Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: NCc1ccc(F)cc1
Product: CC=CCn1c(C)c(C)c2cnnc(NCc3ccc(F)cc3)c21
Temperature: 180 °C

Procedure:
A solution of 0.35 g (0.0015 mole) of 1-(2-butenyl)-7-choro-2,3-dimethylpyrrolo[2,3-d]pyridazine dissolved in 3.5 ml of 4-fluorobenzylamine was heated at 180° C. for 2.5 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and then poured into ice-water. The aqueous mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 30:1 mixture of chloroform and methanol as an eluent to give 0.22 g of 1-(2-butenyl)-7-(4-fluorobenzylamino)-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=1/4) as a flesh-colored powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:4][CH:3]=1.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].N1C=CC=CC=1>ClCCl>[CH2:25]([O:24][C:22](=[O:23])[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:6][CH:7]=1)=[O:27])[CH3:26]
Reactant: CCc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(-c2c(CC)sc3ncnc(N)c23)cc1
Yield: 64.8 %

Procedure:
A solution of Example 78A (0.065 g, 0.25 mmol), ethyl chloro(oxo)acetate (0.028 mL, 0.25 mmol), and pyridine (0.02 mL, 0.25 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight and partitioned between water and dichloromethane. The organic extract was washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by silica gel column chromatography with 5% methanol/dichloromethane to provide 60 mg of the desired product. MS (ESI(+)) m/e 371(M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.15 (t, J=7.46 Hz, 3H); 1.34 (t, J=7.12 Hz, 3H); 2.64 (q, J=7.46 Hz, 2H); 4.34 (q, J=7.12 Hz, 2H); 7.41 (d, J=8.48 Hz, 2H); 7.93 (d, J=8.82 Hz, 2H); 8.27 (s, 1H); 11.00 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[C:10]1([S:16]([N:19]2[C:27]3[CH:26]=[C:25]([Sn:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=[C:23]([NH2:32])[C:22]=3[CH:21]=[N:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:32][C:23]2[CH:24]=[C:25]([Sn:28]([CH3:31])([CH3:30])[CH3:29])[CH:26]=[C:27]3[C:22]=2[CH:21]=[N:20][N:19]3[S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])=[O:8])[N:6]=1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: Cc1nc(C(=O)Cl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-1,3-thiazole-4-carbonyl chloride (350 mg) in DCM (4 ml) was added dropwise to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (300 mg) in DCM (15 ml) and pyridine (0.167 ml). The reaction was stirred at RT overnight. Saturated sodium bicarbonate (aq) (25 ml) was added and the reaction vigorously stirred for 15 min. The DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DCM and purified on a silica cartridge, preconditioned with cyclohexane, washing with cyclohexane followed by elution with ether. The ether was evaporated to give title compound, 373 mg.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O.Cl>CO.O>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22](/[CH:20]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:23][CH:24]=1
Reactant: CC(=O)c1cccnc1Nc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.7 %

Procedure:
A solution of 1-(2-phenylamino-pyridin-3-yl)-ethanone (2.13 g, 10.0 mmol) in methanol (42 mL, 0.24M) was treated with sodium methoxide (25% wt. solution methanol, 4.6 mL, 20.1 mmol) and methyl 4-formylbenzoate (2.04 g, 12.4 mmol). The reaction was stirred at 25° C. over 3 d. At this time, the reaction was diluted with water (100 mL), acidified with a 1N aqueous hydrochloric acid solution, and extracted with a 10% methanol/methylene chloride solution. The combined organics were dried over magnesium sulfate, filtered, rinsed with methylene chloride, and concentrated onto silica gel in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 80 g silica gel column, 20% ethyl acetate/hexanes) afforded 4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (3.43 g, 95%) as an orange solid.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7]1)(=[O:5])[CH3:4]>C(O)C.CCCCCC>[CH2:13]([NH:12][C:10]([C:6]1([C:3](=[O:5])[CH2:4][Br:1])[CH2:9][CH2:8][CH2:7]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)C1(C(=O)NCc2ccccc2)CCC1
Reactant: BrBr
Solvent: CCCCCC
Solvent: CCO
Product: O=C(CBr)C1(C(=O)NCc2ccccc2)CCC1
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
