Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]([NH:14][CH2:15][CH2:16][OH:17])([CH3:13])[CH3:12].C(N(CC)CC)C>O1CCCC1>[CH:11]([N:14]([CH2:15][CH2:16][OH:17])[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)([CH3:13])[CH3:12]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(CCO)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chlorobenzoxazole (23.04 g) was added dropwise to an ice-cooled solution of 2-(isopropylamino)ethanol 15.45 g) and triethylamine (30.3 g) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 30 minutes, then heated at reflux overnight before being cooled and evaporated. The residue was dissolved in dichloromethane (800 ml) and washed with saturated sodium bicarbonate solution (500 ml), water (3×1 l) brine (1 l), dried (MgSO4), filtered and evaporated. The title compound was obtained as an oil following chromatography on silica gel using 1.5% methanol-dichloromethane as solvent.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]5[C:35]=4[N:34]=[CH:33][CH:32]=[CH:31]5)(=[O:25])=[O:24])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[C:36]([O:39][CH2:40][CH2:41]Br)(=[O:38])[CH3:37]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([S:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]5[C:35]=4[N:34]=[CH:33][CH:32]=[CH:31]5)(=[O:25])=[O:24])[CH2:37][C:36]([O:39][CH2:40][CH3:41])=[O:38])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)OCCBr
Reactant: Cc1cc(COc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc12
Product: CCOC(=O)CN(c1ccc2c(C)cc(COc3ccc(C#N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1d from 2-[(4-cyanophenyl)-oxymethyl]-4-methyl-7-(quinoline-8-sulphonylamino)-quinoline and bromoethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][NH2:13].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CC#N.O>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:12][NH2:13])=[CH:4][CH:3]=1
Reactant: NCCCl
Reactant: Cc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(SCCN)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 4-methylbenzenethiol (1.24 g), 2-chloroethylamine HCl (2.3 g) and Cs2CO3 (5.3 g) in CH3CN (30 mL) was stirred at 50° C. for 2 days. To the reaction mixture were added EtOAc (50 mL) and H2O (30 mL). The organic phase was separated, washed with H2O (2×30 mL) and concentrated under reduced pressure to give product 24. Yield: 1.67 g, 95%.
Reaction SMILES: F[C:2]1(F)[C:10]2[C:5](=[C:6]([F:14])[C:7]([F:13])=[C:8]([F:12])[C:9]=2[F:11])[C:4](=[O:15])[O:3]1.C(=O)([O-])[O-:18].[Na+].[Na+]>>[F:11][C:9]1[C:8]([F:12])=[C:7]([F:13])[C:6]([F:14])=[C:5]2[C:4](=[O:15])[O:3][C:2](=[O:18])[C:10]=12
Reactant: O=C([O-])[O-]
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Agent: [Na+]
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 87.5 %

Procedure:
Into a 500 ml glass reactor equipped with a reflux condenser and a stirrer, 100 g (0.413 mol) of the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone separated by distillation from the mixture of Example 2, and 43.8 g (0.413 mol) of sodium carbonate were charged, and the mixture was reacted at 130° C. for 8 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 79.5 g of tetrafluorophthalic anhydride. The yield was 87.5%.
Reaction SMILES: [Br:1][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:11])[CH3:10].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[CH3:10][CH:9]([CH3:11])[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:12][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)CC=CCCCC(C)Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CC(C)CC=CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A solution of 9-bromo-2-methyl-4-decene (0.9 g) and triphenylphosphine (1.5 g) in xylene (50 ml) was heated under reflux for 4 days. The mixture was cooled, the supernatant was decanted and the residue was washed with ether and dried under vacuum to give the title compound as a pale gum.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4][CH2:3]1.[N:23]1[C:32]2[NH:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[CH:33]=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.C(O)C>[CH3:22][O:21][C:18]1[N:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[C@@H:9]([OH:10])[CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:33][C:24]2[CH:25]=[CH:26][C:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:32]=3[N:23]=2)[CH2:3][CH2:4]1
Reactant: O=Cc1ccc2c(n1)NCCC2
Reactant: COc1ccc2nccc([C@@H](O)CN3CCC(N)CC3)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc([C@@H](O)CN3CCC(NCc4ccc5c(n4)NCCC5)CC3)c2n1
Reaction time: 36 h
Yield: 83 %

Procedure:
To a stirred solution of (R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol (2f) (0.30 g, 1.0 mmole) in CH2Cl2 (25 mL) and dry ethanol (10 mL) at RT was added 5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxaldehyde (prepared according to the procedure of WO 98/08840, 0.17 g, 1.0 mmole) and granular Na2SO4 (approximately 200 mg). After 36 h, the reaction was filtered through a sintered-glass funnel and the filtrate was concentrated. The remaining residue was dissolved in dry ethanol and reacted with NaBH4 (0.04 g, 1.0 mmole). After 12 h at RT, the reaction was concentrated under vacuum and the residue was dissolved in a mixture of H2O (2 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous solution was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine then were dried over Na2SO4. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) afforded the title compound (0.37 g, 83%) as a white solid:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([CH2:20][C:21]1[N:26]=[C:25]([CH2:27][C:28]([OH:30])=O)[CH:24]=[CH:23][CH:22]=1)([OH:19])=O>CO.CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:17](=[O:19])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([CH2:27][C:28]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:30])[N:26]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)Cc1cccc(CC(=O)O)n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1cccc(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)n1
