Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([NH2:22])=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[OH-].[Na+].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O.CC(C)=O.CCOC(C)=O>[C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:13]=[C:14]([C:23]([F:25])([F:24])[F:26])[C:15]([NH2:22])=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(C(F)(F)F)c(N)c(C(F)(F)F)c1)NC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1cc(C(F)(F)F)c(N)c(C(F)(F)F)c1)NC(C)=O
Temperature: 37 °C

Procedure:
4 mL Alcalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd) was added to a solution of 3.65 g (20.5 mmol) Na2HPO4 dihydrate in 130 mL water warmed to 37° C. and the pH was adjusted to 7.5 by the addition of NaH2PO4 dihydrate. Then a solution of 3.8 g (9.84 mmol) ethyl 2-acetylamino-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)-propionate in 40 mL acetone was added dropwise at 37° C. with stirring. The pH value of the reaction mixture was constantly kept in the range from 7.4-7.6 by the addition of 1 M NaOH. After the addition had ended the mixture was stirred for 4 h at 37° C. After cooling to RT the reaction mixture was combined with 300 mL DCM, 300 mL 15% K2CO3 solution and 200 mL water. The organic phase was separated off, washed with 7% K2CO3 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the crude product (2.2 g) was further reacted without purification. ESI-MS: (M+H)+387 Rf=0.60 (silica gel, PE/EtOAc 1:1)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[F:22].[NH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]1>ClCCl>[C:32]([O:31][C:30]([NH:29][CH:26]1[CH2:25][CH2:24][N:23]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]3[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=2[F:22])[CH2:28][CH2:27]1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC(NC(=O)OC(C)(C)C)CC3)c(F)cc2c1=O

Procedure:
A solution of EXAMPLE 7C (0.5 g) and 1,1-dimethylethyl piperidin-4-ylcarbamate in dichloromethane (100 mL) was stirred for 2 hours, diluted with dichloromethane (100 mL), washed with water, 10% citric acid, and brine, and dried (MgSO4), filtered, and concentrated.
Reaction SMILES: [CH:1]1([C:7]2[S:8][C:9]([C:13]([O:15]CC)=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:7]2[S:8][C:9]([C:13]([OH:15])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1sc(C2CCCCC2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(C2CCCCC2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.5 %

Procedure:
To 20 ml of methanol, 17.3 g (68 mmol) of ethyl 2-cyclohexyl-4-methylthiazole-5-carboxylate was dissolved, followed by adding 24 g (150 mmol) of 25% sodium hydroxide aqueous solution and stirring at room temperature for 15 hours. Methanol was removed, and the residue was then dissolved in 200 ml of water, and 10% hydrochloric acid was added to make acidic. Crystal precipitated was filtered, washed with water and dried to obtain 12.8 g (yield: 83%) of 2-cyclohexyl-4-methylthiazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(C#N)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[CH3:24][O-:25].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([O:25][CH3:24])[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)cccc32)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)nc(C2(OC)OC(=O)c3c(Cl)cccc32)n1
Reaction time: 0.17 h

Procedure:
1.0 g of 7-chloro-3-cyano-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide is slurried in 20 ml of methanol and the solution cooled with ice and 0.6 ml of sodium methoxide added dropwise. After stirring for 10 min a further 1 ml of sodium methoxide is added and stirring continued for 10 min and the mixture is then quenched with 2N H2SO4. Methanol is removed on a rotovaporator and the residue partitioned between water and ethyl acetate. The organic phase is dried over Na2SO4 and concentrated. Flash chromatography of the residue over silica gel using 25% ethyl acetate/hexane yields a white solid m.p. 180°14 183° C.
Reaction SMILES: ClCCl.[CH2:4]([S:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[C:26](=[O:27])[N:25]([CH3:28])[C:24]([CH3:29])=[N:23]3)=[CH:17][C:15]=2[N:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>O>[CH2:4]([S:11]([C:12]1[S:13][C:14]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[C:26](=[O:27])[N:25]([CH3:28])[C:24]([CH3:29])=[N:23]3)=[CH:17][C:15]=2[N:16]=1)=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nn(-c2cc3nc(SCc4ccccc4)sc3cc2F)c(=O)n1C
Solvent: ClCCl
Solvent: O
Product: Cc1nn(-c2cc3nc(S(=O)Cc4ccccc4)sc3cc2F)c(=O)n1C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
10 mL of dichloromethane was charged with 0.001 mol 1-(2-(benzylthio)-6-fluorobenzo[d]thiazol-5-yl)-3,4-dimethyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred for 10 mins and then 0.0011 mol m-chloroperoxybenzoic acid (MCPBA) were added. After stirring at room temperature for 2 hours, the mixture was poured into 30 mL of water, extracted with 15 mL dichloromethane twice. Organic phases were combined and dried over anhydrous sodium sulfate. Filtration and removal of solvent under vacuum gave the title compound as a white solid in a 91% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:17]([O:19]CC)=[O:18].O.[OH-].[Li+]>C(O)C.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)c1cc2c(n1CCCCOC)C(=O)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCCCn1c(C(=O)O)cc2c1C(=O)CCC2
Yield: 95.1 %

