Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1)(=O)=O.[CH2:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([OH:43])CCNCC2)=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C=O)C.O>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([OH:43])[CH2:29][CH2:28][N:25]([CH2:23][C:6]3[N:7]=[C:8]([C:12]4[S:13][C:14]5[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=5[C:16](=[O:18])[N:17]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:26][CH2:27]2)=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1nc(-c2cccc(CN3CCC(O)(c4ccc(Cl)cc4)CC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 4-(4-chlorophenyl)-4-hydroxypiperidine (0.20 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.20 g, 49%) as pale yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:37][CH2:36][CH2:35][C:33]3[N:34]=[C:30]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[O:31][C:32]=3[CH3:48])=[CH:11][CH:12]=2)[C:4]([OH:23])=[O:3])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(Cl)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-chlorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester by the procedure of Example 29. 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H, J=8.60 Hz), 7.16 (d, 2H, J=8.60 Hz), 6.83 (d, 2H, J=8.60 Hz), 6.79 (d, 2H, J=8.60 Hz), 4.12 (t, 2H, J=6.26 Hz), 3.21 (d, 1H, J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.26 Hz), 2.89-2.83 (m, 3H), 2.05 (d, 2H, J=11.73 Hz), 1.80 (d, 2H, J=11.73 Hz), 1.55 (q, 2H, J=11.73 Hz), 1.40 (s, 3H), 1.37-1.20 (m, 4H). MS (ES+) m/z mass calcd for C28H33ClNO5 498.21, found 498.2.
Reaction SMILES: [C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].C1C=CC=CC=1.[C:27]([NH:31][OH:32])([CH3:30])([CH3:29])[CH3:28]>C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=[N+:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[O-:32])=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 74.2 %

Procedure:
4-Acetoxy-3,5-di-tert-butylbenzaldehyde (113.16 g, 0.41 mol) was placed in a 2 L round-bottomed flask fitted with a magnetic stirrer. Benzene (500 mL) was added and the mixture was stirred until the solids dissolved. To the resulting red solution was added tert-butylhydroxylamine (43.80 g, 0.49 mol) and silica gel (20 g). The mixture was refluxed overnight at which time TLC showed no remaining starting material (Rf=0.31 for product and 0.80 for starting material using 3:1 hexanes/EtOAc). The benzene was removed in vacuo on a rotovap to provide a grey solid. The solid was dissolved in a minimum amount of ethyl acetate and the flask was left to stand in the freezer. The white crystals which formed were separated, washed with hexanes and dried under vacuum to afford 105.78 g of the title compound as a crystalline white solid (74.4% yield), m.p. 227.0-248.9° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([OH:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].C(OC(=O)[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:68].O1CCOCC1>C1(C)C=CC=CC=1>[ClH:68].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:12][C:6]2[CH:5]=[CH:4][C:3]([C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])=[C:2]([OH:1])[C:7]=2[C:8]([F:9])([F:10])[F:11])=[CH:28][CH:27]=1
Reactant: CC(C)C(=O)c1ccc(O)c(C(F)(F)F)c1O
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)C(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Yield: 78 %

Procedure:
Mechanically stir solutions of 1-(2,4-dihydroxy-3-trifluoromethyl-phenyl)-2-methyl-propan-1-one (211 g, 850.1 mmol), (4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (195 g, 821.8 mmol), and triphenylphosphine (212 g; 808.3 mmol) in toluene (9 L) in two separate 22-L Morton flasks. Treat solutions with diisopropyl azodicarboxylate (183 mL, 923 mmol) over a 60 min period, then stir over the weekend at room temperature. Combine the solutions and evaporate to a brown oil. Dissolve the oil in 1,4-dioxane (8 L), treat with 4N hydrogen chloride solution in 1,4-dioxane (3 L, 12 mole), and heat to 92° C. for 6 hrs (out-gassing and precipitation is observed at 52° C. during the warm up period). Cool to room temperature, filter the resulting solid and wash with dioxane, 30% dioxane in hexanes, and hexanes to provide the title compound (510 g, 78% yield) as a tan solid. HPLC Rt=4.71 min; 1H NMR (DMSO-d6) δ 14.00 (s, 1H), 8.4 (bs, 3H), 7.50 (ABq, J=12.0, 8.0 Hz, 4H), 6.92 (d, J=8.0 Hz, 1H), 5.37 (s, 2H), 4.0 (m, 2H), 3.73 (hept, J=4.0 Hz, 1H), 1.12 (d, J=4.0 Hz, 6H); 19F NMR (DMSO-d6) δ-54.10; MS (m/z): 368.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([F:31])=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.Br[CH2:33][CH:34]([CH3:37])[CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.ClCCl>[CH2:11]([CH:10]1[C:9]2[C:4](=[CH:5][C:6]([F:31])=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3][CH:2]1[N:1]1[CH2:35][CH:34]([CH3:37])[CH2:33]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(CCl)CBr
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cc3c(cc2F)CC(N)C3Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CC1CN(C2Cc3cc(F)c(OCCNS(=O)(=O)c4cn(C)cn4)cc3C2Cc2ccccc2)C1