Yield: 7.8 %

Procedure:
Using General Procedure A with 9.7 g (40 mmol) D-Proline benzyl ester hydrochloride and 3.9 g (20 mmol) (6-carboxymethyl-pyridin-2-yl)-acetic acid afforded, after flash chromatography (gradient: 0-10% MeOH/EtOAc), 890 mg (8%) of the title compound as a yellow oil. MS m/e (%): 570 (M+H+, 100).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:12]=[C:11]([SH:13])[N:10]2[N:14]=[CH:15][N:16]=[C:9]2[N:8]=1)=[O:5])C.[OH-].[K+].Cl>O>[C:4]([CH2:6][C:7]1[CH:12]=[C:11]([SH:13])[N:10]2[N:14]=[CH:15][N:16]=[C:9]2[N:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1cc(S)n2ncnc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1cc(S)n2ncnc2n1
Temperature: 60 °C
Yield: 73.7 %

Procedure:
The product obtained in Step 3 (20 g) was added to a solution of 10 g of potassium hydroxide in 200 ml of water, the mixture was heated at 60° C. for two hours. After cooling the resulting yellow solution, its pH was lowered to 2.0 with concentrated hydrochloric acid, and the yellow crystals thus formed were collected by filtration, washed twice with 30 ml of water and dried, giving 13 g of the objective compound as yellow crystals.
Reaction SMILES: [C:1](Cl)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCCCCCCCC.[O:25]=[C:26]([CH2:28][N:29]([C:31](=[NH:33])[NH2:32])[CH3:30])[OH:27].N1C=CC=CC=1.C(=O)=O>ClCCl.CC(C)=O>[C:1]([NH:33][C:31](=[NH:32])[N:29]([CH2:28][C:26]([OH:27])=[O:25])[CH3:30])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(CC(=O)O)C(=N)N
Agent: O=C=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)NC(=N)N(C)CC(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the docosanoyl chloride solution, 12.59 g (96 mmol) of creatine is suspended, with stirring, in 100 ml of dry dichloromethane. To this suspension a catalytic amount (0.1 mmol) of pyridine is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of between about −15° C. and 0° C. When the target temperature is reached the drop wise addition of docosanoyl chloride is commenced. Addition of docosanoyl chloride continues, with cooling and stirring, until all of the docosanoyl chloride is added, after which the reaction is allowed to warm to room temperature with constant stirring. The solution is then filtered to remove any remaining creatine, and the volatile dichloromethane and pyridine are removed under reduced pressure yielding 2-(3-dodecanoyl-1-methylguanidino)acetic acid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11](=[O:23])[C:12]3[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15](F)=[CH:14][C:13]=3Cl)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH4+:24].[OH-].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>O1CCOCC1>[NH2:24][C:15]1[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]([C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[O:23])=[C:13]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[CH:14]=1
Reactant: O=C(Nc1ccc2ncsc2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [NH4+]
Reactant: CCNCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(CC)c1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2ncsc2c1

Procedure:
A solution of the aforementioned amide (3 mmol) in dioxane was reacted with aqueous NH4OH and subsequently with diethylamine using the one-pot procedure described for Example 115 to yield 4-amino-N-benzothiazol-6-yl-2-diethylamino-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH2:60][CH:61]=[O:62])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]([C@@H:61]([OH:62])[CH2:60][CH2:59][C:56]1[CH:57]=[CH:58][C:53]([C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=2)=[CH:54][CH:55]=1)[CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCn1nnc2ccccc2c1=O)N1C(=O)SC[C@@H]1Cc1ccccc1
Reactant: O=CCCc1ccc(-c2ccc(F)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Solvent: ClCCl
Product: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
In a flame-dried flask, 3-{3-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-3-oxopropyl}-1,2,3-benzotriazin-4(3H)-one (0.25 g) was taken up in dichloromethane (10 mL) and cooled to 0° C. Titanium tetrachloride (0.76 mL, 1 M solution) was added drop-wise and the reaction mixture was stirred for 10 to 15 minutes. (−)-Sparteine (0.36 mL) was added slowly to the reaction mixture and stirred at 0° C. for 20 minutes. A solution of the compound obtained from step e above (0.17 g) in dichloromethane (10 mL) was added slowly, and stirring was continued at 0° C. After 3 hours, the reaction was quenched with the drop-wise addition of saturated ammonium chloride solution, and dichloromethane was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as eluant to afford the title compound (0.2 g).