Bromine (0.593 mL, 11.51 mmol) was added dropwise to a 0° C. stirred solution of 1-acetyl-N-benzylcyclobutanecarboxamide (2.22 g, 9.60 mmol) in ethanol (35.5 mL). After 15 minutes, the ice bath was removed. The flask was sealed, and stirring was continued for 6.5 hrs. HPLC and LC/MS after 5 hrs indicated a complete or nearly complete reaction. The reaction was quenched by the addition of 25 mL of sat. aq NaHSO3 soluition. EtOAc was added (50 mL), the layers were separated, the aq layer was extracted with EtOAc (20 mL), the combined EtOAc layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give the crude product (2.80 g) as an oily yellow solid. The crude product was sonicated briefly in hexane. The ppt was collected by filtration, rinsed with hexane, and dried under vacuum to yield 2.33 g of the title compound as a pale yellow solid. LC/MS: m/e 312.08 (one of 2 Br-pattern peaks, M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>C(O)C>[F:1][C:2]([F:17])([F:16])/[C:3](/[C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:25]/[OH:26]
Reactant: CCOC(=O)c1cccc(C(=O)C(F)(F)F)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(/C(=N\O)C(F)(F)F)c1
Temperature: 57 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of ethyl 3-(2,2,2-trifluoroacetyl)benzoate (500 mg, 2.15 mmol) in ethanol was added pyridine (5 mL) and hydroxylamine hydrochloride (500 mg, 7.2 mmol) and the resulting mixture stirred at 57° C. for 3 hours. The reaction mixture was cooled and passed through an ion exchange column eluting with methanol (30 mL). The methanol solution was evaporated in vacuo to give (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate as an oil in 71% yield, 401 mg which was used in the next step without further purification. To a stirred solution of (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate (401 mg, 1.54 mmol) in dichloromethane (10 mL) was added DMAP (17 mg, 0.14 mmol) and the mixture cooled to 0° C. 4-methylbenzene-1-sulfonyl chloride (331 mg, 1.74 mmol) was added portion-wise as a solution in dichloromethane (5 mL). The reaction mixture was then left to stand at room temperature for 18 hours. The mixture was diluted with water (10 mL) and the organic layer separated, dried over magnesium sulfate and evaporated in vacuo to afford (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate as an oil in 78% yield, 500 mg. This material was used in the next step without further purification. A mixture of (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate (500 mg, 1.2 mmol) in diethylether (5 mL) in a 3-necked flask equipped with an internal thermometer and condenser was cooled to −78° C. Ammonia gas was introduced for 5 min and then stirring continued for 45 min. The reaction mixture was warmed to −33° C. and stirred for 2 hours after which it was allowed to warm to room temperature overnight with stirring.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.CS(O[CH2:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([N:36]([CH3:51])[C:37](=[O:50])[CH2:38][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])[C:30]=1[Cl:52])(=O)=O.O>CN(C)C=O>[Cl:52][C:30]1[C:31]([N:36]([CH3:51])[C:37](=[O:50])[CH2:38][N:39]2[C:40](=[O:49])[C:41]3=[CH:48][CH:47]=[CH:46][CH:45]=[C:42]3[C:43]2=[O:44])=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[CH2:28][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reactant: Cc1cc(OCc2ccccn2)c2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a suspension of sodium hydride (59.5 mg) in N,N-dimethylformamide (0.5 ml) was added a solution of 8-hydroxy-2-methyl-4-(2-pyridylmethoxy)quinoline (600 mg) in N,N-dimethylformamide (5 ml) in ice water bath under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same condition. To the mixture was dropwise added a solution of 2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyl methanesulfonate (1 g) in N,N-dimethylformamide (25 ml) in ice water bath under nitrogen atmosphere, and the mixture was stirred for 2 hours at the same temperature and for 1 day at ambient temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (772 mg) as amorphous powder.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:19]3[N:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:22][CH:21]=4)[CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([O:35]C)[CH:15]=4)[C:10]=3[CH:9]=[CH:8][C:7]=2[CH:37]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:19]3[N:18]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]5)=[CH:24][CH:25]=4)[CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([OH:35])[CH:15]=4)[C:10]=3[CH:9]=[CH:8][C:7]=2[CH:37]=1
