Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[CH:37]3)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].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.CO.C1(C)C=CC=CC=1.C1COCC1>[NH:39]1[C:40]2[C:36](=[CH:35][C:34]([C:2]3[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]4[NH:6][C:7]5[CH:8]=[C:9]([C:15]([N:17]6[CH2:18][CH2:19][O:20][CH2:21][CH2:22]6)=[O:16])[CH:10]=[CH:11][C:12]=5[C:13]=4[N:14]=3)=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(-c2ccc3[nH]ccc3c2)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 85 °C

Procedure:
2-Bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxamide (60 mg, 0.149 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (72.3 mg, 0.298 mmol), Potassium phosphate tribasic (134 mg, 0.476 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (24.43 mg, 0.060 mmol) and Pd(OAc)2 (6.68 mg, 0.030 mmol) were mixed with THF (2 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 85° C. in an oil bath for 3.5 hr. LC/MS showed there was trace amount of product formed. The reaction mixture was blown to dryness under N2 blower. To the mixture was added Pd(Ph3P)4 (34.4 mg, 0.030 mmol), Toluene (3 mL), MeOH (1.5 mL) and Na2CO3 (2M) (0.149 mL, 0.298 mmol). The mixture was then heated at 100° C. for 3 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 440.3 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.65 (s, 1H), 11.20 (s, 1H), 8.67 (s, 1H), 8.5 (m, 2H), 8.32 (d, 1H, J=8.2), 8.12 (d, 1H, J=8.5), 7.9 (s, 1H), 7.8 (s, 1H), 7.53(d, 1H, J=8.0), 7.41(m, 1H), 7.30 (d, 1H, J=8.0), 6.57 (s, 1H), 3.66 (bs, 8H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:21]1[CH:26]2[CH:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:28][CH:22]1[CH2:23][C:24](=O)[CH2:25]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:21]1[CH:26]2[CH:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:28][CH:22]1[CH2:23]/[C:24](=[CH:5]\[C:3]#[N:4])/[CH2:25]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC2CC(=O)CC1N2Cc1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CC2C/C(=C\C#N)CC1N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a suspension of NaH (6.98 g, 173 mmol) in tetrahydrofuran (460 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (18.5 mL, 103.8 mmol) in tetrahydrofuran (80 mL). The reaction was refluxed for 1 hour and then cooled at 0° C. again. To the reaction mixture was added a solution of compound 86a (26.0 g, 75 mol) in tetrahydrofuran (80 mL). The reaction was allowed to warm up to room temperature and stirred 2 hours. The reaction mixture was then quenched with saturated aqueous solution of NaHCO3, and most of the THF was removed under reduced pressure. Ethyl acetate (200 mL) was added, washed with water, brine, dried over Na2SO4 and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% EtOAc in hexanes, to give the desired product (2E)-2-[8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-ylidene]acetonitrile 86b (27 g, 98%). MS: calc'd (MH+) 369, measured (MH+) 369.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.FC1C=CC2[N:30](C(C=O)=C(C3C=CC(F)=CC=3)N=2)C=1.C(N1C=NC=N1)=C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[N:23]([CH:22]=[CH2:21])[N:30]=[CH:24][N:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Reactant: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Agent: C=Cn1cncn1
Product: C=Cn1ncnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 1-vinyl-1H-1,2,4-triazole. (55 mg, 36%). m/e+=338 (M+H+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[I:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[C:17]=1[CH:24]=O>CO>[N:1]1([C:6]2[CH:7]=[C:8]([CH3:14])[C:9]3[N:13]=[C:24]([C:17]4[C:18]([O:22][CH3:23])=[N:19][CH:20]=[CH:21][C:16]=4[I:15])[NH:12][C:10]=3[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc(-n2ccnc2)cc(N)c1N
Reactant: COc1nccc(I)c1C=O
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(-n3ccnc3)cc2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