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]2[CH2:15][CH2:16][C:17]3([CH2:19][CH:18]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[O:8]=[C:9]1[NH:14][CH:13]=[C:12]2[CH2:15][CH2:16][C:17]3([CH2:19][CH:18]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]2=[CH:10]1
Reactant: [H][H]
Reactant: CCOC(=O)C1CC12CCc1cnc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC12CCc1c[nH]c(=O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound H6.7 (200 mg, 618 μmol) was dissolved in 5 mL EtOH. To this solution was added palladium on carbon (65.8 mg, 618 μmol) and hydrogen was introduced by balloon. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the catalyst was filtered off and the solvent was removed to provide H6.8 (135 mg, 93.6%). MS ESI (pos.) m/e: 234.2 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:25]([O-:27])=[O:26])=[C:6]([CH2:9][N+:10]3[N:11]([CH2:19][CH2:20][O:21]C(=O)C)[C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.Cl.[NH2:39][C:40]1[S:44][N:43]=[C:42](/[C:45](=[N:49]/[O:50][CH2:51][CH:52]=[CH2:53])/[C:46](Cl)=[O:47])[N:41]=1.CCOCC>ClCCl>[NH2:39][C:40]1[S:44][N:43]=[C:42]([C:45](=[N:49][O:50][CH2:51][CH:52]=[CH2:53])[C:46]([NH:1][C@@H:2]2[C:28](=[O:29])[N:4]3[C:5]([C:25]([O-:27])=[O:26])=[C:6]([CH2:9][N+:10]4[N:11]([CH2:19][CH2:20][OH:21])[C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=4)[CH2:7][S:8][C@H:3]23)=[O:47])[N:41]=1
Reactant: C=CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: CC(=O)Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCOC(C)=O
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC(C)=O)n3CCO)CS[C@H]12)c1nsc(N)n1
Yield: 20.4 %

Procedure:
To a solution of di(trifluoroacetic acid) salt of 7β-amino-3-[3-acetamido-2-(2-acetoxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (1 g) and N-(trimethylsilyl)acetamide (2.01 g) in dichloromethane (20 ml) was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetyl chloride hydrochloride (0.520 g) under stirring and ice-cooling. The mixture was stirred for one hour at room temperature. The reaction mixture was added to ether under stirring and ice-cooling. The produced amorphous solid was dried in vacuo and dissolved in water. The aqueous solution was adjusted to pH 13 with 1N aqueous sodium hydroxide under stirring at -3°~0° C. and stirred for 2 hours at the same temperature. The aqueous solution was adjusted to pH 2 with 1N hydrochloric acid and subjected to column chromatography on Diaion HP-20 and the elution was carried out with 10% aqueous isopropyl alcohol. The fractions containing the object compound were combined, concentrated to remove isopropyl alcohol and lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[3-acetamido-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (222 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[N:4][C:5]([Br:22])=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nccnc2N)cc1F
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a stirred solution of tert-butyl 4-(3-aminopyrazin-2-yl)-2-fluorobenzoate (37.7 g, 130 mmol) in acetonitrile (800 mL) at 0° C. was added N-bromosuccinimide (23.19 g, 130 mmol) in one portion. The reaction was stirred at 0° C. for 2 h, then quenched with saturated NaHCO3 solution (200 mL) and stirred at 0° C. for 30 min. The mixture was diluted with water (300 mL) and extracted with EtOAc (3×250 mL). The combined organics were washed with water (200 mL) and brine (2×200 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified using flash chromatography on silica gel (0 to 40% EtOAc in heptane over 40 min), giving tert-butyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (30.9 g, 64%) as a solid. LCMS (m/z): 368/370 (MH+), 1.03 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 1H) 7.97-7.74 (m, 1H) 7.62-7.39 (m, 2H) 6.64 (s, 2H) 1.54 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:21][OH:22])[O:8][C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[N:5]2[C:16](=[O:20])[N:17]([CH3:19])[N:18]=[C:4]12.N1C=CC=CC=1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:36][C:35]1[CH:37]=[CH:38][C:32]([S:29]([O:1][CH2:2][C:3]2([CH2:21][OH:22])[O:8][C:7]3[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=3[N:5]3[C:16](=[O:20])[N:17]([CH3:19])[N:18]=[C:4]23)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC2(CO)CO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(CO)Oc3ccc([N+](=O)[O-])cc3-n3c2nn(C)c3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,4-Bis(hydroxymethyl)-2-methyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one (1.6 g) and pyridine (0.84 mL, 2 eq.) were dissolved in anhydrous dichloromethane (100 mL). In an ice bath, tosyl chloride (1.2 g, 1.2 eq.) was added to the reaction solution in portions. The reaction was stirred in an ice bath to room temperature overnight. Then triethylamine (1.5 mL, 2 eq.) and more of tosyl chloride (500 mg, 0.5 eq.) were added and stirred at room temperature overnight. LCMS showed mixtures of starting material, mono-tosylated product and bis-tosylated product. The reaction solution was evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=20-100%) to give (4-(hydroxymethyl)-2-methyl-8-nitro-1-oxo-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-4-yl)methyl 4-methylbenzenesulfonate. m/z=462.83 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([CH:9]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[C:36](=[O:37])[CH2:35][O:34][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:32]3)=[CH:26][CH:25]=2)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2([CH2:19][C:20]([O:22]C)=[O:21])[CH2:18][CH2:17]2)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1>C1COCC1.O>[CH:4]1([CH:9]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][N:31]3[C:36](=[O:37])[CH2:35][O:34][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:32]3)=[CH:28][CH:29]=2)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2([CH2:19][C:20]([OH:22])=[O:21])[CH2:18][CH2:17]2)=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)CC1(CCCNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1(CCCNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
71 mg (1.69 mmol) of lithium hydroxide monohydrate were added to a solution of 230 mg (0.42 mmol) of methyl (1-{3-[(cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl)amino]propyl}cyclopropyl)acetate in 2.8 ml of THF and 1.4 ml of water, and the mixture was stirred at RT overnight. After the reaction had gone to completion, the THF was removed under reduced pressure and the reaction solution was diluted with water and then adjusted to pH 2 with 1 M hydrochloric acid. The precipitated solid was filtered off, washed with water and dried under reduced pressure at 45° C. overnight. This gave 217 mg (0.41 mmol, 97% of theory) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([F:20])([F:19])[F:18])=[O:5])C.[Li+].[OH-].Cl>C1COCC1>[C:11]1([C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:17]([F:18])([F:19])[F:20])[N:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of 2-phenyl-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (1.6 g, 5.3 mmol) in THF (16 mL) was added 1 N aqueous LiOH (16 mL, 16 mmol). This mixture was brought to reflux and stirred vigorously for 1 h. The mixture was allowed to cool to 25° C. and 1 N aqueous HCl (35 mL, 35 mmol) was added. The mixture was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were washed with saturated aqueous NaCl (1×50 mL), dried over MgSO4 and concentrated in vacuo to give the carboxylic acid as a white solid (1.32 g, 91%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:37])[CH2:35][CH3:36]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A167) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([N:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br-].[C:21]([O:24][C@@H:25]1[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:30]([O:36][C:37](=[O:39])[CH3:38])[C@@H:29]([C:40]([O:42][CH3:43])=[O:41])[O:28][C@@H:26]1[OH:27])(=[O:23])[CH3:22]>C(#N)C.[Ag]=O>[C:1]([N:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C@:26]1([O:28][C@H:29]([C:40]([O:42][CH3:43])=[O:41])[C@@H:30]([O:36][C:37](=[O:39])[CH3:38])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:25]1[O:24][C:21](=[O:23])[CH3:22])[OH:27])[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cc([N+](=O)[O-])ccc1O
Reactant: COC(=O)[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=[Ag]
Agent: [Br-]
Solvent: CC#N
Product: COC(=O)[C@H]1O[C@](O)(c2ccc([N+](=O)[O-])cc2N(C)C(=O)OC(C)(C)C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Silver oxide (0.23 g, 0.992 mmol) and 2-(N-BOC,N-methylamino)-4-nitrophenol (3) were added to a solution of methyl 2,3,4-tri-O-acetyl-a-D-glucuronate bromide (4) (126 mg, 0.317 mmol) in acetonitrile (5 ml). The reaction mixture was stirred at room temperature for 1 hour, filtered through Celite and concentrated in vacuo. The product was chromatographed on silica gel (eluent dichloromethane/methanol 97.5/2.5). Yield 165 mg (89%).