Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S+:13]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Pb+2].[F:41][C:42]([F:49])([F:48])[CH2:43][S:44]([OH:47])(=[O:46])=[O:45]>CO>[F:41][C:42]([F:49])([F:48])[CH2:43][S:44]([O-:47])(=[O:46])=[O:45].[C:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S+:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: O=S(=O)(O)CC(F)(F)F
Agent: CC(C)(C)Oc1ccc([S+](c2ccc(OC(C)(C)C)cc2)c2ccc(OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Product: O=S(=O)([O-])CC(F)(F)F
Temperature: 50 °C

Procedure:
In 93 g of methanol was dissolved 9.3 g (0.018 mol) of tris(4-tert-butoxyphenyl)sulfonium chloride. 3.5 g (0.013 mol) of lead carbonate and 3.6 g (0.022 mol) of 2,2,2-trifluoroethanesulfonic acid were added to the solution, which was heated at 50° C. After cooling, the precipitate was filtered off and the filtrate was evaporated. 100 g of chloroform was added to the residue, the solution was washed with 100 g of water, and the solution was evaporated again, obtaining 8.2 g (two-steps yield 25%) of tris(4-tert-butoxyphenyl)sulfonium 2,2,2-trifluoroethanesulfonate with 97% purity.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[O:26][C:27]([CH3:30])=[N:28][N:29]=1)=[CH:14][CH:13]=2)(C)(C)C.C(OC(=O)C)C.Cl>C(=O)([O-])O.[Na+]>[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[O:26][C:27]([CH3:30])=[N:28][N:29]=1)=[CH:14][CH:13]=2
Reactant: Cc1nnc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.1 %

Procedure:
A mixture of tert-butyl[2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.20 g, 0.41 mmol) and 4N hydrogen chloride ethyl acetate solution (4 mL) was stirred for 17 h at room temperature. The reaction mixture was concentrated, the residue was washed with diisopropyl ether (5 mL×2) to give a pale yellow powder. The powder was added to aqueous saturated sodium hydrogencarbonate (30 mL), the resulting mixture was extracted with ethyl acetate-tetrahydrofuran (1:1, v/v, 50 mL×2). The organic layers were combined, washed with brine (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1 (v/v)) and recrystallized from n-hexane-ethyl acetate to give 3-(aminomethyl)-2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-phenyl-1(2H)-isoquinolinone (0.11 g, 72%) as pale yellow crystals.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])C=C.C1([SiH3])C=CC=CC=1.C(O)(=O)C>C(Cl)Cl.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>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)[S:13][C:9]=1[C:5]1[NH:6][CH:7]=[CH:8][N:4]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(C)c2)cc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(-c2cc(-c3ccc(Cl)cc3Cl)c(-c3ncc[nH]3)s2)ccn1
Temperature: 40 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
To a solution of 4-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-2-methylpyridine (115 mg, 0.26 mmol) in DCM (10.0 mL) was added phenylsilane (0.16 mL, 1.28 mmol), acetic acid (0.66 mL, 11.5 mmol), and tetrakis(triphenylphosphine)palladium (14.8 mg, 0.01 mmol) at room temperature then the mixture was stirred for 2 h at 40° C. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residual acetic acid was quenched by addition of saturated NaHCO3 (50 mL). The mixture was extracted with DCM (3×70 mL), and the combined DCM layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 3-5% MeOH in DCM) to give crude product which was further purified by column chromatography (SiO2, elution with 100% EtOAc) to provide 51 mg of product (49% yield). LC/MS (FA) ES+ 388. 1H NMR (400 MHz, d6 DMSO) δ: 11.7 (br s, 1H), 8.46 (d, J=5.3 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.57 (br s, 1H), 7.46-7.50 (m, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.10 (br s, 1H), 6.95 (br s, 1H), 2.49 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:18][C:5]1[C:6]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[C:8]#[N:9]
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1cncc(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#Cc1c(F)ccc(N)c1Nc1cncc(F)c1
Yield: 61.5 %