Procedure:
To N-(2-(2-amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (20.7 mg, 0.047 mmol), 10 equivalents 1-bromo-3-chloro-2-methylpropane and potassium carbonate(70.8 mg) in water (1 mL) +1 drop acetonitrile were added. Microwave at 120° C. Evaporated acetonitrile, re-dissolved in dichloromethane and extracted with water and brine, dried over sodium bicarbonate, filtered and evaporated to obtain the crude product and was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% methanol in dichloromethane to afford N-(2-(3-benzyl-6-fluoro-2-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a clear glass m=2.0 mg (8.6%)
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:7]([F:30])=[CH:8][C:9]([Cl:29])=[C:10]([N:12]2[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]2=[O:28])[CH:11]=1.C(N(CC)CC)C>O1CCCC1>[Cl:29][C:9]1[CH:8]=[C:7]([F:30])[C:6]([N:5]=[C:1]=[S:2])=[CH:11][C:10]=1[N:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]1=[O:28]
Reactant: S=C(Cl)Cl
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N=C=S)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thiophosgene (0.50 mL, 6.5 mmol) is added over 45 minutes to a solution of isopropyl 3-(5-amino-2-chloro-4-fluorophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (2.5 g, 6.5 mmol), and triethylamine (1.8 mL, 13.0 mmol) in tetrahydrofuran. The reaction mixture is stirred at room temperature for 4 hours, diluted with tetrahydrofuran, and filtered. The filtrate is concentrated in vacuo to give the title product as an orange oil which is identified by NMR spectral analyses.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:13]=1)=O.[OH-].[Na+].[ClH:24]>CO>[ClH:24].[NH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:13]=1
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCN)cc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
To a suspension of 10.0 g of 5-[2-(trifluoroacetylamino)ethyl]-2-methoxybenzenesulfonamide in 100 ml of methanol were added 60 ml of 10% sodium hydroxide aqueous solution with stirring at room temperature and the reaction mixture was stirred for 30 minutes. The reaction mixture was acidfied with 13 ml of hydrochloric acid. The precipitate was filtered and recrystallized from water to give 4.22 g of the desired compound as colorless needles, m.p. 263°-266° C.
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[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].C(=O)(O)[O-].[Na+].[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(OCC)(=O)C.CC(C)=O.O>[C:33]1([NH:39][C:40](=[O:41])[NH:1][CH:2]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)[C:3]([NH:5][CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:14]4[NH:18][N:17]=[N:16][N:15]=4)[C:10]([CH3:12])([CH3:13])[S:11][C@H:7]23)=[O:4])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)Nc3ccccc3)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a stirred solution of 0.78 g. (0.002 mole) of 6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 40 ml. of 1:1 acetone-water, the pH of which has been adjusted to 6.0 by the addition of sodium bicarbonate solution, is added 0.238 g. (0.002 mole) of phenyl isocyanate, at ambient temperature. Stirring is continued at ambient temperature for a further 30 minutes, and then 50 ml. of ethyl acetate is added. The pH of the aqueous phase is lowered to 1.5 with 1 N hydrochloric acid, and then the organic layer is removed, dried and evaporated to dryness in vacuo. The residue is re-dissolved in a small volume of ethanol, to which 0.2 ml. of triethylamine is then added. The resulting solution is added dropwise to 200 ml. of ether, with vigorous stirring, and then the solid which precipitates is filtered off. This affords 0.8 g. (66% yield) of 6-(2-[3-phenylureido]-2-[p-hydroxyphenyl] acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its triethylamine salt, m.p. 165°-170° C. (dec.). The infrared spectrum of the product (KBr disc) shows absorptions at 1790 cm-1 (β-lactam) and 1670 cm-1 (amide I). The NMR spectrum (DMSO-d6 /D2O) shows absorptions at 7.60-6.70 ppm (multiplet, 9H, aromatic hydrogens), 5.80-5.50 ppm (multiplet, 3H, C-5 and C-6 hydrogens, and side-chains methine hydrogen), 5.05 ppm (singlet, 1H, C-3 hydrogen), 3.05 ppm (quartet, 6H, N--CH2CH3), 1.55 ppm (singlet, 3H, C-2 methyl hydrogen), 1.10 ppm (triplet, 9H, N--CH2CH3) and 0.95 ppm (singlet, 3H, C-2 methyl hydrogens).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:25]([F:28])([F:27])[F:26])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.[ClH:29].C(OCC)C>C(OCC)C.CO>[ClH:29].[Br:1][C:2]1[C:3]([C:25]([F:28])([F:27])[F:26])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)c(Br)cc32)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n1C1CCNCC1
Reaction time: 20 h
Yield: 88.6 %

