Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:19])=[C:13]([C:15]([O:17]C)=[O:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>C(O)C.O>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:19])=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COC(=O)c1nc(CNC(=O)OC(C)(C)C)sc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1sc(CNC(=O)OC(C)(C)C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-(N-Boc-aminomethyl)-5-methylthiazole-4-carboxylate (22.0 g, 77 mmol) was dissolved in ethanol (100 ml), and a solution of LiOH (2.2 g, 92 mmol) in water (50 ml) was added. After the mixture had been stirred for 30 minutes at room temperature, the ethanol was removed on a rotary evaporator and the solution which remained was diluted with water (70 ml). The aqueous phase was washed with ethyl acetate (3×) and brought to pH 2 with 20% strength NaHSO4 solution, during which process a pale brown oil separated out. The aqueous phase was extracted with dichloromethane and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The pale brown residue was extracted by stirring in diisopropyl ether. The colorless precipitate which remained was filtered off with suction and washed with diisopropyl ether. Yield: 6.9 g (25.4 mmol, 33%, colorless solid).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([CH3:6])([CH3:5])[CH:3]1[NH:7][C:8]([NH2:10])=[S:9].Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH3:1][C:2]1([CH3:11])[C:4]([CH3:5])([CH3:6])[CH:3]1[NH:7][C:8]1[S:9][C:13]2([C:17](=[O:18])[N:10]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CC1(C)C(NC(N)=S)C1(C)C
Product: CC1(C)C(NC2=NC(=O)C3(CCC3)S2)C1(C)C

Procedure:
Synthesis was performed from N-(2,2,3,3-tetramethylcyclopropyl)thiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [O:1]=[O:2].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O-:9])=[O:8].[Mg+2].ClC1C=C(C=CC=1)C([O-])=[O:19]>CO>[O:1]=[O:2].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][OH:19])=[O:8]
Reactant: O=C([O-])c1cccc(Cl)c1
Agent: O=O
Agent: [Mg+2]
Solvent: CO
Product: O=C(OO)c1cccc(Cl)c1

Procedure:
The product formed in the process described in Example 1 was analyzed using Fourier Transform Infrared spectroscopy (FT-IR). The spectrum produced showed absorptions at 1714 cm-1 and 1680 cm-1 (solid state analysis) which are assigned as carbonyl stretching frequencies. Spectra were also obtained for the corresponding 3-chloroperoxybenzoic acid (absorption at 1718 cm-1) and magnesium bis(3-chlorobenzoate) (absorptions at 1615 cm-1 and 1570 cm-1). A portion of the product formed in Example 1 was decomposed by storage for 7 days at 60° C. The spectrum of this material was essentially that of magnesium 3-chlorobenzoate. Analysis in methanol solution resulted in spectra for the product produced in Example 1 (absorption at 1680 cm-1) and for 3-chloroperoxybenzoic acid (absorption at 1740 cm-1). These results show that the product produced in Example 1 is different from the starting material or the simple magnesium carboxylate salt. Also, the absorption locations for the product from Example 1 are consistent with the values expected for magnesium bis(3 -chloroperoxybenzoate)tetrahydrate.
Reaction SMILES: [NH:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11]I>C(O)C>[CH3:11][N:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(O)Nc1ccccc1
Solvent: CCO
Product: CC(O)N(C)c1ccccc1
Reaction time: 8 h

Procedure:
In a 250 ml container, take 50 g (0.365 mole) of 2 N anilinoethanol, 52.5 g (0.35 mole) of methyl iodide and 66 ml of ethanol. The solution is left overnight under ethanol reflux.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)O)=[C:4]([CH3:17])[CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].ClC1C=C(Cl)C=CC=1C([C:34]1[C:42]2[C:37](=[C:38]([CH2:44][S:45][CH3:46])[CH:39]=[C:40](F)[CH:41]=2)[NH:36][CH:35]=1)CCO.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:34]2[C:42]3[C:37](=[C:38]([CH2:44][S:45][CH3:46])[CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(O)c1ccc(F)cc1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
509 mg (2.17 mmol) of the compound from Example 82A and 437 mg (1.97 mmol) of indium(III) chloride were added to 350 mg (1.97 mmol) of the compound from Example 8 in 15 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate, and the solid was filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 174 mg (22% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:21])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[N:18][C:19]#[N:20])SC)[N:9]=1.[CH3:22][NH2:23]>C(O)C>[CH3:1][N:2]=[C:3]([NH2:21])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:23][CH3:22])=[N:18][C:19]#[N:20])[N:9]=1
Reactant: CN
Reactant: CN=C(N)Nc1nc(CCCCNC(=NC#N)SC)cs1
Solvent: CCO
Product: CN=C(N)Nc1nc(CCCCNC(=NC#N)NC)cs1
Reaction time: 8 h