To a solution of 5-imidazol-1-yl-3-methyl-benzene-1,2-diamine (175 mg, 0.93 mmol) in methanol (8 mL) was added a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (245 mg, 0.93 mmol) in methanol (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 h and then at room temperature for 2 h. After concentration, the residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to give the title compound (291 mg, 60%). 1H NMR (300 MHz, CD3OD) δ 8.13 (1H, s), 7.98 (1H, d, J=5.4 Hz), 7.62 (1H, d, J=5.4 Hz), 7.59 (2H, s), 7.33 (1H, s), 7.16 (1H, s), 3.90 (3H, s), 2.67 (3H, s). LCMS (M+H)+ m/z 432 (t=0.99 min.).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[O:28]>ClCCl>[OH:28][N:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:20])[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccccc1N=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1ccccc1N(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), 1-methyl-2-nitrosobenzene (121 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)(=[O:11])=[O:10])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.Cl.[NH:54]1[C:58]2([CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:57][NH:56]/[C:55]/1=[N:64]\[C:65]([C:67]1[C:72]([NH2:73])=[N:71][C:70]([NH2:74])=[C:69]([Cl:75])[N:68]=1)=[O:66]>CN(C=O)C.[OH-].[Na+]>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([N:61]1[CH2:62][CH2:63][C:58]2([NH:54]/[C:55](=[N:64]/[C:65]([C:67]3[C:72]([NH2:73])=[N:71][C:70]([NH2:74])=[C:69]([Cl:75])[N:68]=3)=[O:66])/[NH:56][CH2:57]2)[CH2:59][CH2:60]1)=[O:17])(=[O:10])=[O:11])([CH3:2])[CH3:3]
Reactant: CC(C)OCCCNS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)OCCCNS(=O)(=O)c1cccc(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(3-Isopropoxy-propylsulfamoyl)-benzoic acid (Intermediate V) (1.10 g, 3.65 mmol) in DMF (20 ml) is added HATU (1.53 g, 4.02 mmol) and N-methyl morpholine (1.204 ml, 10.95 mmol) and the solution is stirred at room temperature for 5 minutes. 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (1.60 g, 4.02 mmol) is added and the reaction stirred at room temperature for 45 minutes. The reaction mixture is diluted with 2N NaOH (150 ml) and the crude product extracted into EtOAc (2×250 ml). The organic phase is dried over MgSO4 and the solvent evaporated in vacuo to yield a yellow oil. Purification on a Waters preparative Delta 3000 HPLC using a gradient of water (+0.1% TFA) and acetonitrile yields a yellow oil. 2N NaOH is added to the oil and the product is extracted into EtOAc (2×400 ml). The organic phases are combined, dried over MgSO4 and the solvent concentrated in vacuo to a volume of approximately 150 ml. To this solution is added iso-hexane (400 ml) and a pale yellow solid precipitates. This solid is collected by filtration and rinsed with iso-hexane to afford the title compound; [M+H]+ 607.98; 1H Nmr (DMSO): 1.00 (6H, d, J=6.0 Hz), 1.55 (2H, m), 1.69-1.79 (4H, m), 2.81 (2H, t, 5.9 Hz), 3.29 (2H, tr, J=6.0 Hz), 3.42 (1H, m), 3.44 (2H, br), 3.29-3.82 (4H, m), 6.15-7.30 (3H, br), 7.66 (1H, d, J=7.4 Hz), 7.70 (1H, dd, J=7.4 Hz, J=7.4 Hz), 7.76 (1H, s), 7.86 (1H, d, J=7.4 Hz), 7.44-8.00 (1H, br), 8.00-9.05 (3H, br).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[CH2:14]([N:16]([CH2:19]C)[CH2:17][CH3:18])[CH3:15].N1CCCC1>O1CCCC1>[N:16]1([CH2:19][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[CH2:17][CH2:18][CH2:15][CH2:14]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: Cn1c(=O)c2c(ncn2CN2CCCC2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Equivalent amounts of theophylline and triethylamine were allowed to equilibrate with 2 equivalents of 37% aqueous H2C=O for a few minutes until a solution was obtained. Then, 2 equivalents of pyrrolidine was added and the mixture was diluted with tetrahydrofuran and allowed to stir at room temperature overnight. The solution was then concentrated in vacuo at <40°. The residue was triturated with ether and the suspension filtered. The residue from the suspension was dried to give the desired 7-(1-pyrrolidinyl)methyltheophylline in 72% yield; mp 105°-108°, lit mp 108° (J. Org. Chem. 24, 562 (1959); NMR, UV and TLC consistent with the desired product.
