O)N(C)C[C@@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (7S)-3-hydroxy-5-methyl-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (246 mg, 0.856 mmol) in DMF (3 mL) were added HOAT (175 mg, 1.28 mmol), and EDC (246 mg, 1.28 mmol). The reaction mixture was stirred at ambient temperature 15 minutes then methyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (226 mg, 1.03 mmol) and triethylamine (0.13 g, 1.28 mmol) were added. The reaction was stirred at ambient temperature overnight. The solvent was removed in vacuo, and the resulting residue was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the product as a light pink solid. 1H NMR (400 MHz, d6-DMSO) δ 9.60 (bs, 1H), 8.60 (t, J=6.2 Hz, 1H), 7.61 (dd, J=9.5, 2.3 Hz, 1H), 7.45 (m, 2H), 7.36 (m, 3H), 7.04 (d, J=7.1 Hz, 2H), 5.75 (t, J=4.0 Hz, 1H), 4.68 (ABX, J=15.8, 6.2 Hz, 2H), 4.18 (dd, J=13.4, 4.5 Hz, 1H), 3.86 (s, 3H), 3.81 (dd, J=13.4, 4.0 Hz, 1H), 2.88 (s, 3H); ES MS (M+1)-453.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].O.[NH3:14]>C(O)C>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([OH:10])[CH2:11][NH2:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CO1
Reactant: N
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@@H](O)CN
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(R)-1-Oxiranylmethylcarbamic acid tert-butyl ester (2.26 g, 13.05 mmol) obtained in Step 2 above was dissolved in ethanol (15 ml), and then 28% ammonia water (6 ml) was added thereto at room temperature. After the solution was stirred at room temperature for 1.5 hour, the solvent was distilled off under reduced pressure. After the resulting residue was dissolved in methanol, the solvent was distilled off under reduced pressure to give a crude product of ((S)-3-amino-2-hydroxypropyl)carbamic acid tert-butyl ester (2.38 g) as a yellow oily material.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:34][CH:33]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (483 mg) in DMF (5 mL) was added potassium carbonate powder (744 mg) and 4-methylsulphonylbenzyl bromide (1.68 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40%-75% EtOAc/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)=[N:6][C:7]=1[C:8]([NH:10][CH2:11][CH3:12])=[O:9].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[N:6][C:5]([C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([NH:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:18])[CH:14]=2)=[CH:4][N:3]=1
Reactant: NCc1ccccc1
Reactant: CCNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1nc(-c2cccc(C(=O)NCc3ccccc3)c2)cnc1N
Reaction time: 18 h
Yield: 42 %

Procedure:
Methyl 3-{5-amino-6-[(ethylamino)carbonyl]pyrazin-2-yl}benzoate (480 mg, 1.6 mmol) was suspended in a 20 mL of 1:1 MeOH-5% aqueous sodium hydroxide and heated at 90-95° C. for 4 hours. The homogeneous reaction mixture was cooled to room temperature, concentrated to half the initial volume, cooled in an ice-bath, and acidified to pH of 4 with concentrated HCl. A white solid precipitated and was collected, washed with water and dried in vacuo to give 3-{5-amino-6-[(ethylamino)carbonyl]pyrazin-2-yl}benzoic acid (445 mg, 97% yield). The pyrazine acid (40 mg, 0.14 mmol) was dissolved in DMF (1 mL), and then 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol), and 4-methylmorpholine (30 mg, 0.28 mol) were added sequentially. After one hour benzylamine (30 mg, 0.27 mmol) was added to the reaction mixture and stirring was continued at room temperature for 18 hours. The mixture was then diluted with ethyl acetate (10 mL), washed with water, saturated sodium bicarbonate solution then brine and dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give 3-amino-N-ethyl-6-(3-{[(phenylmethyl)amino]carbonyl}phenyl)pyrazine-2-carboxamide (a tan color solid, 22 mg, 42% yield): 1H NMR (400 MHz, DMSO-d6): 9.14 (s, 1H), 8.88 (s, 1H), 8.87-8.85 (b, 1H), 8.51 (s, 1H), 8.37-8.34 (d, 1H), 7.87-7.85 (d, 1H), 7.63-7.59 (b, 1H), 7.58-7.54 (t, 1), 7.34-7.23 (m, 4H), 4.53-4.52 (d, 2H), 3.38-3.29 (m, 2H), 1.171.14 (t, 3H); MS (EI) for C21H21N5O2: 376 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](NCCCCCC(O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:22]([CH2:25]C)[CH2:23][CH3:24])C.C[N:28](C)[CH2:29][CH2:30]Cl>C(OCC)(=O)C>[CH3:25][N:22]([CH3:20])[CH2:23][CH2:24][O:10][C:9](=[O:8])[CH:29]([NH2:28])[CH2:30][CH2:1][CH2:2][CH2:3][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CCN(CC)CC
Reactant: CN(C)CCCl
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)CCOC(=O)C(N)CCCCC(=O)OCc1ccccc1

