Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14][NH2:15]>>[CH3:14][NH:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CN
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Product: CCOC(=S)c1cnc(C)nc1NC
Yield: 88 %

Procedure:
Commercially available ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (9.70 g) was reacted with methylamine in a similar manner to the second stage in Step 1 of Reference Example 1. The reaction mixture was purified by silica gel chromatography (chloroform/methanol) to give ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate (8.37 g, yield 88%). Subsequently, the resulting compound was treated in a similar manner to Steps 1 and 2 of Reference Example 1 to give 4-methylamino-2-methylthiopyrimidine-5-carbohydrazide (5.78 g, yield 74%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][CH:7]2[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]2([CH3:16])[CH3:1])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC2CCN(C(=O)OC(C)(C)C)CC2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
tert-Butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (3.3 g, 14.53 mmol, 1 eq) and 4-methoxybenzylamine (3.98 g, 29.07 mmol, 2 eq) were dissolved in dichloromethane (40 ml), and stirring was carried out for 2 h at RT. The reaction mixture was cooled to 0° C., and Na(OAc)3BH (9.24 g, 43.61 mmol, 3 eq) was added in portions. Then stirring was carried out for 16 h at RT. The reaction mixture was diluted with dichloromethane (150 ml), washed with water and sat. NaCl solution (in each case 100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (Alox neutral, 10% ethyl acetate in hexane) (colourless oil). Yield: 38% (1.948 g, 5.59 mmol).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH3:21])[CH2:12][CH2:13][CH2:14][C:15]([O:18][CH2:19][CH3:20])([CH3:17])[CH3:16])(=O)=O)=CC=1.[OH:23][C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1>>[CH2:19]([O:18][C:15]([CH3:16])([CH3:17])[CH2:14][CH2:13][CH2:12][CH:11]([O:23][C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1)[CH3:21])[CH3:20]
Reactant: CCOC(C)(C)CCCC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc2c(c1)OCC2
Product: CCOC(C)(C)CCCC(C)Oc1ccc2c(c1)OCC2

Procedure:
5-ethoxy-1,5-dimethylhexyl p-toluenesulfonate and 6-hydroxy-2,3-dihydrobenzofuran are reacted to produce 6-[(5-ethoxy-1,5-dimethylhexyl)-oxy]-2,3-dihydrobenzofuran of boiling point (bulb-tube) 127° C./0.02 mmHg; nD24 = 1.5023.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>ClCCl>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([C:39](=[O:40])[CH2:38][O:37][C:34](=[O:36])[CH3:35])[CH2:14][C:5]=2[CH:4]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC(C)C)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.090 g, 0.23 mmol) and triethylamine (0.066 ml, 0.48 mmol) in dichloromethane (5 ml) was added acetoxy acetyl chloride (0.031 g, 0.25 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.073 g, 70%) as white solid. MS m/e: 461 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(-c3cccnc3)n2)cc(OC)c1OC
Yield: 52.2 %

Procedure:
Using Method C with 200 mg (0.68 mmol) 2a and 100 mg (0.82 mmol) 3-pyridylboronic acid, 120 mg (52.1%) pure title compound were obtained after purification of the whole batch by column chromatography (Kieselgel 60, 0.040-0.063; eluent: AcOEt:MeOH 1:1). Reaction time: 3 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 3.67 (s, 3H, CH3O(4′)), 3.85 (s, 6H, CH3O(3′+5′)), 7.26 (s, 2H, Harom(2+6)), 7.59 (m, 1H, Harom 5′), 8.25 (s, 1H, HP5), 8.49 (d, 1H, Harom 6′, J=7.90), 8.63 (s, 1H, HP3), 8.69 (d, 1H, Harom 4′, J=3.18), 9.51 (d, 1H, Harom 2′, J=2.21), 9.51 (s, 1H, NHamine); MS, (C18H18N4O3), m/z: 339.1 [M++1, 100].
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[Br:7][C:5]1[N:6]=[C:2]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Br:8]
Reactant: C1CNCCN1
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Product: C[Si](C)(C)CCOCn1c(N2CCNCC2)nc(Br)c1Br
Yield: 28.2 %