Procedure:
(6-Fluoro-2-(5-fluoropyridin-3-ylamino)-3-nitrobenzonitrile (1.73 g, 6.26 mmol), iron powder (712 mg, 12.5 mmol), and ammonium chloride (966 mg, 18.8 mmol) in methanol (40 mL) and water (12 mL) were heated at 90° C. for 1 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as brown solid (948 mg, 61%). 1H NMR 400 MHz δ (CDCl3): 8.05 (1H, d, J=2.4 Hz), 8.03-7.99 (1H, m), 7.01 (1H, d, J=2.1 Hz), 6.99 (1H, s), 6.59 (1H, dt, J=10.2, 2.4 Hz), 5.78 (1H, br s), 3.84 (2H, br s).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[N:7](C)[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].N([O-])=[O:18].[Na+].NC(N)=O>O>[F:16][C:5]1[CH:4]=[CH:3][C:2]([OH:18])=[CH:15][C:6]=1[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10]
Reactant: CN(C(=O)C(F)(F)F)c1cc(N)ccc1F
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(O)ccc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Compound 32-NH2—H (248 mg, 1.12 mmol) was dissolved in 35% aq. H2 SO4 (2 mL) cooled to 0° C., and NaNO2 (96.6 mg 1.4 mmol) in water (1 mL) was added carefully through a Teflon® tube to the bottom of the flask. An exothermic reaction was observed and the brown gas evolved. The mixture was stirred for 5 min, several crystals of urea were added to the reaction mixture, and then the reaction solution was transferred into the blue solution of Cu(NO3)2*3H2O (3.75 g, 15.5 mmol) in water (36 mL). The color of the solution changed to green. With vigorous stirring, the powder of Cu2O (132 mg, 0.920 mmol) was added, and the evolution of nitrogen was complete in several minutes. The reaction mixture was extracted with ether (3×200 mL); combined organic solutions were washed with brine (100 mL) and dried. The solvent was removed in vacuo, and the residue was filtered through SiO2 (50 mL), eluting with CH2 Cl2/EtOAc mixture (4:1). The title compound was isolated as a brown solid (116 mg, 52%) with m.p. 151-153° C. (ether/hexane). This procedure may be easily scaled-up. 1H NMR (CD3OD, 300 MHz, ppm): δ=6.70 (ddd, 4JHH=3.0, 4JHF=3.9, 3JHH=9.0, 1H, H-4), 7.03 (dd, 3JHH=9.0, 3JHF=10.1, 1H, H-3), 7.08 (dd, 4JHH=3.0, 4JHF=6.2, 1H, H-6); 13C NMR (CD3 OD, δ5.5 MHz, ppm): δ=113.4 (s, C-4/6), 115.4 (d, 3JCF=7.2, C-6/4), 117.2 (d, 2JCF=21.3, C-3), 117.4 (q, 1JCF=298, CF3), 124.4 (d, 2JCF=13.8, C-1), 150.5 (d, 1JCF=239, C-2), 154.8 (s, C-5), 157.1 (q, 2JCF=37.7, CO); EI-MS: m/z (rel. int., %)=223 (100) [M], 154 (21), 126(22), 99 (22); elemental analysis (%): C, 42.92; H, 2.44; N, 6.54 (found); C, 43.07; H, 2.26; N, 6.28 (calc.).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12](=[S:14])[NH2:13])[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3].Br[CH:30]1[C:35](=O)[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31]1.CCN(C(C)C)C(C)C>C(O)C>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12]2[S:14][C:30]3[CH2:31][N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34][C:35]=3[N:13]=2)[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed by DIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight at reflux then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux for a further 3 hrs. The cooled mixture was partitioned between saturated NaHCO3 solution (30 mL) and EtOAc (30 mL) and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (20 mL) dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a bright yellow foam (0.313 g, 73%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>C1(C)C=CC=CC=1>[C:20]([O:19][C:15]([NH:16][N:17]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 17 h
Yield: 73.4 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2 g, 10 mmol, 1 eq) in toluene (50 mL) was added tert-butyl carbazate (1.3 g, 10 mmol, 1 eq). The contents were stirred at 70° C. for 17 h. Precipitate was formed upon cooling down to rt. Filtration of the heterogeneous mixture gave a white solid (2.3 g). The filtrate was concentrated to dryness and triturated with ether carefully to collect another crop of solid (400 mg). The two solid product crops were combined (2.7 g, 85%) and used directly in the next step. 1H-NMR (CH3CN-d3) δ 8.11 (s, 1H), 3.49 (m, 4H), 2.34 (m, 4H), 1.47 (s, 9H), 1.45 (s, 9H); LCMS RT=3.04 min; [M+Na]+=336.1.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])/[CH:11]=[CH:12]/[CH3:13].NC1C(F)=CC(/C(/C)=C/C(OCC)=O)=C(F)C=1>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2](/[C:12](/[CH3:13])=[CH:11]/[C:10]([O:15][CH2:16][CH3:17])=[O:14])=[C:3]([Cl:9])[CH:4]=1
Reactant: C/C=C/C(=O)OCC
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: CCOC(=O)/C=C(\C)c1cc(F)c(N)cc1F
Product: CCOC(=O)/C=C(\C)c1ccc(N)cc1Cl
Yield: 31 %

