Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][C@H:9]([NH2:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].[C:18]([O:22][C:23](=[O:52])[CH2:24][CH:25]([CH2:29][CH2:30][CH2:31][S:32][C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26](O)=[O:27])([CH3:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[CH:9]([NH:17][C:26](=[O:27])[CH:25]([CH2:24][C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:52])[CH2:29][CH2:30][CH2:31][S:32][C:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 86.4 %

Procedure:
To H-Asp (OtBu)-OtBu hydrochloride salt (28 mg, 0.10 mmol) in dry DMF (2 mL) was sequentially added at room temperature 2-(3-tritylsulfanyl-propyl)-succinic acid 4-tert-butyl ester (50 mg, 0.10 mmol), HOBt (14 mg, 0.10 mmol), PYBOP (56 mg, 0.11 mmol) and DIPEA (37 uL, 0.20 mmol). The usual aqueous work up yielded the title compound (62 mg, 86%) as a colorless residue: 1H NMR (CDCl3, 400 MHz) δ 7.41-7.38 (m, 6H), 7.29-7.25 (m, 6H), 6.60-6.57 (m, 1H), 4.68-4.56 (m, 1H), 3.18-3.14 (m, 2H), 2.89-2.80 (m, 1H), 2.74-2.52 (m, 2H), 2.43-2.36 (m, 1H), 2.32-2.19 (m, 1H), 2.12-2.07 (m, 2H), 1.83-1.80 (m, 2H), 1.60-1.53 (m, 1H), 1.45-1.40 (m, 27H); 13C DEPT) (CDCl3, 100 MHz) δ 129.4, 127.7, 126.4, 49.0, 48.7, 46.1, 42.5, 37.8, 37.6, 37.2, 31.6, 31.5, 29.6, 27.9, 27.8, 27.7, 26.3, 26.2, 26.0.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC>[C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][CH:6]1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(=O)C(C(C)(C)C)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)C1CCC(O)C(C(C)(C)C)C1
Temperature: 23 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
380 g of 2,4-di-tert-butylcyclohexanone (mixed isomers) in 200 ml of ether are added dropwise with vigorous stirring to a suspension of 34.3 g (903 mmol) of lithium aluminium hydride in 1800 ml of ether over 4 hours, and the batch is subsequently stirred at 23° C. for 1 hour and admixed with 500 ml of 5% hydrochloric acid by vigorous stirring. The organic phase is separated off and washed twice with 250 ml of water each time. The organic phase is dried over MgSO4, evaporated and dried under reduced pressure to leave 337.80 g (88% of theory) of 2,4-di-tert-butylcyclohexanol (mixed isomers) as colourless wax.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([OH:17])[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[N:27]=[CH:28][C:21]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([O:17][C:20]2[N:25]=[CH:24][N:23]=[C:22]3[N:26]([C:29]4[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=4)[N:27]=[CH:28][C:21]=23)[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1
Reactant: Cc1ncccc1-n1ncc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1cccnc1C)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.8 %

Procedure:
Sodium hydride (21.49 mg, 0.54 mmol) was added to (S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (110 mg, 0.45 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (110 mg, 0.45 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×20 mL). The combined organics were washed with saturated brine (10 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 5% MeOH in DCM to afford the product (24.0 mg, 11.8%). 1H NMR (400 MHz, CDCl3) δ1.23 (t, 3H), 2.45 (s, 3H), 3.59-3.72 (m, 2H), 4.05-4.16 (m, 2H), 6.06 (t, 1H), 7.31-7.38 (m, 1H), 7.66-7.71 (m, 1H), 7.73-7.78 (m, 1H), 8.21-8.27 (m, 2H), 8.42 (s, 1H), 8.57 (s, 1H), 8.64-8.69 (m, 1H), 8.89 (s, 1H). m/z (ESI+) (M+H)+=454.31; HPLC tR=1.83 min
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[CH:5][C:4]1=[O:15]>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH2:5][C:4]1=[O:15]
Reactant: COC1=CC(=O)C(CCC(C)C)(OC)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Yield: 90.7 %