Procedure:
A solution of 1,1-dimethylethyl 4-[6-bromo-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinecarboxylate (D68, 0.95 g, 2.0 mmol) in diethyl ether (50 ml) and methanol (10 ml) was treated at room temperature with 1M HCl/diethyl ether (10 ml, 10 mmol) and stirred for 20 hrs. The precipitate was filtered off, washed with diethyl ether and dried to afford the title compound as a beige solid (0.71 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[CH:31]([N:34]([CH2:38][CH2:39]Cl)[CH:35]([CH3:37])[CH3:36])([CH3:33])[CH3:32]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:39][CH2:38][N:34]([CH:35]([CH3:37])[CH3:36])[CH:31]([CH3:33])[CH3:32])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCN(C(C)C)C(C)C)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 2-(N,N-diisopropylamino)ethyl chloride essentially as previously described. MS 595, 597.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([O:19]C)=O)[C:12](S(C)(=O)=O)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH2:31]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][C:17](=[O:19])[N:31]([CH3:30])[C:12]2=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(CC(=O)OC)c(=O)c1OCc1ccccc1
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N2C
Temperature: 22 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of intermediate 3, ethyl 5-(benzyloxy)-1-(methoxycarbonylmethyl)-2-(methylsulfonyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (0.790 g, 1.86 mmol) in tetrahydrofuran (10 ml) was treated with a 2 M solution of methylamine in tetrahydrofuiran (10 ml, 20.0 mmol) and the resulting mixture was stirred at 22° C. for 1 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by recrystallization of the solid residue from ethyl acetate/hexane gave 0.705 g (83% yield) of the title ester as white crystals; mp 167° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (3H, t, J=7.1 Hz, CH3), 3.29 (3H, s, NCH3), 4.37 (2H, q, J=7.2 Hz, OCH2), 4.55 (2H, s, CH2), 5.23 (2H, s, OCH2), 7.3–7.5 (5H, m, aromatics). Anal. Calcd for C17H17N3O5: C, 59.47; H, 4.99; N, 12.23. Found: C, 59.5, H, 5.07; N, 12.40.
Reaction SMILES: C([N:4]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][C:10]2[C:9](=[O:18])[N:8]([CH2:19][CH2:20][CH3:21])[CH:7]=[N:6][C:5]1=2)C=C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(#N)C.O>[CH2:19]([N:8]1[C:9](=[O:18])[C:10]2[NH:11][C:12]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[N:4][C:5]=2[N:6]=[CH:7]1)[CH2:20][CH3:21]
Reactant: C=CCn1c(-c2cccs2)nc2c(=O)n(CCC)cnc21
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CCCn1cnc2nc(-c3cccs3)[nH]c2c1=O
Temperature: 100 °C
Yield: 10.5 %