Procedure:
A mixture of 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (653 mg, 1.5 mmol) and piperazine (1.03 g, 12.0 mmol) under Ar was irradiated at 130° C. for 15 min in a microwave reactor. The reaction mixture was partitioned between DCM and water (100 mL, 1/1). The layers were separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The resulting was purified by flash chromatography (SiO2, 100:0-90:10 DCM-MeOH) to provide 186 mg of 1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperazine as a colorless oil:
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:19][NH:18][CH:17]([C:20]([NH:22][CH3:23])=[O:21])[CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.[Na].N>CO.ClCCl>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C@H:15]3[CH2:19][N:18]([CH3:1])[C@H:17]([C:20]([NH:22][CH3:23])=[O:21])[CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1
Reactant: CNC(=O)C1CC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1
Reactant: C=O
Agent: N
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)[C@@H]1C[C@@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
TFA (5 ml) was added to (2S,4R)-tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-2-(methylcarbamoyl)pyrrolidine-1-carboxylate under argon. The resulting solution was stirred at 25° C. for 1 hour. The solution was evaporated under reduced pressure, adsorbed with ammonia in methanol solution. The crude product was purified by flash chromatography on silica gel eluting with 1 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N-methyl-pyrrolidine-2-carboxamide (38 mg) as a pale yellow solid. 37% Aqueous formaldehyde (8.42 μl) at 0° C. was added to a stirred solution 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N-methyl-pyrrolidine-2-carboxamide (38 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) over a period of 5 minutes under argon. The resulting solution was stirred at 0° C. for 5 minutes. Sodium triacetoxyhydroborate (23.96 mg, 0.11 mmol) was added and the mixture was stirred 5 minutes at 25° C. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N,1-dimethyl-pyrrolidine-2-carboxamide (30 mg) after overnight stirring in acetonitrile as a solid. NMR Spectrum: (DMSOd6) 2.23-2.32 (m, 1H), 2.35 (s, 3H), 2.47-2.56 (m partially hidden by DMSOd5, 1H), 2.65 (d, 3H), 2.76-2.84 (m, 1H), 3.19-3.27 (m, 1H), 3.47-3.56 (m, 1H), 4.89-4.99 (m, 1H), 7.41-7.50 (m, 2H), 7.67 (bs, 2H), 7.77-7.82 (m, 1H), 7.83-7.87 (m, 1H), 7.90 (q, 1H), 7.97 (s, 1H), 8.37 (s, 1H), 8.44 (d, 1H), 8.53 (d, 1H) Mass spectrum: M+H+ 418
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Product: NS(=O)(=O)c1ccc(C=Nc2ccc(Cl)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-chloroaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 72%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[O:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34]([O:36][CH2:37]I)=[O:35])[CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:37][O:36][C:34]([O:33][CH:30]3[CH2:29][CH2:28][O:27][CH2:32][CH2:31]3)=[O:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: O=C(OCI)OC1CCOCC1
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)OC3CCOCC3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 90.7 %