Procedure:
Using 4-bromo-3-chloroaniline (10.0 g) and ethyl crotonate (10.0 ml), Compound 12a (3.56 g, 31%) was obtained as a brown solid in the same manner as Compound 10a was synthesized.
Reaction SMILES: [I-].[C:2]([CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][N+:7]([CH3:10])([CH3:9])C)(=[O:4])[CH3:3].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])C=NC[CH2:20]2.C(O)C.O>ClCCl>[CH2:11]([CH:5]1[CH2:6][N:7]2[CH2:9][CH2:20][C:19]3[C:24]([CH:10]2[CH2:3][C:2]1=[O:4])=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH3:15])[CH:18]=3)[CH:12]([CH3:13])[CH3:14]
Reactant: CC(=O)C(CC(C)C)C[N+](C)(C)C
Reactant: COc1cc2c(cc1OC)CCN=C2
Agent: [I-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Yield: 37.1 %

Procedure:
(2-Acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (800 mg, 2.55 mmol, 1.00 equiv) was added to a solution of 6,7-dimethoxy-3,4-dihydroisoquinoline (100 mg, 2.62 mmol, 1.00 equiv) and ethanol (10 mL). The resulting solution was heated at reflux for about 5 hours, and then water (20 mL) was added. Following standard extractive workup with dichloromethane (3×50 mL), the crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:4)) to afford the title compound as a white solid (300 mg, yield=36%). 1H NMR (300 MHz, CDCl3), δ 6.63 (s, 1H), 6.55 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.55 (s, 1H), 3.22-3.28 (m, 1H), 2.94-3.14 (m, 4H), 2.31-2.65 (m, 4H), 1.73-1.81 (t, 1H, J=11.4), 1.33-1.39 (m, 1H), 0.996-1.067 (t, 1H, J=10.5), 0.79-0.85 (m, 6H) LC-MS: m/z=318 (MH)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>C1COCC1.O>[CH2:1]([O:8][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A solution of benzyl alcohol (0.52 mL, 5 mmol) in THF (20 mL) was treated with NaH (60%, 0.2 g, 5 mmol) and succinic anhydride (0.502 g, 5 mmol) and refluxed for 4 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with EtOAc several times. The combined organic layer was washed H2O and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel using EtOAc:Hex (1:1) as eluant to give 20 as white solid (0.866 g, 57%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:20][C:21]([Cl:28])([Cl:27])[CH2:22][O:23][C:24](Cl)=[O:25]>O.C(OCC)(=O)C>[Cl:20][C:21]([Cl:28])([Cl:27])[CH2:22][O:23][C:24](=[O:25])[NH:17][C:7]1[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A cooled (0° C.) biphasic solution of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (26.6 g, 100 mmol) in water (80 mL) and ethyl acetate (180 mL) was treated with NaOH (10 g, 250 mmol) followed by trichloroethylchloroformate (29.7 g, 140 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The layers were separated and the organic layer was washed with brine (100 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to provide 40.3 g of pale yellow solid (99% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Reactant: C1CCNCC1
Product: O=C(O)c1ccc(Br)c(S(=O)(=O)N2CCCCC2)c1
Yield: 88 %

Procedure:
Compound 3.1 was prepared from 4-bromo-3-chlorosulfonyl-benzoic acid 2.1 and piperidine a1 in 88% yield according to general method B. MS (M−1)=346.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:24]([NH:29][C:30](=[O:50])[CH2:31][NH:32][C:33](=[O:49])[C:34]2[CH:39]=[C:38]([NH:40][C:41]3[NH:42][CH2:43][CH:44]([OH:47])[CH2:45][N:46]=3)[CH:37]=[C:36]([OH:48])[CH:35]=2)[CH2:25][C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2([CH2:21][O:22]C)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:14]=1.C1OCCOCCOCCOCCOC1.[I-].[Na+].C(=O)=O.CC#N.B(Br)(Br)Br>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:24]([NH:29][C:30](=[O:50])[CH2:31][NH:32][C:33](=[O:49])[C:34]2[CH:39]=[C:38]([NH:40][C:41]3[NH:46][CH2:45][CH:44]([OH:47])[CH2:43][N:42]=3)[CH:37]=[C:36]([OH:48])[CH:35]=2)[CH2:25][C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2([CH2:21][OH:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:14]=1
Reactant: COCC1(c2cc(Cl)cc([C@H](CC(=O)O)NC(=O)CNC(=O)c3cc(O)cc(NC4=NCC(O)CN4)c3)c2)CCOCC1
Agent: BrB(Br)Br
Agent: C1COCCOCCOCCOCCO1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C2(CO)CCOCC2)c1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a solution of (3S)-3-(3-chloro-5-(4-(Methoxymethyl)tetrahydro-2H-pyran-4-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid TFA salt (Example 16) (85.5 mg, 0.117 mmol) in anhydrous dichloromethane (2.0 mL) was added a solution of 15-crown-5 (155.0 mg, 0.702 mmol) saturated with sodium iodide in dichloromethane (6.0 mL) at room temperature and the reaction mixture was cooled to −30° C. (dry-ice/CH3CN) and a 1.0 M BBr3 solution in dichloromethane (350 μL, 0.35 mmol) was added and the reaction mixture stirred at −30° C. for 2 h to give an orange suspension. After 2 hr the reaction mixture was allowed to warm slowly to room temperature and stirred at room temperature overnight to give an orange-cream suspension. The suspension was filtered, washed with dichloromethane (2×10 mL) and dried in vacuo to give a yellow-cream solid. The crude product was purified by reverse-phase HPLC with a gradient 10-50% CH3CN in water containing 0.05% TFA to give the desired product (Example 17), after lyophilization, as a colorless lyophilized solid (64.5 mg). LC/MS analysis of the product shows the desired product's mass: m/z 604 (35ClM+H), m/z 606 (37ClM+H), m/z 626 (35ClM+Na), and m/z 628 (37ClM+Na), Calcd for C28H34ClN5O8:604.05.
Reaction SMILES: [NH2:1][C:2](=[N:28][N+:29]([O-:31])=[O:30])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)=[O:17])[NH:8]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>>[NH2:1][C:2](=[N:28][N+:29]([O-:31])=[O:30])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=1)=[O:17])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(CO)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(CO)cc1
Yield: 83 %