Procedure:
The above compound, 9-allyl-1-propyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g, 0.33 mmol) and Wilkinson's catalyst were taken in acetonitrile:water (6:1, 7 ml) and refluxed for 5 h at 100° C. Solvent was removed and further purified by preparative TLC to get pure 1-propyl-8-thiophen-2-yl-1,7-dihydro-purin-6-one (9 mg, 10%).
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@H:16]1[C@@H:19]([CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[N:18]([S:27]([OH:30])(=[O:29])=[O:28])[C:17]1=[O:31])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:19]([CH2:20][N:21]3[CH2:25][CH2:24][O:23][C:22]3=[O:26])[N:18]([S:27]([OH:30])(=[O:29])=[O:28])[C:17]2=[O:31])[N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCOC1=O)c1csc(N)n1)C(=O)O
Yield: 13 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (100 mg, 0.148 mmol), DCM (1.5 mL) and TFA (569 μl, 7.39 mmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (10 mg, 12%) as a white solid. LCMS: Rt=0.32 min, m/z=521.0 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J=8.8 Hz, 1H), 6.89 (s, 1H), 5.22 (dd, J=8.8, 5.7 Hz, 1H), 4.23-4.11 (m, 3H), 3.75-3.62 (m, 2H assumed; obscured by water), 3.60-3.51 (m, 1H assumed; obscured by water), 3.34 (dd, J=14.6, 5.5 Hz, 1H), 1.44 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([CH:28]=O)[C:24]([CH3:30])=[N:23]1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([C:25]3[C:24]([CH3:30])=[N:23][N:22]([CH3:21])[C:26]=3[CH3:27])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: Cc1nn(C)c(C)c1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1nn(C)c(C)c1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 34.7 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 1,3,5-Trimethyl-1H-pyrazole-4-carbaldehyde (38.8 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 36.49 mg (37%) of the title compound. (300 MHz, DMSO-d6) 12.47 (s, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.21 (s, 1H), 7.00 (d, J=9 Hz, 1H), 6.32 (m, 1H), 6.26 (m, 1H), 5.17 (t, J=17 Hz, 9 Hz, 1H), 3.73 (s, 3H), 2.85 (s, 1H), 2.77 (s, 1H), 2.57 (d, J=8 Hz, 1H), 2.47 (s, 3H), 2.35 (s, 3H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=412 (M+H), HPLC: 1.97 min. (G Method)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]#[N:30])=[CH:22][CH:21]=1>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[N:4][C:3]=1[CH2:2][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]#[N:30])=[CH:24][CH:25]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Reactant: N#CCCCc1ccc(O)cc1
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCC#N)cc1

Procedure:
According to the method described for Reference Example 45, 4-chloromethyl-5-methyl-2-(2-naphthyl)oxazole was allowed to react with 4-(4-hydroxyphenyl)butyronitrile to give 4-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]butyronitrile. Recrystallization from chloroform-ether gave colorless prisms, m.p.149°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C1N=CN([C:20]([N:22]2[CH:26]=[N:25][CH:24]=[CH:23]2)=[O:21])C=1.C1C2[C:31](=[CH:32][CH:33]=[CH:34]C=2)[CH:30]=[C:29](N)N=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][C:20]([NH:22][C:26]3[N:25]=[CH:24][C:23]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:21])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc2ccccc2cn1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c(NC(=O)Nc3cc4ccccc4cn3)nc12
Temperature: 60 °C

Procedure:
To a stirring mixture of 1.0 g (5.2 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid methyl ester (Intermediate A) and 0.86 g (5.2 mmol) of CDI in 3.0 mL of DMF was added 0.75 g (5.2 mmol) of Isoquinolin-3-ylamine. The reaction mixture was heated at 60° C. for 30 min, and then cooled to room temperature. 5.0 mL of water was added. The resulting solid was filtered washed with water (10 ml) and ether (10 mL), and dried to provide the 2-(3-isoquinolin-3-yl-ureido)-1H-benzoimidazole-4-carboxylic acid methyl ester as a solid which was hydrolyzed as described in general procedure B to provide 0.75 g (40%) of 2-(3-isoquinolin-3-yl-ureido)-1H-benzoimidazole-4-carboxylic acid. LCMS: 348 (M+1)+.
Reaction SMILES: [H-].[Li+].C(S)CC.[CH3:7][C:8]([CH3:28])([O:10][C:11](=[O:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:25][CH3:26])[C:21]([O:23]C)=[O:22])[CH3:9]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:28][C:8]([CH3:9])([O:10][C:11](=[O:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:25][CH3:26])[C:21]([OH:23])=[O:22])[CH3:7]
Reactant: CCC(C(=O)OC)c1ccccc1OCC(=O)OC(C)(C)C
Agent: CCCS
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C(=O)O)c1ccccc1OCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
Suspend lithium hydride (1.01 g, 126.4 mmol) in hexamethylphosphoramide (50 mL) and treat with 1-propanethiol (11.5 mL, 126.4 mmol). Stir for 1.5 hours and add to a solution of 4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]oxy-alpha-ethyl-benzeneacetic acid, methyl ester (5.57 g, 18.06 mmol) in hexamethylphosphoramide (50 mL) under a nitrogen atmosphere. Stir for 20 hours and pour into ice cold 5% hydrochloric acid (500 mL). Extract into ethyl ether (4×300 mL), wash with water (500 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography (5→10→20% isopropanol/hexane) to give the title compound (4.01 g).