Procedure:
In the same manner as in Example 81, 194 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 136 mg of (tetrahydropyran-4-yl)oxycarbonyloxymethyl iodide.
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][C:26](=[O:41])[N:27]2[C@H:30]2[C:39]3[C:34](=[C:35]([F:40])[CH:36]=[CH:37][CH:38]=3)[O:33][CH2:32][CH2:31]2)=[CH:23][N:22]=1>COC(OC)OC>[F:19][C:17]1[CH:16]=[CH:15][C:14]2[N:20]([C:21]3[N:29]=[C:28]4[C:24]([NH:25][C:26](=[O:41])[N:27]4[C@H:30]4[C:39]5[C:34](=[C:35]([F:40])[CH:36]=[CH:37][CH:38]=5)[O:33][CH2:32][CH2:31]4)=[CH:23][N:22]=3)[CH:1]=[N:12][C:13]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(F)ccc1Nc1ncc2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Solvent: COC(OC)OC
Product: O=c1[nH]c2cnc(-n3cnc4cc(F)ccc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A catalytic amount of p-TsOH was added to a solution of the above amine in trimethylorthoformate (2 mL). The mixture was stirred at RT for 15 hr then the solvents were reduced and the resultant material partitioned between DCM and brine and separated. The crude product was purified via column chromatography (eluted with 5% MeOH/DCM) to yield the titled compound (9 mg). 1H-NMR (300 MHz, CDCl3) δ 10.0 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.8 (dd, 1H), 7.4 (d, 1H), 7.1 (m, 2H), 6.8 (m, 2H), 5.9 (dd, 1H), 4.7 (m 1H), 4.4 (td, 1H), 2.9 (m, 1H), 2.4 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:23][CH2:24][CH2:25][N:26]1[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[NH:28][C:27]1=[O:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:31][C:30]1([CH3:32])[N:26]([CH2:25][CH2:24][NH:23][C:2]2[N:7]=[C:6]([C:8]3[S:9][C:10]([S:13]([C:16]4[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=4)(=[O:15])=[O:14])=[CH:11][CH:12]=3)[CH:5]=[CH:4][N:3]=2)[C:27](=[O:34])[NH:28][C:29]1=[O:33]
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: Cc1ccc(S(=O)(=O)c2ccc(-c3ccnc(Cl)n3)s2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)c2ccc(-c3ccnc(NCCN4C(=O)NC(=O)C4(C)C)n3)s2)cc1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A mixture of 2-chloro-4-(5-tosylthiophen-2-yl)pyrimidine (100 mg, 0.23 mmol), 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione (33 mg, 0.26 mmol) and triethylamine (28 mg, 0.27 mmol) in toluene (3 mL) was heated at 160° C. for 35 min in a Personal Chemistry microwave reactor. Upon cooling to rt the precipitate was filtered and washed with diethyl ether. The solid was put into 2 mL of methanol and the suspension was stirred for about 15 min and filtered to afford the title compound as pale yellow crystals (56 mg, 50%). MS (M+H)+ 486.
Reaction SMILES: C1(=O)[N:5]([C:6]2[C:11]([N:12]3C(=O)C4=CC=CC=C4C3=O)=[N:10][C:9]3=[N:23][S:24][N:25]=[C:8]3[N:7]=2)C(=O)C2=CC=CC=C12.NN>>[NH2:12][C:11]1[C:6]([NH2:5])=[N:7][C:8]2=[N:25][S:24][N:23]=[C:9]2[N:10]=1
Reactant: O=C1c2ccccc2C(=O)N1c1nc2nsnc2nc1N1C(=O)c2ccccc2C1=O
Agent: NN
Product: Nc1nc2nsnc2nc1N

Procedure:
The cyclization reaction of o-diaminobenzene (compound II) in an aqueous solution of glyoxal and sodium hydrogen sulfite gives quinoxaline (compound III; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). Quinoxaline is in turn oxidized by an aqueous solution of potassium permanganate to produce 2,3-pyrazinedicarboxylic acid (compound IV; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). 2,3-pyrazinedicarboxylic acid is then chlorinated with phosphorus pentachloride at 300° C. to produce 2,3,5,6-tetrachloropyrazine (compound V; See C. G. Allison et al., J. Chem. Soc. (C), 1970, page 1023). The reaction of 2,3,5,6-tetrachloropyrazine with ammonium chloride at a temperature of 120° C. gives 2,3-diamino-5,6-dichloropyrazine (compound VI; See Palamidess et al., Ed. Sc. XXI-fasc, 11, 1966, page 810). The cyclization reaction of 2,3-diamino-5,6-dichloropyrazine with thionyl chloride in the presence of pyridine in xylene produces 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VII; See Y. C. Tong, J. Heterocyclic Chem., 12, 1975, page 451 ) The 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine is reacted with potassium phthalimide in the presence of dimethyl formamide (DMF) at a temperature of 60° C. to produce 5,6-diphtalimido-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VIII; See Example 1). The 5,6-diphthalimido-[1,2,5]thiadiazolo[3,4-b]pyrazine is then reacted with an aqueous solution of hydrazine at 0° C. to produce 5,6-diamino-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound IX; See Example 2). Finally the cyclization reaction of 5,6-diamino[1,2,5]thiadiazolo[3,4-b]pyrazine with thionyl chloride in the presence of pyridine in methylene chloride gives bis[1,2,5]thiadiazolo[3,4-b: 3',4'-e]pyrazine (compound I; See Example 3).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)[NH2:4].[CH3:14]C1C2NC=NC=2C=C(C#N)C=1>>[OH:1][N:2]=[C:3]([C:5]1[CH:13]=[C:12]([CH3:14])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)[NH2:4]
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: Cc1cc(C#N)cc2nc[nH]c12
Product: Cc1cc(C(N)=NO)cc2nc[nH]c12