Procedure:
A solution of Example 11B (35 mg, 0.127 mmol) in methanol (0.25 mL) and 1 N NaOH (0.25 mL) was stirred at 40° C. for 6 hours. The solution was concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound (30 mg, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.30-0.47 (m, 1H), 0.67 (dd, J=13.97, 6.62 Hz, 6H), 0.75-0.93 (m, 1H), 1.10-1.37 (m, 1H), 1.70-1.95 (m, 1H), 1.98-2.21 (m, 1H), 2.81 (s, 3H), 5.70-5.83 (m, 1H), 7.47 (t, 1H), 7.60 (d, 1H), 7.65 (t, 1H), 7.90 (d, J=7.72 Hz, 1H); MS (ESI) m/z 260.9 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[N:22]([C:23](=[O:33])[C:24]2[C:29]([F:30])=[CH:28][C:27]([F:31])=[CH:26][C:25]=2[F:32])[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[S:19]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.CO.O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:20]2[S:19][CH:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH2:10][C:6]3[O:7][CH:8]=[CH:9][C:5]=3[C:3]([OH:4])=[O:2])[N:22]([C:23](=[O:33])[C:24]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[CH:26][C:25]=3[F:32])[N:21]=2)=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccoc1COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccoc1COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 12 h

Procedure:
To a solution of 2-{2-[5(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-furan-3-carboxylic acid methyl ester (0.49 mmol) in THF/MeOH/H2O (3:2:1), is added LiOH (3 N) (4.9 mmol). After stirring for 12 hours, the reaction is acidified with HCl (1 N) and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified using preparative LC/MS to give 2-{2-[5(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro [1,3,4]thiadiazol-2-yl]-phenoxymethyl}-furan-3-carboxylic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.26-7.23 (m, 3H), 7.20 (d, J=1.9, 1H), 7.10-7.05 (m, 1H), 7.03-6.99 (m, 1H), 6.86 (d, J=8.1, 1H), 6.78-6.74 (m, 3H), 6.55 (d, J=1.9, 1H), 6.55-6.50 (m, 2H), 5.38-5.21 (m, 2H); LC/MS (ES+): 557.1 (M+1)+.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH:55]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56]1>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:61][S:58]([CH:55]2[CH2:57][CH2:56]2)(=[O:60])=[O:59])=[O:35])[CH2:27][CH2:28]1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained (0.17 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.75-8.62 (m, 1H), 7.68-7.58 (m, 1H), 6.63-6.50 (m, 1H), 3.76 (s, 2H), 3.15-3.05 (m, 1H), 2.09-1.74 (m, 7H), 1.69-1.57 (m, 2H), 1.50-1.41 (m, 2H), 1.22-1.09 (m, 5H), 1.00-0.89 (m, 2H), 0.70-0.60 (m, 2H); MS (ES+) m/z 446.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH:4]=[O:5])[CH3:3].[CH:6]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[C:10]=1[S:21]Cl)([CH3:8])[CH3:7].O>C1COCC1>[CH3:1][C:2]([S:21][C:10]1[C:11]([CH:18]([CH3:19])[CH3:20])=[CH:12][C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:9]=1[CH:6]([CH3:8])[CH3:7])([CH3:3])[CH:4]=[O:5]
Reactant: CC(C)C=O
Reactant: CC(C)c1cc(C(C)C)c(SCl)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(SC(C)(C)C=O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a suspension of KH (383 mg, 9.5 mmol, Aldrich; washed with hexanes to remove oil and dried in vacuum) in THF (10 mL) was added dropwise isobutyric aldehyde (0.79 mL, 8.7 mmol, Aldrich) in THF (3 mL). The suspension was stirred for 25 min at RT under Ar (evolution of H2). A solution of 2,4,6-triisopropylphenylsulfenyl chloride (2.35 g, 8.7 mmol) in THF (10 mL) was then added at once. The color immediately changed from red to yellow. The solution was stirred at RT for 10 min, water (20 mL) was added to the reaction mixture under Ar (caution —H2 evolution). The solution was extracted with ethyl ether (2×30 mL), the extracts were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (13×4.3 cm) in toluene/hexane 1/5 followed by 1/4. Fractions containing the product were evaporated to give a light yellow oil that slowly crystallized, m=2.034 g (68.5%). Rf=0.33 (toluene/hexane 1/3). 1H NMR (CDCl3) 9.34 (s, 1H); 7.00 (s, 2H); 3.85 (septet, 2H; J=6.9 Hz); 2.86 (septet, 1H; J=6.9 Hz); 1.29 (s, 6H); 1.24 (d, 6H; J=6.9 Hz); 1.18 (unresolved broad d, 12H).
Reaction SMILES: [CH3:1]I.[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]=[C:20]2[C:16](=[N:17][C:18]([SH:22])=[N:19]2)[C:15](=[O:23])[N:14]=1)[CH2:4][CH3:5].[OH-].[Na+].Cl>>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]=[C:20]2[C:16](=[N:17][C:18]([S:22][CH3:1])=[N:19]2)[C:15](=[O:23])[N:14]=1)[CH2:4][CH3:5]
Reactant: CI
Reactant: CCCOc1ccccc1C1=NC(=O)C2=NC(S)=NC2=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(SC)=NC2=N1

