Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][C@@H:15]([CH3:18])[CH2:14][NH:13]1.C(=O)(O)[O-].[Na+]>C(O)CCCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][C@H:15]([CH3:18])[NH:16][CH2:17][C@@H:12]2[CH3:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@H]1CN[C@@H](C)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCO
Product: C[C@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1

Procedure:
A mixture of 4-fluoronitrobenzene (30.34 g, 0.22 mole), cis-2,5-dimethylpiperazine (25 g, 0.22 mole) and sodium bicarbonate (24 g, 0.28 mole) in n-pentanol (150 ml) was heated under nitrogen at 90°-100° for 18 hours. After filtration, the n-pentanol was removed under reduced pressure and the residue was partitioned between methylene chloride and water. The organic phase was separated, washed again with water, dried over magnesium sulphate, and concentrated under reduced pressure. The residue was triturated with ice water to yield a yellow solid. The solid was filtered off and dried to yield the title compound, m.p. 93°-4° (37 g, 71%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>C(#N)C.O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[N:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CCCNCCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CC#N
Solvent: O
Product: CCCN(CCC)c1ccc([N+](=O)[O-])cn1
Yield: 89.6 %

Procedure:
N,N-dipropylamine (3 ml, 22 mmol) was added to a solution of 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) in acetonitrile (7 ml) and heated to reflux overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was then washed with water, brine and dried. Evaporation to dryness gave (5-nitro-pyridin-2-yl)-dipropylamine (630 mg, 90%) as oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([N:16]=[N+]=[N-])[C@H:13]([N:19]2[C:23]3[N:24]=[C:25]([NH2:29])[NH:26][C:27](=[O:28])[C:22]=3[S:21][C:20]2=[O:30])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([NH2:16])[C@H:13]([N:19]2[C:23]3[N:24]=[C:25]([NH2:29])[NH:26][C:27](=[O:28])[C:22]=3[S:21][C:20]2=[O:30])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)C[C@H]2N)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of compound [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-azido-tetrahydrofuran-2-yl]methyl benzoate (compound 33b, 200 mg, 0.466 mmoL) and triphenylphosphine (364 mg, 1.39 mmoL) in THF (10 mL) was added water (0.5 mL) at room temperature. After being stirred at 80° C. for 1 hour, the reaction was filtered and the filtrate was concentrated in vacuo to afford 80 mg crude product of [(2S,4R,5R)-4-amino-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]methyl benzoate (compound 33c), which was used in next step directly. MS obsd. (ESI+) [(M+H)+]: 404.
Reaction SMILES: CC(C)(C)C([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15](=[O:33])[NH:16][C:17](=[O:32])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=3)[N:21]([CH3:31])[CH:20]=2)=[CH:6]1)=O.O(C)[Na]>CO>[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15](=[O:33])[NH:16][C:17](=[O:32])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=3)[N:21]([CH3:31])[CH:20]=2)=[CH:6]1
Reactant: Cn1cc(C2=C(c3cn(C(=O)C(C)(C)C)c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Agent: CO[Na]
Solvent: CO
Product: Cn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.7 g (3.61 mmol) of 3-[1-(2,2-dimethyl-propionyl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (4) from Step E above in 60 ml of methanol was treated with 5.6 ml (8.96 mmol) of a 1.6 molar solution of NaOCH3 in methanol. The reaction was stirred at room temperature for 1 hour, poured in 2N-HCl/ice and extracted with ethyl acetate. The organic extracts were dried on anhydrous MgSO4 and concentrated to yield, after chromatographic purification, 394.7 mg (28%) of 3-(1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (I) as a red solid mp>280° C. MS: (M+), m/z 386.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[SH-:14].[Na+]>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [SH-]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(S)cnn(C(C)(C)C)c1=O
Temperature: 0 °C
Yield: 96.7 %