Reactant: COc1ccc2c(c1)CN(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(OC)ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: Oc1ccc2c(c1)CN(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
A solution of the product of Example 13 (195 mg, 0.39 mmol) in methylene chloride (25 mL) was treated with ethanethiol (200 mg, 220 mL, 3.2 mmol) and aluminum chloride (320 mg, 2.4 mmol). After stirring for 4 h at ambient temperature, the mixture was quenched carefully with THF (25 mL) and saturated sodium bicarbonate (25 mL). The layers were separated, the aqueous layer was extracted with THF (25 mL), and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by radial chromatography (silica gel, 1:1 hexane:ethyl acetate, 10-20% methanol, under an ammonia atmosphere) to provide 110 mg (60%) of the title compound as a tan foam. An analytical sample was crystallized from methanol as a light red solid: 1H NMR (300 MHz, dimethylformamide-d7) d 9.92 (br s, 1H), 9.74 (br s, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.98 (dd, J=9.0, 2.1 Hz, 1H), 6.84 (dd, J=8.4, 2.1 Hz, 1H), 6.73 (m, 5H), 3.92 (t, J=5.9 Hz, 2H), 2.57 (t, J=5.9 Hz, 2H), 2.38 (m, 4H), 1.4-1.5 (m, 4H), 1.3-1.4 (m, 2H); IR (KBr) 3560, 3490 cm-1 ; MS (FD+) m/e 466 (M+); Anal. calc'd. for C30H30N2O3.0.5H2O: C, 75.75; H, 6.58; N, 5.89. Found: C, 75.32; H, 6.76; N, 5.95.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O-:14])=[O:13]>C(#N)C>[C:8]([C:7]1[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])(=[O:22])=[O:23])=[O:26])=[N:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH3:10])#[N:9]
Reactant: Cc1cc(C)c(C#N)c(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC#N
Product: Cc1cc(C)c(C#N)c(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 0.5 g (4.3 mmol) 2-amino-4,6-dimethyl-3-pyridinecarbonitrile [Archiv. Pharm., 288, 174 (1955)] in 20 ml of acetonitrile was added 1.3 g (5.7 mmol) o-nitrobenzenesulfonyl isocyanate. The mixture was then heated to reflux (80°) for four hours followed by stirring at ambient temperature overnight. A crystalline product was collected, 0.5 g, m.p. 174°-176° dec. An infrared spectrum (nujol mull) exhibited absorptions at 1700, 1720 and 2240 cm-1 ; and a proton magnetic resonance spectrum (90 MHz NMR) exhibited absorptions at 2.5 (s, 3H), 2.6 (s, 3H), 7.05 (s, H), 7.7 (s br, NH), 7.8 (m, 3H), 8.4 (m, 1H), 9.7 (s br, NH) ppm indicating the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:13][CH2:14]1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 135 °C
Reaction time: 8 h
Yield: 584.3 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (4.0 g, 2.3 mmol), morpholine (3.45 ml, 41 mmol) and anhydrous potassium carbonate (3.2 g, 23 mmol) in N,N-dimethylacetamide (40 ml) was stirred at 130-140° C. under nitrogen overnight. The reaction mixture was then cooled to room temperature, poured onto ice and allowed to stand for 2-3 h. The yellow-brown precipitate was collected by filtration to afford 5-morpholino-2-nitroaniline (3.0 g, 58%), mp 183-185° C. (lit. (8) mp 187.5° C.).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.NCCC1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[N:37]1[CH:38]=[CH:39][C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCc1ccncc1
Product: O=C(NCCc1ccncc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-(2-aminoethyl)pyridine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 364 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.25 (1H, s) 8.40-8.46 (2H, m) 8.21 (1H, t, J=5.54 Hz) 8.02 (1H, d, J=5.32 Hz) 7.77 (1H, d, J=5.47 Hz) 7.47 (1H, d, J=5.42 Hz) 7.32 (1H, dd, J=3.49, 2.56 Hz) 7.21-7.27 (2H, m) 6.81 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.49, 1.88 Hz) 3.47-3.55 (2H, m) 2.85 (2H, t, J=7.15 Hz)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH3:32][NH:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:32][N:33]([CH3:34])[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added dimethylamine hydrochloride (24.02 mg, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The reaction was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (21 mg, 19% yield). m.p.=99.2° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.04 (m, 3 H) 2.12-2.21 (m, 1 H) 2.43-2.49 (m, 4 H) 2.94 (s, 6 H) 3.14-3.23 (m, 4 H) 3.35-3.43 (m, 3 H) 3.54-3.64 (m, 1 H) 3.94-4.03 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.99 (d, J=1.77 Hz, 1 H) 7.29 (d, J=8.84 Hz, 2 H) 7.62 (d, J=1.52 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C24H30N6O2, 435; found, 435.