Procedure:
Methyl iodide (0.5 g) was added to a stirred solution of 2-(2-propoxyphenyl)-8-mercaptopurin-6-one (10 g) in 1 Normal sodium hydroxide solution (8 ml). After 2.5 hours at room temperature the solution was neutralised with dilute hydrochloric acid to give the crude product which was recrystallised three times from aqueous ethanol to give the title compound, 0.32 g, m.p. 245°-247° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][N:6]([CH2:8][C:9]([O:11]CC)=[O:10])[C:5](=[O:14])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1.[Li+].[OH-]>O1CCOCC1>[CH3:1][C:2]1([CH3:21])[CH2:7][N:6]([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:14])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1
Reactant: CCOC(=O)CN1CC(C)(C)N=C(c2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)CN(CC(=O)O)C(=O)C(c2ccccc2)=N1

Procedure:
1,2-Diamino-2-methylpropane (7.4 ml) and methylbenzoyl formate (10 ml) were dissolved in absolute ethanol (250 ml) and heated at reflux for 18 hours. The reaction was concentrated to half volume and hot hexane (225 ml) was added. The solution was filtered and the filtrate was placed in the refrigerator overnight. The resultant crystals were filtered, and dried to give 5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl-2-(2H)-pyrazine. Mass Spec. m/c 203 (M+H)+. Anal Calcd. for C12H14N2O 1/2H2O: C, 69.70; H, 6.82; N, 13.55. Found: C, 70.10; H, 7.04; N, 13.63. 5,6-Dihydro-5,5-dimethyl-2-oxo-3-phenyl (3.5 g) was dissolved in dry THF (35 ml), 1M THF solution of sodium bis-trimethylsilyl amide (17.2 ml) was cannulated into the solution under nitrogen. After the addition was complete, the solution was stirred for an additional 20 minutes. Ethyl bromoacetate (2 ml) in dry THF (2 ml) was added dropwise. Stirring was continued for 48 hours. The solution was then poured into water and extracted twice with ether. The ethereal extracts were washed with saturated brine, dried, and concentrated in vacuo to give ethyl 5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl-1-(2H)-pyrazineacetate as white crystals. This ester was dissolved in dioxane (7 ml) and treated with 1M aqueous solution of LiOH (6.8 ml) at room temperature overnight. The solution was concentrated in vacuo, the residue was treated with 1N HCl (15 ml) and extracted with ethyl acetate. The organic extracts were dried and concentrated in vacuo to give 5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl1-(2H)-pyrazineacetic acid as white crystals; NMR (CDCl3): 7.4-7.8 (m, 5H), 4.3 (s, 2H), 3.5 (s, 2H), 1.4 (s, 6H). Mass spec m/e 261 (M+H)+. Using the same procedure and protocol described in Example 1, 5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl-1-(2H)-pyrazineacetic acid can be coupled to BOC-Ser(OBzl)-Tyr-(O-2-Br-CBZ)-D-Trp-(N-formyl)-Leu-Arg-(Tos)-Pro-O-Resin to give after cleavage from the resin, removal of protecting groups, work up and HPLC purification N-(5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl-1-(2H)-pyrazineacetyl)-Ser-Tyr-D-Trp-Leu-Arg-ProNHEt.
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>>[Br:22][CH2:23][CH2:24][C:25]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:26]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reactant: O=C(Cl)CCBr
Product: O=C(CCBr)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Yield: 65 %