Procedure:
To 75ml of ethanol were added 17.0 g (0.085 mol) of 2-tert.-butyl-5-chloro-4-methyl-3(2H)-pyridazinone and 8.5 g (0.106 mol) of 70% sodium hydrosulfide, and the mixture was stirred under reflux for 4 hours. After cooling, the mixture was poured into 300 ml of ice-water and extracted with 200 ml of ethyl ether. The ether layer was washed with 100 ml of water and dried over anhydrous sodium sulfate. The solvent was then distilled off therefrom to give 16.3 g of a crude product.
Reaction SMILES: COC1C=CC(C[N:8]([CH2:30][C:31]2[N:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[C:9]2[C:10](=[O:29])[N:11]([CH3:28])[N:12]=[C:13]([O:15][CH2:16][C@H:17]3[CH2:19][C@@H:18]3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:14]=2)=CC=1.C([O-])(O)=O.[Na+].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C@H:18]2[CH2:19][C@@H:17]2[CH2:16][O:15][C:13]2[CH:14]=[C:9]([NH:8][CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[C:10](=[O:29])[N:11]([CH3:28])[N:12]=2)=[N:21][CH:22]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: COc1ccc(CN(Cc2cn(C)nn2)c2cc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)nn(C)c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@H]2C[C@@H]2COc2cc(NCc3cn(C)nn3)c(=O)n(C)n2)nc1

Procedure:
A solution of 4-((4-methoxybenzyl)((1-methyl-1H-1,2,3-triazol-4-yl)methyl)amino)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (55 mg, 0.11 mmol) in TFA (2 mL) was stirred at room temperature for 2 h, then pH was adjusted to 7˜8 with saturated NaHCO3 solution. Extracted with EtOAc (20 mL*3), washed with H2O and brine, and concentrated. The residue was purified by Prep-HPLC (CH3CN in 0.05% TFA/H2O 30-95% v/v as mobile phase) to give title compound as a TFA salt, the structure was confirmed by NOE. ESI-MS: 398.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ 8.34 (d, 1H), 8.03 (dd, 1H), 7.86 (s, 1H), 7.80 (d, 1H), 5.88 (s, 1H), 4.47 (s, 2H), 4.30 (dd, 1H), 4.11 (dd, 1H), 4.06 (s, 3H), 4.01 (s, 3H), 3.62 (s, 3H), 2.36-2.32 (m, 1H), 2.01-1.96 (m, 1H), 1.41-1.41 (m, 2H).
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:18]([S:21](Cl)(=[O:23])=[O:22])[CH2:19][CH3:20].[OH-].[Na+]>CCN(C(C)C)C(C)C.C(Cl)Cl>[N:2]1([C:8]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][N:13]([S:21]([CH2:18][CH2:19][CH3:20])(=[O:23])=[O:22])[CH2:12][CH2:11]2)=[O:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: CCCS(=O)(=O)Cl
Reactant: N#CC1(C(=O)N2CCOCC2)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(C#N)(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(morpholin-4-ylcarbonyl)piperidine-4-carbonitrile hydrochloride (I-3) (10.40 g, 40 mmole) in DIEA-DCM (1:4, 200 mL) was added n-C3H7SO2Cl (6.28 g, 44 mmole) at 0° C. The resultant mixture was stirred for 1 h at 0° C. After this time, LCMS indicated that the reaction was complete. 2N NaOH (60 mL) was added to the reaction. The resultant reaction mixture was stirred for 1 h at rt. After this time, the DCM layer was separated. The aqueous solution was extracted with DCM (3×150 mL). The combined DCM solution was washed with brine, dried over MgSO4, filtered, and concentrated to afford the title compound (I-4) which was pure enough for next step reaction. Analytical LCMS: single peak (214 nm), 2.406 min.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N+:24]=4[O-:29])[S:22][C:15]=23)=[C:11]([F:32])[CH:10]=1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.[C:43]1([CH2:49][C:50]([N:52]=[C:53]=[S:54])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[F:32][C:11]1[CH:10]=[C:9]([NH:8][C:53]([NH:52][C:50](=[O:51])[CH2:49][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[S:54])[CH:31]=[CH:30][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N+:24]=3[O-:29])[S:22][C:15]=12
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc[n+]4[O-])sc23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cccc[n+]4[O-])sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A mixture of 432 (243 mg, 0.53 mmol) in 3:1 mixture of DCM/TFA (8 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resultant solid was dissolved in 1:1 mixture of EtOH/toluene (10 mL) and treated with 2-phenylacetyl isothiocyanate (140 mg, 0.8 mmol). The reaction mixture was stirred for 1 hour at room temperature and concentrated. The residue was purified by flash chromatography using the gradient 0-20% MeOH in EtOAc as an eluent yielding 430 (101 mg, 36% yield). MeOH-d4/CDCl3 (1:1) 8.5 (d, 1H, J=5.4 Hz), 8.38 (m, 3H), 8.0 (d, 1H, 11.9 Hz), 7.62 (t, 1H, J=7.7 Hz), 7.45 (m, 2H), 7.2-7.4 (m, 6H), 6.64 (5.1 Hz), 3.75 (s, 2H). LCMS: (M+H) 531.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:4]([NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][NH:14][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=[C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: CC(C)(C)CNc1cc(NCC(C)(C)C)nc(Cl)n1
Product: CC(C)(C)CNc1cc(NCC(C)(C)C)nc(N2CCNCC2)n1
Yield: 78.3 %