Procedure:
The title compound was prepared following the procedure described for Intermediate 1, step 2, but starting from 7-methyl-1H-benzimidazole-5-carbonitrile obtained in step 2 (900 mg; 5.73 mmol) as a beige solid (985 mg, 90%). 1H NMR (DMSO-d6) δ 12.60 (br s, 1H), 9.46 (s, 1H), 8.29-7.57 (m, 3H), 5.76 (s, 2H), 2.51 (m, 3H). LC/MS (Method B): 191.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:20])[C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[C:25]([CH:29]=[O:30])[CH:26]=[N:27][CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:30][CH2:29][C:25]1[CH:24]=[C:23]([C:7]2[C:6]([CH3:20])=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4]3)[CH:28]=[N:27][CH:26]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1c(-c2cncc(CO)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 1,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (85 mg, 0.30 mmol) was added (5-bromo-pyridin-3-yl)-methanal (CAS#37669-64-0, 61 mg, 0.33 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.370 mL, 0.74 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (135 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 7.5%). Further purification was accomplished via reverse phase HPLC (10 to 40% acetonitrile/Water w/0.1% NH4OH) to furnish 5-(5-hydroxymethyl-pyridin-3-yl)-1,4-dimethyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 269.1288 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H), 3.15 (s, 3H), 3.56 (s, 2H), 4.60 (s, 2H), 5.35 (br. s., 1H), 6.93 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.65 (t, J=2.1 Hz, 1H), 8.40 (d, J=2.3 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C.[NH2:61][CH2:62][CH2:63][N:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1>CN(C=O)C>[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49]([NH:61][CH2:62][CH2:63][N:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1)=[O:50]
Reactant: NCCN1CCCC1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCN2CCCC2)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
HATU (0.105 g, 0.28 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.097 g, 0.25 mmol) and Hünig's base (44 μL, 0.25 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 1-(2-Aminoethyl)-pyrrolidine (157 μL, 1.25 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo, the crude material added into water (10 mL) and the aqueous layer extracted into DCM. The product was purified by flash-column chromatography (DCM→10% ammonia/MeOH/DCM) to yield the title compound as off-white solid (0.051 g, 42% yield).
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].[Br:27][CH2:28][C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C>O>[Br:27][CH2:28][C:29]([NH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])=[O:30]
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(O)CBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CBr)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred slurry of 4.27 g. (10 mmole) of 6-(2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml. of water, at 0° C., is added 1.39 g. (10 mmole) of bromoacetic acid in 6 ml. of water. The pH is adjusted to 6.0, and then 1.9 g. (10 mmole) of 1-ethyl-3-(dimethylaminopropyl)-carbodimide hydrochloride in 9 ml. of water is added. The mixture is stirred for 3 hours at pH 6. At this point, the pH is raised to 7.0, and the reaction mixture is washed with ethyl acetate. The pH is then lowered to 2.0, and the product is extracted into ethyl acetate. The dried extracts are concentrated to dryness in vacuo to give 2.0 g. (40% yield) of the title compound, m.p. 128°-135° C. IR (KBr disc): 1800 cm-1 (β-lactam) and 1653 cm-1 (amide I). NMR (in DMSO-d6 /D2O): 7.43 ppm (s, 5H), 5.73 ppm (s, 1H), 5.63 ppm (m, 2H), 5.23 ppm (s, 1H), 4.02 ppm (s, 2H), 1.60 ppm (s, 3H), 1.00 ppm (s, 3H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.[C:13](CC(OC)=O)#N.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:12][C:5]1[CH:13]=[C:2]([OH:4])[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: COC(=O)CC#N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc(O)c2ccccc2n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 200 ml three neck flask, equipped as described previously was charged with 16.3 g isatoic anhydride, 9.9 g methyl cyanoacetate, 8.3 g anhydrous potassium carbonate (molecular weight 138.2), and 16 g DMF. The reaction mixture was agitated at 28° to 30° C. for 1 hr. There was a slow evolution of gas during this period. The temperature was then gradually raised to 90° C. over a period of 90 minutes and kept at 90° C. for an additional 15 minutes. The gas evolution, which became strong and steady at the elevated temperature, gradually came to a stop at the end of the heating period. The reaction mixture, while still hot, was then dissolved in a charge of 60 ml of water and transferred into a 300 ml autoclave; an additional 20 ml portion of water was used to wash the flask. A 12 g charge of sodium hydroxide (molecular weight 40) pellets was added: the autoclave was closed, and heated at 135° to 140° C. with constant agitation for four hours. The desired product was isolated as described in Example 1. The yield was 12.93 g pure 2,4-dihydroxyquinoline (m.p. 353°-355° C.), 80.23 percent of theory based on isatoic anhydride.