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (5 g, 0.018 mol) was reacted according to the procedure of Example 142 with 3-bromopropionyl chloride (6.8 g, 0.04 mol, 4 ml), using a bath temperature of 100° C. A white crystalline product was obtained in 65% yield (4.9 g), m.p. 133°-134° C. Anal. calc. for C19H17N2O4Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.79; H, 4.12; N, 6.69; Br, 19.25. The product has the formula: ##STR1607##
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[O:6].[H-].[Na+].[NH4+].[Cl-]>C1COCC1.[Cl-].[Na+].O>[CH3:12][O:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6]
Reactant: COCCCNC(=O)NCCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCN1CCNC1=O
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A 0° C. solution of 1-(2-chloroethyl)-3-(3-methoxypropyl)urea (0.300 g, 1.541 mmol) in THF (8 mL), under Ar, was treated with NaH (60% in mineral oil, 0.154 g, 3.85 mmol) allowed to warm to RT and stirred. The mixture was cooled to 0° C., treated slowly with satd. NH4Cl, then brine, warmed to RT and stirred for 10 min. The layers were separated, the aqueous layer extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-(3-methoxypropyl)imidazolidin-2-one (214 mg, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.21 (s, 1 H), 3.31-3.24 (m, 4 H), 3.21-3.15 (m, 5 H), 3.06-3.01 (m, 2 H), 1.66-1.58 (m, 2 H); MS (ESI) m/z: 159.1 (M+H+).
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[C:9]([C:14]([OH:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.[CH3:25]C(C)=O>O>[C:4]1(=[O:19])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[C:9]([C:14]([O:16][CH3:25])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:1](=[O:24])[C:2]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:3]12
Reactant: CC(C)=O
Reactant: CC1=C(C(=O)O)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Solvent: O
Product: COC(=O)C1=C(C)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Reaction time: 3 h

Procedure:
To a solution of 17.3 g. (0.05 mol.) of 7-phthalimido-3-methyl-3-cephem-4-carboxylic acid in 50 ml. of acetone and 20 ml. of water, 5 g. (0.05 mol.) of KHCO3 were slowly added. The resulting solution was evaporated to dryness, and 38 ml. of DMF and 5 ml. of methyl iodide were added to the residue. The mixture was stirred for 3 hrs. at room temperature. To this mixture were then added 100 g. of ice, and the resulting solid product was filtered. The product was crystallized from a mixture of 100 ml. of 2-propanol and 100 ml. of acetone. Yield: 7.91 of crystals, m.p. 187°-188°; ir (CHCl3) 1790 and 1735 cm-1, nmr (CDCl3) δ 2.31 (s, 3, CH3), 3.0 and 3.75 (ABq, 2, J=15 Hz), 3.85 (s, 3, CH3), 5.15 (d, 1, J=4.4 Hz), 5.74 (d, 1, J=4.4 Hz) and 7.73 (m, 4, ArH).
Reaction SMILES: [CH:1]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([OH:10])[C:4]([OH:11])=[C:3]2C([O:14][C:15](=[O:16])[C:2]=12)=O>O>[CH:1]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([OH:10])[C:4]([OH:11])=[CH:3][C:2]=1[C:15]([OH:16])=[O:14]
Reactant: O=C1OC(=O)c2c1cc(=O)c(O)c(O)c2O
Solvent: O
Product: O=C(O)c1cc(O)c(O)c(O)c(=O)c1
Yield: 67.9 %

Procedure:
5 mg of puberulonic acid are dissolved in 300 μl of water and treated at 105° for 15 hours under nitrogen, using a Pico-tag apparatus (Waters-Millipore). The reaction solution is freeze dried, obtaining about 3 mg of puberulic acid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([CH:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([CH3:21])[N:13]=[C:14]([CH3:20])[CH:15]=2)[NH:10]1)[CH3:8].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH2:26]([O:25][C:23]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([CH3:20])=[N:13][C:12]=2[CH3:21])[C:17](=[O:19])[CH2:18][CH:9]1[CH2:7][CH3:8])=[O:24])[CH3:27]
Reactant: CCC1CC(=O)c2cc(C)nc(C)c2N1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)N1c2c(cc(C)nc2C)C(=O)CC1CC