Procedure:
The reaction of 2-chloro-4,6-bis(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 4 leads to the title product in a yield of 78.3%, m.p.: 132°-136° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>C1COCC1>[CH3:11][O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1
Reactant: CC(=O)c1cc(CO)on1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COCc1cc(C(C)=O)no1
Temperature: 60 °C

Procedure:
To a solution of 1-[5-(hydroxymethyl)-1,2-oxazol-3-yl]ethanone (1.00 g, 7.09 mmol) in dry THF (20 mL) under an atmosphere of nitrogen was introduced cesium carbonate (2.31 g, 7.09 mmol) and methyl iodide (5.03 g, 35.43 mmol). The reaction mixture was warmed to 60° C. for 16 hr, cooled to RT and the solids removed by filtration. The filtrate was re-treated with additional cesium carbonate (4.31 g, 13.23 mmol) and methyl iodide (9.59 g, 67.58 mmol) and warmed to 60° C. for 34 hr. After cooling to RT, the reaction mixture was filtered, concentrated in vacuo and the residue re-dissolved in EtOAc (50 mL). The EtOAc solution was washed with water (25 mL), brine (25 mL), dried (Na2SO4) and filtered. After concentrating the filtrate in vacuo, the residual oil was purified by silica gel flash column chromatography (95:5-50:50 gradient of heptane/EtOAc) to furnish the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) delta 2.66 (3H, s), 3.44 (3H, s), 4.59 (2H, s), 6.64 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[O:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:4][CH:3]=1>C(O)=O.[Zn]>[CH:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]1[C:17](=[O:19])[C:18]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:10]([O:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:11]=[N:12][C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[O:25]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccnc3)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccnc3)cnc21
Temperature: 50 °C
Yield: 16.7 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (71 mg, 0.128 mmol) in HCOOH (3 mL) was added Zn dust (40.9 mg, 0.641 mmol). The reaction was heated at 50° C. for 2 h, cooled and filtered. The filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) (three times) to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(pyridin-3-yloxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (10.3 mg, 16.7% yield) as an oil. LCMS: MH+ 481 and TR=1.399 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:29])=[CH:26][CH:25]=1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C2c3c(C)c(NC(=O)c4ccc(F)cc4)c(C)c(C)c3OC2(C)C)cc1
Yield: 43 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 43%. Melting point: 148-120° C. (Ethyl acetate-hexane)
Reaction SMILES: C(O[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:10][C:9]=1[N+:25]([O-])=O)(=O)CC([O-])=O.Cl.[CH3:29][CH2:30][OH:31]>C(Cl)(Cl)Cl>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([C:11]2[CH:10]=[C:9]3[C:8]([CH2:29][C:30](=[O:31])[NH:25]3)=[CH:13][CH:12]=2)=[O:24])=[CH:20][CH:19]=1
Reactant: O=C([O-])CC(=O)Oc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
[2-Nitro-4-(4-nitrobenzoyl)phenyl] malonate (4.15 g, 9.61 mmol) was dissolved in EtOH (24 mL) after which Sn powder (9.16 g, 77 mmol) was added followed by dropwise addition of concentrated HCl(aq) (26 mL). The reaction mixture was allowed to reflux for 3 hours, filtered while hot and then allowed to cool to room temperature. The cooled reaction mixture was diluted with CHCl3 (400 mL) and then extracted once with H2O (400 mL). The aqueous layer was then neutralized with NaHCO3 (pH=7) and then extracted with a 95% EtOAc/5% i-prOH solution (3×400 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solution was then concentrated in vacuo affording the 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one in 51% yield (1.24 g, 4.90 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])#[N:19]>>[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])#[N:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(C#N)c4)nc23)CC1