Reaction SMILES: C(O[C:4]1[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][N:9]=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]([NH:27][NH2:28])=O)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:32]([O:31][C:30]([NH:29][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:25]1[N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:5][C:4]2=[N:28][N:27]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC1=NCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NN)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(c1ccc(Cl)cc1)c1nnc2n1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
A solution of tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate (0.762 g, 3.34 mmol) and tert-butyl 1-(4-chlorophenyl)-2-hydrazinyl-2-oxoethylcarbamate (1.00 g, 3.34 mmol) in toluene (6.67 mL, 3.34 mmol) was heated to reflux and stirred at this temperature for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried and concentrated to give a residue that was purified by reverse phase chromatography (Biotage SP4, 40+M, C18, 10% to 100% ACN/H2O) to afford tert-butyl 3-((tert-butoxycarbonylamino)(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.92 g, 60%). LCMS (APCI+) M+H+: 463 (25%), 464 (90%), 466 (25%), 467 (5%); rt=3.56 minutes. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.12 (d, J=7.8 Hz, 1H), 5.87 (d, J=7.8 Hz, 1H), 4.84 (d, J=17.6 Hz, 1H), 4.75 (d, J=17.6 Hz, 1H), 3.93 (m, 1H), 3.80 (m, 1H), 3.73 (m, 1H), 3.49 (m, 1H), 1.47 (s, 9H), 1.41 (s, 9H).
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([C:5]1[N:6]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:28]=1)[CH3:4].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH2:3]([C:5]1[N:6]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:12][C:11]=3[N:10]=[C:9]([NH2:2])[C:8]=2[N:28]=1)[CH3:4]
Reactant: CCc1nc2c[n+]([O-])c3cc(OCC(=O)N4CCOCC4)ccc3c2n1CC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(OCC(=O)N4CCOCC4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ammonium hydroxide (0.5 mL) was added to a solution of 2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-5-oxido-1H-imidazo[4,5-c]quinoline (0.53 g, 1.28 mmol) in dichloromethane (3 mL), and the mixture was cooled to 0° C. p-Toluenesulfonyl chloride (0.29 g, 1.5 mmol) was added in small portions over a period of 20 minutes. The reaction was stirred at ambient temperature overnight. The reaction mixture was partitioned between dichloromethane and 1% aqueous sodium carbonate. The organic fraction was washed with 1% aqueous sodium carbonate (2×30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate, isolated by filtration, washed with cold hexanes, and dried under high vacuum at 55° C. to provide 0.391 g of 2-ethyl-1-(2-methylpropyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolin-4-amine as off-white needles, mp 219-220° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH:28]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29]1>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32]([CH:28]4[CH2:31][CH2:30][CH2:29]4)=[O:33])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: O=C(Cl)C1CCC1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C3CCC3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and cyclobutanecarbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.68 (t, J=7.33 Hz, 3H) 1.30 (qd, J=7.49, 7.33 Hz, 2H) 1.78-1.89 (m, 1H) 1.91-2.03 (m, 1H) 2.12-2.16 (m, 2H) 2.18-2.27 (m, 5H) 6.73 (s, 1H) 7.60-7.70 (m, 3H) 7.83-7.94 (m, 4H) 8.14 (d, J=8.08 Hz, 1H) 10.11 (s, 1H); ESI-MS: m/z calc'd for C26H26N4O2S 458.58. found 459.3 (M+H)+.