Procedure:
Prepared analogously to Example 23b) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(tert.-butoxycarbonyl)-N-[[4-(hydroxymethyl)phenyl]methyl]-ornithinamide by the action of trifluoroacetic acid in a yield of 83% of theory.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[ClH:43].CO>C1COCC1.O>[ClH:43].[S:14]([N:11]1[C:8]2=[N:9][CH:10]=[C:5]([CH2:4][NH2:1])[N:6]=[C:7]2[CH:13]=[CH:12]1)([C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=1)(=[O:15])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN=[N+]=[N-])cnc32)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Temperature: 45 °C
Yield: 95.4 %

Procedure:
To a solution of 2-(azidomethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (32.6 g, 99.0 mmol) in THF (100 mL) and water (50 mL) was added Ph3P (31.3 g, 119 mmol). The reaction mixture was heated to about 45° C. for about 16 h. The mixture was allowed to cool to ambient temperature followed by removal of THF under reduced pressure. The mixture was partitioned between EtOAc (500 mL) and brine (250 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was diluted with EtOAc to IL total volume. To the rapidly stirring solution was added drop-wise 4N HCl (4N in dioxane, 30.0 mL, 120 mmol) resulting in formation of a tan precipitate. MeOH (10 mL) was added and the mixture was filtered after about 15 min. The precipitate was triturated with Et2O (1000 mL) for about 10 min, filtered, and washed with Et2O (500 mL) to provide (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (32.0 g, 90%) as a tan solid: LC/MS (Table 2, Method a) Rt=1.44 min; MS m/z: 303 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:20][C:19]2[C:14](=[N:15][C:16]([S:21]([CH3:24])(=[O:23])=[O:22])=[N:17][CH:18]=2)[N:13]([CH3:25])[C:12]1=[O:26].[H][H]>O1CCCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([S:21]([CH3:24])(=[O:22])=[O:23])=[N:17][CH:18]=3)[N:13]([CH3:25])[C:12]2=[O:26])[CH:4]=1
Reactant: CN1C(=O)N(c2cc([N+](=O)[O-])ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: [H][H]
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cc(N)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Yield: 98 %

Procedure:
5.94 g 3-(2-chloro-5-nitro-phenyl)-7-methanesulfonyl-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one were dissolved in 200 mL tetrahydrofuran. Pd(CaCO3)/C was added to the solution which was then treated with hydrogen (1 atm) for 18 h. The solution was then filtrated and the solvent evaporated. The residue was extracted with diethyl ether and the title product obtained in 98% yield.
Reaction SMILES: C(OCC1C=CC=CC=1)C1C=CC=CC=1.O1C=CC=C1.C([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:39]=[CH:38][O:37][CH:36]=1)C1C=CC=CC=1.[H][H]>[C].[Pd]>[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:39]=[CH:38][O:37][CH:36]=1
Reactant: [H][H]
Reactant: c1ccc(COc2ccccc2-c2ccoc2)cc1
Agent: [Pd]
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: c1ccoc1
Product: Oc1ccccc1-c1ccoc1

Procedure:
The benzylether prepared by the procedure outlined in sub paragraph A above was converted to the hydrophenyl furane and follows: 10.2 grams 3-(2-benzyloxyphenyl)-furane was placed in 50 ml. of a 1:1 solution of methanol/acetic ester, and was hydrogenated with hydrogen in the presence of 1.5 gram 10% palladium carbon, at room temperature and slight pressure. After absorption of one equivalent of hydrogen, the catalyst was filtered off and the solvent carefully drawn off at 20° C. An intensely colored, unstable substance remained, which was identified by its NMR spectrum as the desired phenol.