Yield: 89.9 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.012 gm (0.072 mMol) 3-cyanobenzoyl chloride, 0.021 gm (92%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:46][C:47]1[CH:51]=[CH:50][N:49]([CH2:52][C:53]([CH3:56])([OH:55])[CH3:54])[N:48]=1>ClCCl>[OH:55][C:53]([CH3:56])([CH3:54])[CH2:52][N:49]1[CH:50]=[CH:51][C:47]([NH:46][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:2]=3[Cl:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:48]1
Reactant: COc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A solution of (S)-2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (200 mg, 0.57 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (96 mg, 0.62 mmol) and 1-hydroxybenzotriazole (80 mg, 0.60 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 105 mg, 0.68 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2-Chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (198 mg, 71%) as an off-white solid: LR-ES-MS m/z calculated for C24H31ClN4O5 [M]− 490, observed [M+H]+ 491; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.05 (s, 3H), 1.06 (s, 3H), 1.43 (br. s., 1H), 1.48-1.65 (m, 1H), 1.68-1.84 (m, 1H), 3.89 (br. s., 2H), 3.90 (s, 3H), 4.19 (d, J=18.6 Hz, 1H), 4.60 (d, J=18.6 Hz, 1H), 4.68 (s, 1H), 4.80 (s, 1H), 4.89 (dd, J=10.9, 4.8 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.09 (dd, J=8.5, 1.3 Hz, 1H), 7.13 (dd, J=8.5, 1.3 Hz, 1H), 7.41 (t, J=8.5 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[N:25]1([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:33]1[CH2:34][CH2:35][CH2:36][CH:31]([CH2:30][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:32]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1CNCC(CN2CCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCC(CN3CCCC3)C2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 3-(pyrrolidin-1-ylmethyl)piperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.05 minutes; C26H29Cl2N5O2 (514.45); mass spectrum: (M+H)+=514.2.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N=C=N.Cl.Cl.[NH:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][NH:26]/[C:25]/1=[N:34]\[C:35]([C:37]1[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=1)=[O:36].CN1CCOCC1>CN1C(=O)CCC1>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([N:31]3[CH2:32][CH2:33][C:28]4([NH:24]/[C:25](=[N:34]/[C:35]([C:37]5[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=5)=[O:36])/[NH:26][CH2:27]4)[CH2:29][CH2:30]3)=[O:17])=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2)cc1
Agent: Cl
Agent: N=C=N
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(Toluene-4-sulfonyl)-1H-pyrrole-3-carboxylic acid (0.023 g, 0.085 mmol) in NMP (850 l) is added to PS-carbodiimide (190 mg of 1.3 mmol/g loading, 0.24 mmol), followed by a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (0.08 mmol) and N-methyl morpholine (8 l, 0.08 mmol) in NMP (1 ml), and the resulting reaction mixture is shaken at room temperature. The reaction mixture is filtered and the resin is washed with NMP (1 ml). The collected filtrate is concentrated in vacuo and the residues are purified by mass-directed preparative HPLC. The purified fractions are evaporated under vacuum to afford the title compound; [M+H]+ 572.08
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:24][C:14]3=[N:15][C:16](Cl)=[C:17]([N+:20]([O-:22])=[O:21])[C:18](=[O:19])[N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:25]>C(O)C.CN(C)C=O>[NH2:25][C:16]1[N:15]=[C:14]2[S:24][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[N:12][N:13]2[C:18](=[O:19])[C:17]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(Cl)nc3s2)cc1
Reactant: N
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(N)nc3s2)cc1

Procedure:
1.9 g of 2-(4-tert-butylphenyl)-7-chloro-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in a mixture of 20 ml of ethanol and 10 ml of dimethylformamide, and 5 ml of concentrated aqueous ammonia was added dropwise to the suspension while maintaining at a temperature of 60° C. to 70° C. After heating at that temperature for 2 hours, the mixture was cooled and the precipitate formed was separated by filtration to obtain 1.3 g of 7-amino-2-(4-tert-butylphenyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as pale yellow prisms having a melting point higher than 300° C.