Procedure:
To a solution of 2-(2-methylguanidino)-4-[4-(3-cyano-2-methylisothioureido)butyl]thiazole (0.38 g.) in ethanol (10 ml.) was added 33% w/v ethanolic methylamine (40 ml.). The mixture was stirred overnight, evaporated to dryness and the residue triturated with water. The solid thus obtained was filtered and dried to give 2-(2-methylguanidino)-4-[4-(2-cyano-3-methylguanidino)butyl]thiazole, m.p. 119°-122° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reaction time: 64 h
Yield: 88.9 %

Procedure:
To a solution of methyl 3-amino-5-bromo-2-methylbenzoate (3.0 g, 12 mmol) in 1,2-Dichloroethane (48 ml) under nitrogen, was added oxan-4-one (2.3 ml, 25 mmol) followed by acetic acid (4.2 ml, 74 mmol). The reaction mixture was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (7.8 g, 37 mmol). After stirring for 64 hours, deionized water (100 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (4×50 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in-vacuo. The residue was purified by flash column chromatography (50 g silica, Isolute cartridge, 10-30% EtOAc:Heptanes) to give the title compound (3.5 g 85%) as a white solid. LC-MS 99.8%, 2.18 min (3.5 minute LC-MS method), m/z=327.9, 328.9, 329.9, 330.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.24 (d, J=1.73 Hz, 1H) 6.85 (d, J=1.58 Hz, 1H) 4.03 (dt, J=11.82, 3.31 Hz, 2H) 3.88 (s, 3H) 3.66 (br.s., 1H) 3.56 (td, J=11.55, 1.97 Hz, 2H) 3.47-3.55 (m, 1H) 2.24 (s, 3H) 2.06 (d, J=13.56 Hz, 2H) 1.47-1.60 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][C:6]1[N:11]=[C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:9]2=[CH:8][C:7]=1[C:17](OCC)=[O:18]>CC(O)C>[CH3:5][C:6]1[N:11]=[C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:9]2=[CH:8][C:7]=1[C:17]([NH:3][C:2]([NH2:4])=[NH:1])=[O:18]
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Reactant: N=C(N)N
Solvent: CC(C)O
Product: Cc1nc2c(cc1C(=O)NC(=N)N)CCCCC2
Yield: 31.2 %

Procedure:
In an atmosphere of argon, metallic sodium (325.2 mg, 0.014 g atom) was dissolved in anhydrous methanol (20.0 ml) at room temperature, and the solution was mixed with guanidine hydrochloride (1.35 g, 14.1 mmol) at 0° C. After 1 hour of stirring at room temperature, the thus precipitated sodium chloride was removed by filtration using a glass filter and the resulting filtrate was evaporated under reduced pressure to obtain free guanidine. Guanidine and ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (500.0 mg, 2.02 mmol) were suspended in 2-propanol (12.0 ml) and heated under reflux for 18 hours. After cooling, the solvent was evaporated under reduced pressure, and the resulting residue was mixed with water and extracted with ethyl acetate. The thus obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and then the thus formed crystals were washed with ether to obtain the title compound (165.1 mg, 31.2%) as white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[C:6]1([S:5][CH2:4][CH2:3][CH2:2][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[C:20]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29]4)=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCCCSc1ccccc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(Nc1cccc(C2CCN(CCCSc3ccccc3)CC2)c1)C1CC1

Procedure:
Prepared by Procedure G and Scheme B1 using [(3-chloropropyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 395.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH3:9])[CH3:8])=[N:4][CH:3]=1.CO.[OH2:19].[OH2:20].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>ClCCl.[O-]S([O-])(=S)=O.[Na+].[Na+].O>[Br:1][C:2]1[S:6][C:5]([C:7]([S:10]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:20])=[O:19])([CH3:9])[CH3:8])=[N:4][CH:3]=1
Reactant: O
Reactant: COC(=O)CCSC(C)(C)c1ncc(Br)s1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=S([O-])([O-])=S
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCS(=O)(=O)C(C)(C)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
The product of Step 3 (12.50 g, 38.5 mmol) was taken up in dichloromethane (250 mL)/methanol (125 mL), and magnesium monoperoxyphthalate hexahydrate (35.8 g, 57.8 mmol) was added. The reaction was stirred at room temperature for 2 h. The white slurry was diluted with 10% Na2S2O3 and water and extracted with CH2Cl2 (2×). The combined organic layers were washed with saturated NaHCO3, dried (MgSO4), filtered and evaporated. Flash chromatography (0-40% ethyl acetate in hexanes) afforded 13.12 g (96%) of methyl 3-{[2-(5-bromo-1,3-thiazol-2-yl)propan-2-yl]sulfonyl}propanoate as a white solid. ESI: [M+H]+ m/z 355.9/357.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[CH:7]=[CH:6]2.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([N:32]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=[C:13]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc2cc(C(=O)CCC(=O)c3ccccc3)ccc2c1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Yield: 87.2 %