Reaction SMILES: [O:1]1[CH:5](NC(=O)NO)[CH2:4][C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.C[Si](N=C=[O:25])(C)C>C1COCC1>[O:1]1[CH2:5][C:4](=[O:25])[C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(NO)NC1Cc2ccc3ccccc3c2O1
Solvent: C1CCOC1
Product: O=C1COc2c1ccc1ccccc21
Temperature: 60 °C
Yield: 35 %

Procedure:
N-{3-(2,3-Dihydronaphtho[1,2-b]furyl}-N-hydroxyurea. To a solution of N-{3-(2,3-dihydronaphtho[1,2-b]furyl}-N-hydroxyamine (72 mg, 0.36 mmol) in THF (4 mL) was added trimethylsilylisocyanate (98 μL, 0.72 mmol). The resulting solution was heated at 60° C. for 1 h, then allowed to cool and concentrated under reduced pressure. The residue was dissolved in EtOAC and washed successively with H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was triturated with Et2O. The solid residue was purified by flash chromatography, eluting with 3% MeOH/CH2Cl2 and recrystallized from MeOH/CH2Cl2 to provide the title compound (31 mg, 35%). m.p. 191°-192° C.
Reaction SMILES: [NH:1]1[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O.[C:10]1([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[Na+].C1C=CC=CC=1.C(Cl)(Cl)Cl.CO>[C:10]1([CH2:16][CH2:17][CH2:18][C:19]([N:1]2[CH2:8][S:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: O=C(O)[C@@H]1CSCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: O=C(O)[C@@H]1CSCN1C(=O)CCCc1ccccc1
Yield: 81.9 %

Procedure:
6.65 g of L-thioproline was dissolved in 100 ml of 1N sodium hydroxide. After the addition of 50 ml of water to the solution, a solution prepared by dissolving 9.10 g of 4-phenylbutanoyl chloride in 50 ml of benzene was added dropwise with stirring. Subsequently, 50 ml of 1N sodium hydroxide was further added and the mixture was stirred overnight. The benzene layer was removed and the water layer was washed twice with 70 ml of ether. To this water layer was added 7% hydrochloric acid to acidify it, followed by extraction with 70 ml of ethyl acetate three times. The extract was dried over anhydrous sodium sulfate. Ethyl acetate was evaporated to obtain an oily residue, which was subjected to column chromatography on silica gel using chloroform-methanol as an eluent to obtain a fraction of 11.4 g of N-(4-phenylbutanoyl)-L-thioproline as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.N1C=CN=C1.Cl[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O>[Si:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=c1[nH]c2cc(O)ccc2o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a solution of 5-hydroxy-1,3-benzoxazol-2(3H)-one (Itoh, et al., J. Org. Chem. 2002 (67):7424-7428) (1.00 g, 6.6 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added imidazole (0.54 g, 7.9 mmol), followed by chloro-tert-butyldimethylsilane (1.10 g, 7.3 mmol). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0 to 50% gradient) to afford 5-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzoxazol-2(3H)-one (1.53 g, 87%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.04 (br s, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.60-6.53 (m, 2H), 0.98 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>CN(C=O)C.C(OCC)C>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)c1cccc(F)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A solution of 1,3-difluoro-2-nitrobenzen (5.0 g, 31.4 mmol) in 50 mL of dry DMF was added K2CO3 (4.41 g, 32 mmol) and diethyl malonate (3.6 mL, 31.4 mmol). The reaction mixture was heated to 65° C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with 2 N HCl and extrated with diethyl ether. The ether layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified via column chromatograph to afford diethyl (3-fluoro-2-nitrophenyl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ 7.50˜7.55 (m, 1H), 7.38˜7.40 (rn, 1H), 7.23˜7.28 (m, 1H), 4.82 (s, 1H), 3.77 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](C)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[C:3]2[C:10]([Cl:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1c[nH]c2ncnc(Cl)c12
Temperature: 43 °C
Yield: 81.8 %

Procedure:
Following the procedure in Pdulo, J. S.; Saxena, N. K.; Nassiri, M. R.; Turk, S. R.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 31:2086 (1988), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (Example 1A, 20. g, 0.13 mol) was suspended in anhydrous dichloromethane (500 mL), followed by addition of N-chlorosuccinimide (20.8 g, 0.160 mol). The reaction mixture was refluxed at 43° C. for 8 hours. The reaction was cooled down, and the white solid was filtered, washed with dichloromethane (300 mL), and dried to give 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine (20 g, 83%)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COc1ccccc1B(O)O