Procedure:
This compound can be obtained by reacting a suspension of K2CO3 (3-5 eqv) in THF with a solution of 2-ethyl-6,8-dimethyl-2,3-dihydro-1H-[1,7]naphthyridin-4-one in THF and ethyl chloroformate (1.5 to 2 eqv), typically at a temperature from about RT to about 50° C., followed by a typical workup procedure.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:2][NH2:3])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
2.75 mol of hydrazine hydrate was added to a solution of 0.275 mol of ethyl ester of 4-(4-chloro benzyloxy) benzoic acid (X) in 300 ml ethanol. The reaction medium was reflux-heated for 48 hours. After cooling, the expected product was separated by filtration and recrystallised from ethanol.
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:31])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]2=[O:20])=O)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[C:25]1([CH2:24][CH2:23][CH2:22][CH2:21][N:14]2[C:15](=[O:20])[CH:16]3[NH:11][CH:12]([CH2:19][CH2:18][CH2:17]3)[C:13]2=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: O=C1C2CCCC(C(=O)N1CCCCc1ccccc1)N2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1C2CCCC(N2)C(=O)N1CCCCc1ccccc1
Yield: 92.4 %

Procedure:
2,4-Dioxo-3-(4-phenylbutyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 13, 0.57 g, 1.36 mmol) was dissolved in THF (3 mL), and 10% palladium on activated carbon (0.12 g) was added. Hydrogen was applied via balloon for 1 hour. The black suspension was then filtered through compacted Celite, and the THF was removed by high-vacuum rotary evaporator to give Compound 14 (0.36 g, 92%) as a thick oil, which was of sufficiently good quality to be advanced to the next step without further purification.
Reaction SMILES: C[C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].C1(=O)O[C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH:18]1[CH:17]=[CH:16][C:12]([C:13]([C:7]2[CH:6]=[CH:5][C:3]([OH:4])=[CH:2][C:8]=2[OH:9])=[O:14])=[CH:11][CH:19]=1
Reactant: Cc1c(O)cccc1O
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1ccc(O)cc1O
Temperature: 0 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
Under an argon atmosphere, 2-methylresorcinol (10.0 g, 80.6 mmol) and phthalic anhydride (11.2 g, 75.6 mmol) were combined in dry nitrobenzene (250 mL). The mixture was cooled to 0° C. and aluminum(III) chloride (23.5 g, 176 mmol) was added in one portion. The resulting dark olive slurry was allowed to warm to room temperature and stirred for an additional 16 h under argon. The reaction was poured into a vigorously stirring mixture of hexanes (300 mL) and 1 M HCl (1 L). The precipitate was filtered and recrystallized twice from methanol/water to afford benzophenone 1 as a beige powder (16.0 g, 78% yield). 1H NMR (CD3OD, 500 MHz): δ 8.05 (1 H, dd, J1=8.0 Hz, J2=1.0 Hz), 7.62 (2 H, dt, J1=33.0 Hz, J2=9.0 Hz), 7.33 (1 H, d, J=7.5 Hz), 6.74 (1 H, d, J=8.5 Hz), 6.20 (1 H, d, J=8.5 Hz), 2.05 (3 H, s). HRMS (ESI) calcd for [M−H]− 271.0601, found 271.0601.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([N:18]=[CH:19][C:20]([S:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([N:33]([CH3:46])S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:28]3)=[N:21]2)=[CH:16][CH:15]=1.SCCO>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([N:18]=[CH:19][C:20]([S:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH:30]([NH:33][CH3:46])[CH2:31][CH2:32]3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N(C)S(=O)(=O)c4ccccc4[N+](=O)[O-])CC3)nc2c1
Agent: OCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CNC1CCN(CCSc2cnc3ccc(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (36 μL, 0.24 mmol, 1.2 eq) is added at room temperature to a stirred solution of N-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-N-methyl-2-nitro-benzenesulfonamide (104 mg, 0.20 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 2-mercaptoethanol (56 μL, 0.90 mmol, 1.5 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine as a yellow oil (43 mg, 62% yield).