Procedure:
A solution of N-benzyloxycarbonyl-6-aminocaproic acid, (2.65 g, 0.010 mole) in ethyl acetate (60 ml) was treated with triethylamine (2.8 ml, 0.020 mole) and 1.48M β-dimethylaminoethyl chloride (17 ml, 0.025 mole) and refluxed for 16 hrs. The reaction mixture was filtered and the filtrate extracted with saturated NaCl (3 × 50 ml), 5% NaHCO3 (3 × 50 ml), saturated NaCl (3 × 50 ml), dried over MgSO4, filtered and evaporated to dryness. The product was obtained as a viscous oil, 1.55 g (46.1%).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][C:6](=[NH:8])[NH2:7].C[O-].[Na+].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:28](OC)=[O:29])=[CH:22][CH:21]=1)#[N:13]>CO>[CH2:33]([C:32]1[N:8]=[C:6]([CH2:5][CH2:4][O:3][CH3:2])[NH:7][C:28](=[O:29])[C:27]=1[CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:15]2[C:14]([C:12]#[N:13])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:25][CH:24]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: COCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(CCOC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 43.5 %

Procedure:
A solution of 3-methoxypropanimidamide hydrochloride (4.0 g), 28% sodium methoxide (8.7 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (5.0 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (2.5 g, 44%) as a pale-yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1>N1CCCCC1.C(O)C>[O:16]=[C:10]1[C:9](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:22]=2[CH2:21][CH2:20][NH:19][C:18]3=[O:17])[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 27.6 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (79 mg, 0.36 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (50 mg, 0.3 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol followed by 0.1% of acetic acid in water and dried to give 30 mg (23%) of the title compound.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[Cl:13][CH2:14][S:15](Cl)(=[O:17])=[O:16]>C(OCC)C.C(OCC)(=O)C>[C:1]([NH:5][S:15]([CH2:14][Cl:13])(=[O:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CC(C)(C)NS(=O)(=O)CCl
Reaction time: 5 h
Yield: 64.3 %

Procedure:
At 0° C., to a mixture of tert-butylamine (10.3 g, 141 mmol) and N-methylmorpholine (14.9 g, 147 mmol) in diethyl ether (200 mL) was added dropwise a solution of chloromethanesulfonyl chloride (20 g, 134 mmol) in diethyl ether (400 mL). After stirred for 5 h, the solution was diluted with ethyl acetate (200 mL). The organic phase was washed with HCl solution (1 N), water and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a colorless oil (16 g).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21]COC)=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:25][CH3:26])[C:9]=3[C:8]2=[O:27])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:25][CH3:26])[C:9]=3[C:8]2=[O:27])=[CH:28][CH:29]=1
Reactant: COCOc1c2c(c(OC)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Crude diether 8 (0.0223 g, 0.0527 mmol) was dissolved in 1 mL dichloromethane. Ten equivalents of trifluoroacetic acid was added. The mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated and azeotroped with toluene (2×) to give crude 7-(4-fluoro-benzyl)-9-hydroxy-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione 9 which was triturated with 8 mL of 1:1 diethylether/hexane and filtered to give 9 (0.0161 g, 0.0456 mmol, 83% for two steps). 1H NMR (CDCl3) δ 9.0 (br s, 1 H), 8.7 (d, 1 H), 7.7 (d, 1H), 7.5 (m, 2 H), 7.0 (t, 2 H), 4.8 (s, 2H), 4.4 (s, 3H). (M+1).