Procedure:
Ethyl 1-(4-methoxybutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (250 mg) and lithium hydroxide monohydrate (54 mg) were dissolved in ethanol (4 ml) and water (2 ml), and the mixture was stirred at 60° C. for 3 hr. The solvent was concentrated under reduced pressure, and the residue was neutralized with 1N hydrochloric acid, extracted with ethyl acetate (10 ml×2), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (215 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([O:21][C:22](=[O:28])[NH:23][CH2:24][C@H:25]1[CH2:27][O:26]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:27][C@@H:25]([OH:26])[CH2:24][NH:23][C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:28])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(NC[C@H]1CO1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CNC(=O)OCc2ccccc2)CC1
Yield: 37 %

Procedure:
The compound was prepared in analogy to Example 17, step 17.1, starting from 1-Boc-piperazine (20.41 g) and [(2S)-oxiranylmethyl]-carbamic acid benzyl ester (22.75 g). A yellowish oil (16.0 g; 37% yield) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C:9]([CH2:11][CH3:12])=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:7]2[N:23]=[CH:24][C:25]([C:26]#[N:27])=[C:6]12)=[O:4].[CH2:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:11]([C:9]1[CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:38]2[CH2:39][CH2:40][N:35]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:36][CH2:37]2)[C:6]2[N:7]([N:23]=[CH:24][C:25]=2[C:26]#[N:27])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=1)[CH3:12]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3ccccc3)CC2)C1

Procedure:
A mixture of 3.8 g of 4-chloroacetyl-4,5-dihydro6-ethyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 1.8 ml of 1-benzyl piperazine and 1.1 g of sodium carbonate in 128 ml of toluene was reacted as described in Example 146, giving 3.7 g of the desired product, mp 97°-99° C.
Reaction SMILES: C(OC([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([O:25][C@H:26]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]3[CH2:51][CH2:50]3)[CH:38]=2)[CH2:27][C:28]2[C:33]([Cl:34])=[CH:32][N+:31]([O-:35])=[CH:30][C:29]=2[Cl:36])=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:36][C:29]1[CH:30]=[N+:31]([O-:35])[CH:32]=[C:33]([Cl:34])[C:28]=1[CH2:27][C@@H:26]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:45])[F:46])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)[O:25][C:23](=[O:24])[CH2:22][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:14]1
Reactant: CC(C)(C)OC(=O)N(c1cn(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c2ccccc12)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cn(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c2ccccc12
Yield: 81.3 %

Procedure:
A solution of (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (297 mg, 0.385 mmol) and 4N HCl in dioxane (2 ml, 8.00 mmol) in DCM (4 ml) was stirred at room temperature for 18 hours. The volatiles were removed under vacuum and the crude was purified by flash chromatography on silica gel (DCM:EtOAc=6:4) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(methylsulfonamido)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (210 mg, 0.313 mmol, 81% yield). MS/ESI+ 670.36 [MH]+; [αD]=+7.7, c=0.6, MeOH; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.18 (br. s., 1H), 8.51 (s, 2H), 7.67 (d, 1H), 7.29 (s, 1H), 7.04-7.20 (m, 4H), 7.02 (d, 1H), 6.91 (dd, 1H), 7.06 (t, 1H), 6.01 (dd, 1H), 5.23 (d, 1H), 5.06 (d, 1H), 3.85 (d, 2H), 3.42 (dd, 1H), 3.20 (dd, 1H), 2.86 (s, 3H), 1.08-1.31 (m, 1H), 0.54-0.68 (m, 2H), 0.30-0.48 (m, 2H))
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3].Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3]
Reactant: ClCCN1CCCC1
Reactant: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Product: NC(=O)Nc1cc(-c2cccc(OCCN3CCCC3)c2)sc1C(N)=O

Procedure:
Prepared by the method of Example 9(b) using the product of Example 6 and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:22])[C:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[C:6]2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@H]1[C@H](NC)CCCC1>O1CCOCC1.[Cu]I>[N:29]1([C:2]2[N:7]3[N:8]=[C:9]([CH3:22])[C:10]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]=[CH:14][CH:13]=4)=[C:6]3[N:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: Cc1nn2c(Cl)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nn2c(-n3ccnc3)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Temperature: 100 °C
Reaction time: 120 h
Yield: 14.8 %