Procedure:
In a similar manner as described in step 4 of Example 1, the title compound was prepared from 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (0.300 g, 0.942 mmol), prepared in step 3 of Example 1, and benzyl amine (0.121 g, 1.13 mmol). The crude material was dissolved in methylene chloride and filtered through silica gel (95 g, 200–300 mesh). The solvent was removed under reduced pressure to give 1-benzyl-2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole as a white solid (0.32 g, 87%), mp 152–153° C. Elemental Analysis for C28H23NO Calc'd: C, 86.34; H, 5.95; N, 3.60. Found: C, 85.46; H, 6.06; N, 3.58.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:12]=[C:11]([I:13])[C:10]([CH3:14])=[CH:9][N:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:13][C:11]1[C:10]([CH3:14])=[CH:9][N:8]=[C:7]([NH2:6])[CH:12]=1
Reactant: COc1ccc(CNc2cc(I)c(C)cn2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine (118 g, 310 mmol) in DCM (1900 mL) was added TFA (360 mL, 4830 mmol). The reaction mixture was allowed to stir at rt for 2 h and was then concentrated. The residue was dissolved in EtOAc and diluted with saturated aqueous NaHCO3. The mixture was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 4-iodo-5-methylpyridin-2-amine (53 g, 75%) which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31]>>[CH2:9]1[O:8][C:7]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:23]=[C:2]([C:27]3[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C1COC(c2ccco2)(c2ccco2)c2cc(Br)ccc2N1
Product: O=C1COC(c2ccco2)(c2ccco2)c2cc(-c3ccc(F)c(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5,5-di(2-furyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluoro benzeneboronic acid generally according to the coupling procedure of example 1. 1H NMR (DMSO-d6): δ 10.28 (s, 1H), 7.77 (dd, J=1.95, 0.98 Hz, 2H), 7.66 (dd, J=8.3, 1.95 Hz, 1H), 7.59 (dd, J=7.32, 2.44 Hz, 1H), 7.45 (dd, JHF=JHH=8.79 Hz, 1H), 7.33-7.36 (m, 1H), 7.32 (d, J=8.79 Hz, 1H), 6.89 (d, J=2.44 Hz, 1H), 6.51 (dd, J=3.42, 1.95 Hz, 2H), 6.27 (dd, J=3.42, 0.98 Hz, 2H), 4.17 (s, 2H); MS (ESI) m/z 422/424 ([M−H]−); Anal. calcd for C23H15ClFNO4: C, 65.18; H, 3.57; N, 3.30. Found: C, 64.16; H, 3.66; N, 2.78.
Reaction SMILES: [CH:1]([Si:4]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([Cl:17])(=[O:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)([CH3:3])[CH3:2].C1C(=O)N([Br:31])C(=O)C1>C(Cl)Cl>[Br:31][C:7]1[C:8]2[C:13](=[CH:12][C:11]([S:14]([Cl:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:18]([CH3:20])[CH3:19])[CH:21]([CH3:23])[CH3:22])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(S(=O)(=O)Cl)cc21
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2ccc(S(=O)(=O)Cl)cc21
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A 250-mL round-bottom flask was charged with 1-(triisopropylsilyl)-1H-indole-6-sulfonyl chloride (4.2 g, 11.29 mmol) and DCM (57 ml) to give a clear, maroon solution. n-Bromosuccinimide (2.210 g, 12.42 mmol) was added in one portion, and the resulting mixture was stirred overnight. Silica gel (10.6 g) was added, and the mixture was concentrated. The impregnated silica gel was eluted onto a silica gel column with 0 to 20% EtOAc/Heptane to give to give 3-bromo-1-(triisopropylsilyl)-1H-indole-6-sulfonyl chloride (3.809 g, 8.45 mmol, 74.8% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ=8.20 (dd, J=0.4, 1.6 Hz, 1 H), 7.89-7.71 (m, 2 H), 7.55 (s, 1 H), 1.72 (quin, J=7.5 Hz, 3 H), 1.18 (d, J=7.7 Hz, 18 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.Cl.[N:16]([O-])=O.[Na+].N(N1C(=O)C=CNC1=O)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:16][C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6](=[O:12])[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: C=C(C)Cn1c(N)cc(=O)n(C)c1=O
Agent: Cl
Agent: O=Nn1c(=O)cc[nH]c1=O