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
Methyl 4-bromo-3-methylbenzoate (ABCR, 4.90 g; 21.39 mmol; 1 eq.), 2-methoxyphenylboronic acid (3.575 g; 23.53 mmol; 1.10 eq.), potassium carbonate (14.781 mg; 107 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (2.5 mg; 2.14 mmol; 0.10 eq.) were mixed in toluene (24.5 mL) and water (24.5 mL) under N2 atmosphere. The reaction mixture was degassed with N2 for 10 min and was heated under reflux for 6 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (500 mL). The filtrate was concentrated under vacuum to afford brown oil. It was taken in EtOAc (500 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 (200 mL), water (200 mL) and brine (200 mL). It was dried over MgSO4, filtered off and concentrated under vacuum giving a brown oil. It was purified by flash chromatography (cHex/EtOAc 9:1), affording the title compound as a colorless oil (4.38 g, 80%). 1H NMR: (DMSO-d6, 300 MHz) δ 7.94 (s, 1H), 7.89-7.86 (dd, J=8.06 Hz, J=1.61 Hz, 1H), 7.51-7.46 (m, 1H), 7.34-7.31 (d, J=8.13 Hz, 1H), 7.21-7.09 (m, 3H), 3.95 (s, 3H), 3.79 (s, 3H), 2.19 (s, 3H). LC/MS (Method A): 257.0 (M+H)+. HPLC (Method A) Rt 4.85 min (Purity: 98.9%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCOC(C)=O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(Cl)c1N1CCCCC1
Temperature: 80 °C
Yield: 66 %

Procedure:
To a flask containing 2,3-dichloronitrobenzene (387 mg, 2.01 mmol) was added 3 mL of piperidine, and the result was heated to 80° C. overnight. The reaction was diluted with EtOAc (30 mL), washed with water (2×30 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative tlc (20% EtOAc-hexane) yielded 320 mg (66%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 7.56-7.50 (m, 2H), 7.04 (t, 1H, J=8.1 Hz), 3.04 (br s, 4H), 1.69 (br s, 4H), 1.59 (br s obscured by water, 2H).
Reaction SMILES: [C:1]([NH:18][C@@H:19]([C:23](O)=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].ON1C(=O)CCC1=O.C(N=C=NC(C)C)(C)C.[NH:43](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:44]([C:48]([O:50]N1C(=O)CCC1=O)=[O:49])[CH:45](C)C.N[C@@H](C(O)=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(COC)OC.C1COCC1.O>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([NH:18][C@H:19]([CH:20]([CH3:22])[CH3:21])[C:23]([NH:43][C@H:44]([CH3:45])[C:48]([OH:50])=[O:49])=[O:24])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Agent: CC(C)N=C=NC(C)C
Agent: C[C@@H](N)C(=O)O
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A flame dried flask was charged with Fmoc-D-Valine (200 mg, 0.59 mmol) and 5.9 mL anhydrous THF. N-hydroxysuccinimide (75 mg, 0.65 mmol) was added, followed by diisopropylcarbodiimide (0.1 mL, 0.65 mmol), and the reaction was stirred at an ambient temperature overnight, at which time LC-MS revealed conversion to product. The reaction mixture was diluted with CH2Cl2 and washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated to dryness. The material was carried forward without further purification. LC-MS: tR 13.89 min, m/z (ES+) found 437.0 (M+H)+. Crude Fmoc-D-Val-OSu (0.59 mmol) was dissolved in dimethoxyethane (1.5 mL) and THF (0.8 mL). D-alanine (73 mg, 0.89 mmol) was dissolved in 2.3 mL water and added to the reaction mixture, followed by sodium bicarbonate (99 mg, 1.2 mmol). The resulting slurry was stirred at room temperature overnight, at which time the reaction had clarified and LC-MS revealed completion. The reaction was poured into 50 mL CH2Cl2 and the organic layer was washed with 50 mL 0.1 M HCl and then brine, dried over sodium sulfate, and then concentrated to dryness. The crude product was purified by radial chromatography on a 1 mm chromatotron plate eluted with CH2Cl2 to provide 60 (128 mg, 54%). TLC: Rf=0.18, 10% MeOH in CH2Cl2. Analytical HPLC (0.1% formic acid): tR 9.47 min. LC-MS: tR 13.09 min, m/z (ES+) found 411.1 (M+H)+, m/z (ES−) found 409.2 (M−H)−.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28]CC)=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7])(=O)C.[OH-].[Na+].Cl>C(O)C.[Cl-].[Na+].O>[OH:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(NC(=O)COC(C)=O)c3)cs2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(CO)Nc1cccc(-c2csc(Cn3cc(C(=O)O)cn3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution (4 mL) of the compound (270 mg, 0.63 mmol) obtained in Example 45a in ethanol was added 2N aqueous sodium hydroxide solution (1.7 mL, 3.4 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (tetrahydrofuran-ethyl acetate-hexane) to give the title compound (110 mg, 33%) as colorless crystals.