Procedure:
A 20 mL microwave vial was charged with 7-chloro-2-methyl-5-(4-morpholinyl)-3-(1-naphthalenylmethyl) pyrazolo[1,5-a]pyrimidine (200 mg, 0.509 mmol), imidazole (243 mg, 3.56 mmol), potassium phosphate (324 mg, 1.527 mmol), copper(I) iodide (58.2 mg, 0.305 mmol) and (1R,2R)-diaminomethylcyclohexane (87 mg, 0.611 mmol) in 1,4-Dioxane (5 mL). The reaction was purged with nitrogen and sealed. The reaction mixture was stirred at 100° C. for 5 days. After cooling the reaction, EtOAc (30 mL) was added in. The reaction was filtered and the filtrate was washed with brine (10 mL×3), dried (MgSO4) and concentrated to give the crude. The residue was purified on silica column (EtOAc/Hexane: 20˜60%), then (0˜3% MeOH/DCM) to give the product (32 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.24 (s, 3H) 3.71 (s, 8H) 4.37 (s, 2H) 6.90 (s, 1H) 7.19 (s, 1H) 7.30-7.60 (m, 4H) 7.77 (d, J=7.83 Hz, 1H) 7.84-7.97 (m, 1H) 8.08 (t, J=1.39 Hz, 1H) 8.35-8.55 (m, 1H) 8.70 (s, 1H); LC/MS: MS (ES+) m/e 425.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1Oc1ccc(N)cc1
Yield: 99.4 %

Procedure:
A mixture of 430A (7.34 g, 29.9 mmol) and 10% Pd/C (1.47 g, 20 wt %, 50 wt % H2O) was stirred under H2 balloon in MeOH (60 ml) for 12 h. The catalyst was removed by filtration on celite. The filtrate was concentrated in vacuo to give 430B (6.40 g, 99%) as a white solid. It has a retention time of 3.77 min (standard ∠Cl method, 8 min run). MS found: (M+H)+=216.1
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:31])[NH:21][C:22]1[O:26][N:25]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1)(C)(C)C>C(Cl)Cl>[C:27]([C:24]1[CH:23]=[C:22]([NH:21][C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[CH2:14][C:13]([OH:32])=[O:12])=[O:31])[O:26][N:25]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)CN1CCC[C@H]1C(=O)Nc1cc(C(C)(C)C)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2CC(=O)O)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 20% trifluoroacetic acid in methylene chloride (20 mL) is added to [(S)-2-(3-tert-butyl-isoxazol-5-ylcarbamoyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester (0.23 g; 0.654 mmol) and the reaction mixture is stirred at room temperature overnight. After this time, the mixture is concentrated in vacuo and purified by preparative HPLC to afford title compound. ESI m/z 296 [M+H]+/294 [M−H]−
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8](C(O)=O)[CH:7]=[CH:6][C:5]=12.C([N:15](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[NH2:15][C:8]1[CH:7]=[CH:6][C:5]2=[N:1][O:2][N:3]=[C:4]2[CH:9]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1ccc2nonc2c1
Temperature: 105 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a solution of 2,1,3-benzoxadiazole-5-carboxylic acid (102 mg, 0.621 mmol) in THF (3 mL) was added triethylamine (103 mL, 0.739 mmol) followed by DPPA (160 μL, 0.739 mmol) at room temperature. The mixture was stirred for 4 h, diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4, concentrated and purified by flash chromatography on silica gel with 0 to 50% EtOAc in CH2Cl2. The resulting material was dissolved in AcOH (2 mL) and water (0.7 mL) was added dropwise yielding a slightly cloudy solution which was heated at 105° C. for 30 min. The mixture was cooled, made basic with sat. Na2CO3 solution and extracted several times with THF. The combined organic layers were dried over MgSO4, concentrated and purified by flash chromatography on silica gel eluting with 0 to 15% MeOH in CH2Cl2 to give 34 mg (41%) of compound 480A as a yellow solid. HPLC: 100% at 1.27 min (retention time) (YMC S5 ODS column, 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 min containing 0.2% H3PO4, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 136.0 [M+H]+.
Reaction SMILES: C(OC([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:42])[C:16]([NH:18][CH:19]2[C:40](=[O:41])[N:21]3[C:22]([C:37]([OH:39])=[O:38])=[C:23]([CH2:26][S:27][C:28]4[N:32]([CH2:33][C:34]([OH:36])=[O:35])[N:31]=[N:30][N:29]=4)[CH2:24][S:25][C@H:20]23)=[O:17])[N:14]=1)=O)(CC)(C)C>C(O)=O>[NH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:42])[C:16]([NH:18][CH:19]2[C:40](=[O:41])[N:21]3[C:22]([C:37]([OH:39])=[O:38])=[C:23]([CH2:26][S:27][C:28]4[N:32]([CH2:33][C:34]([OH:36])=[O:35])[N:31]=[N:30][N:29]=4)[CH2:24][S:25][C@H:20]23)=[O:17])[N:14]=1
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4CC(=O)O)CS[C@H]23)cs1
Solvent: O=CO
Product: Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4CC(=O)O)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 33.6 %