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Product: C=C(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Methallylamine (211 g, 2.97 mol) is added to a solution of concentrated hydrochloric acid (250 ml) in water (1.91), followed by portionwise addition of potassium cyanate (240 g, 2.97 mol). The reaction is then heated for 2 hours at 80° C., prior to cooling and evaporation to afford (2-methyl-allyl)-urea (244.5 g), mp 114-115° C. The urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride (536 ml) and the reaction is heated at 70° C. for 1 hour, cooled to 0° C. and diluted with ether. The resultant solid is collected by filtration, washed with ether, suspended in water (2.2 l) and heated to 75° C. 2M aqueous sodium hydroxide solution is then added portionwise over 30 min to maintain pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 ml), further cooled to 10° C. and the resultant solid is collected by filtration, washed with cold water and dried to afford 6-amino-1-(2-methyl-allyl)-1H-pyrmidine-2,4-dione, mp 267-269° C. The uracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20° C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour. After standing overnight, the reaction is cooled to 5° C. and the solid collected by filtration to give 6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 162-163° C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.551) and concentrated hydrochloric acid (72 ml). A solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30 minutes and the reaction is stirred at 20° C. for 3 hours. The solid is collected by filtration, washed successively with water, methanol and ether to afford 6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyriridine-2,4-dione, mp 213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water (950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69 mol) is added portionwise. After cooling to room temperature, the solid is collected by filtration to afford 5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 152-153° C.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:72]2[N:73]=[C:74]([NH:77]C(OC(C)(C)C)=O)[S:75][CH:76]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42]([CH3:71])[C:43](=[N:63]C(OC(C)(C)C)=O)[N:44](C(OC(C)(C)C)=O)[CH2:45][CH2:46][CH2:47][NH:48]C(=O)OC(C)(C)C)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:48][CH2:47][CH2:46][CH2:45][NH:44][C:43](=[NH:63])[N:42]([CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:72]3[N:73]=[C:74]([NH2:77])[S:75][CH:76]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)[CH3:71]
Reactant: CN(Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)C(=NC(=O)OC(C)(C)C)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1)C(=N)NCCCN
Yield: 7.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(4-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)imino)-2,11,11-trimethyl-9-oxo-10-oxa-2,4,8-triazadodecyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (27 mg, 0.022 mmol), TFA (103 μl, 1.34 mmol) and DCM (223 μl). The crude material was purified by reverse phase preparative HPLC (XSELECT C18, 5μ, 30×100 mm, ACN/H2O w/0.1% formic acid buffer), affording the title compound (1.1 mg, 7%) as a white solid. LCMS: Rt=0.32 min, m/z=643.3 (M+1) Method 2m_acidic. 1H NMR (500 MHz, D2O) δ ppm 7.65 (s, 1H) 7.00 (s, 1H) 5.48 (d, J=5.7 Hz, 1H) 4.89-4.83 (m, 1H) 4.60-4.45 (m, 2H) 3.25 (td, J=6.9, 3.6 Hz, 2H) 2.95 (t, J=7.7 Hz, 2H) 2.91 (s, 3H) 1.98-1.74 (m, 2H) 1.23-1.10 (m, 2H) 1.05-1.00 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C[O-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][O:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 81.1 %

Procedure:
To a solution of (25)-1-(tert-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (1.50 g) in methanol (5 ml) were added 4-chlorophenol (1.90 g) and 1M sodium methoxide in methanol (7.1 ml), followed by 19 hour' reflux at 70° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 2N sodium hydroxide, saturated ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a etude product of the title compound (1.95 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])O1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[OH:35])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: CC(C)COC(=O)N1CCN(c2cncc(Cl)n2)CC1
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+]
Product: CC(C)COC(=O)N1CCN(c2cncc(-c3ccccc3O)n2)CC1
Temperature: 120 °C

Procedure:
6′Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid isobutyl ester (54 mg, 0.18 mmol), 47.9 mg (0.22 mmol) of 2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol, 3.2 mg (2.7 pmol) of Pd(PPh3)4, 49.2 mg (0.35 mmol) of K2CO3 were charged to a microwave reactor vial. The reaction mixture was heated by microwave irradiation at 120° C. for 15 minutes. The reaction was filtered and purified by reverse phase HPLC (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give 33. LCMS: m/z 357.2 (M+H)+ at 3.53 minutes (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).