Procedure:
A mixture of 7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (870 mg.) and 99% formic acid (16 ml.) was stirred for 3.5 hours at ambient temperature. The solvent was distilled off and to the residue was added diethyl ether (20 ml.). Insoluble material was collected by filtration and dissolved in 5% sodium bicarbonate aqueous solution (20 ml.) The aqueous solution was washed with ethyl acetate (20 ml.) and to the resulting aqueous solution was added ethyl acetate (60 ml.). The mixture was adjusted to pH 2.0 with 10% hydrochloric acid with stirring to precipitate powder. The precipitates were collected by filtration, well stirred in ethyl acetate (50 ml.) to remove impurities and collected by filtration to give 7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (240 mg.). The aqueous layer in the filtrate of pH 2.0 as mentioned above was separated and allowed to stand overnight. Precipitates were collected by filtration further to give the same object compound (120 mg.). Total yield 360 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[N+:9]([C:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:6]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])[nH]n1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 3,5-dinitro-1H-pyrazole (2.5 g, 15.81 mmol) and potassium carbonate (4.36 g, 31.62 mmol) in DMF (50 mL) at 0° C. was added (2-(chloromethoxy)ethyl)trimethylsilane (3.07 mL, 17.39 mmol) and the mixture was stirred at rt for 6 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography eluting with 0-20% EtOAc/hexane to afford 3,5-dinitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a colorless oil (2.7 g, 59%). 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 6.00 (s, 2H), 3.72-3.67 (m, 2H), 0.97-0.91 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:4]=[CH:3]1.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:4]=[CH:3]1
Reactant: COC(=O)CCC1C=CC(=O)CC1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: COC(=O)CCC1C=CC(O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 0.36 g of methyl 4-oxocyclohex-2-enepropionate and 500 ml of 0.4M cerium chloride in methanol there was added carefully 0.07 g of sodium borohydride and the mixture was stirred for 10 minutes at room temperature. The reaction was quenched with 2 ml of water and the methanol solvent was removed under reduced pressure. The residue was partitioned between 10 ml of water and 50 ml of ether and the separated organic layer was dried over magnesium sulfate. Evaporation of the solvent from the organic solution gave methyl 4-hydroxycyclohex-2-enepropionate as a clear oil which was used without further purification. 1H NMR (CDCl3) δ 3.56 (s, 3H); 3.90-4.30 (m, 1H); 5.50-5.75 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Mg].[CH2:11](Br)[CH:12]=[CH2:13].[Cl-].[NH4+]>C1COCC1.C(=O)=O>[CH2:13]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH:12]=[CH2:11]
Reactant: O=Cc1cccc(Br)c1
Reactant: C=CCBr
Agent: O=C=O
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1cccc(C=O)c1
Reaction time: 8 h
Yield: 101.3 %

Procedure:
The ethylene acetal of 3-bromobenzaldehyde (10 g) is converted into the Grignard reagent by reaction with magnesium (1.13 g) in dry THF (ca. 250 ml). Cuprous bromide (0.9 g) is added and the mixture is cooled in cardice. Allylbromide (8.52 g) in dry THF is then added and the mixture is stirred overnight following which saturated ammonium chloride is added, the mixture is extracted with diethyl ether (3 times), the ether extract is washed, dried and the solvent evaporated to yield the crude ethylene acetal of 3-allylbenzaldehyde (8 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH:4]=[CH2:5].[Br:7][C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1>C1COCC1>[CH2:3]([O:6][C:11]1[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])[CH:4]=[CH2:5]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a mixture of anhydrous THF (200 mL) and 95% NaH (757 mg, 29.96 mmol) at 0° C. under N2 was added allyl alcohol (2.04 mL, 29.96 mmol) dropwise. After 0.5 hour, 4-bromo-1-fluoro-2-nitro-benzene (5.07 g, 23.04 mmol) was added dropwise. The reaction was warmed from 0° C. to room temperature under N2 overnight, and inorganic salt was filtered. The filtrate was concentrated with silica gel powder (20 g), and purified by flash chromatogrphy eluting with 10% ethyl acetate in hexanes (1 L) and 20% ethyl acetate in hexanes (1 L) to give the title compound (5.06 g, 85%). MS (DCI) m/z 257.35 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 4.65–4.70 (m, 2 H) 5.35 (m, 1 H) 5.48 (m, 1 H) 6.02 (m, 1 H) 6.97 (d, J=9.16 Hz, 1 H) 7.61 (dd, J=8.99, 2.54 Hz, 1 H) 7.97 (d, J=2.37 Hz, 1 H).