Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH:28]=[CH2:29])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][S:15](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)(=[O:17])=[O:16])(=[O:7])=[O:6])[CH:2]=[CH2:3].[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]=[C:31]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH2:1]([N:4]([CH2:27][CH:28]=[CH2:29])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][S:15](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([C:31]2[O:30][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH:32]=2)=[CH:22][CH:21]=1)(=[O:17])=[O:16])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)/C=C/c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)/C=C/c1ccc(-c2cc3ccccc3o2)cc1
Temperature: 120 °C
Yield: 38 %

Procedure:
A mixture of (E)-N,N-diallyl-4-(2-(4-bromophenyl)vinylsulfonamido)pyridine-3-sulfonamide (0.47 g, 0.94 mmol), 2-benzofuranboronic acid (0.20 g, 1.23 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.039 g, 0.050 mmol), cesium carbonate (0.46 g, 1.41 mmol), 1,2-dimethoxyethane (9 mL) and water (1 mL) under an atmosphere of argon was heated at 120° C. for 15 min in a microwave. The reaction mixture was partitioned between ethyl acetate and diluted hydrochloric acid, the organic phase was dried over magnesium sulfate and the solvent was evaporated. Purification by column chromatography, using chloroform/methanol (98:2) as the eluent, gave the title compound in 38% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][CH2:10][CH:12]1[CH2:13][O:14]1
Reactant: ClCC1CO1
Reactant: Cc1ccc(O)cc1C
Product: Cc1ccc(OCC2CO2)cc1C

Procedure:
The title compound was prepared from 3,4-dimethyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@@H:11]1[C@@H:14](SC)[N:13]([C:17](=[C:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:26]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Si:1]([O:8][C@H:9]([C@@H:11]1[C@@H:14]([Cl:26])[N:13]([C:17](=[C:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1SC
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1Cl
Temperature: -10 °C
Yield: 36.1 %

Procedure:
To a solution of methyl 2-[(3S,4R)-3-[(1S)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (60 mg) in dichloromethane (2 ml) was added a solution of chlorine (24 mg) in carbon tetrachloride (0.2 ml) at -50° C. The solution was allowed to warm to -10° C. during 30 minutes and cooled to -50° C. An additional solution of chlorine (12 mg) in carbon tetrachloride (0.1 ml) was added. The solution was allowed to warm to -5° C. and evaporated. The residue was chromatographed on silica gel (1.5 g, eluting with 8-10% ethyl acetate in hexane) to give 21.0 mg (36.1%) of methyl 2-[(3S,4R)-3-[(1S)-1-(tert-butyldimethylsilyloxy)ethyl]-4-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate. NMR (CDCl3)δ: 0.12 (s, 6H), 0.93 (s, 9H), 1.34 (d, J=6.5 Hz, 3H), 2.01 (s, 3H), 2.29 (s, 3H), 3.56 (dd, J=1.5, 5 Hz, 1H), 3.77 (s, 3H), 4.30 (dq, J=5, 6.5 Hz, 1H), 5.80 (d, J=1.5 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[Cl:24][C:25]1[C:30]([S:31](Cl)(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1>>[Cl:24][C:25]1[C:30]([S:31]([N:22]2[CH2:21][CH2:20][C:3]3([C:7](=[O:8])[N:6]([C:9]4[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=4)[CH2:5][CH2:4]3)[CH:2]([OH:1])[CH2:23]2)(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2O

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 2 step A) and 2-chloro-pyridine-3-sulfonyl chloride. Colourless solid. MS (ESI): 506.0 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([C:16]2[S:20][C:19]([NH2:21])=[N:18][N:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:11]1([C:16]2[S:20][C:19]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:18][N:17]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1nnc(C2CCCC2)s1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1nnc(C2CCCC2)s1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a 20 ml scintillation vial was added 2-fluorobenzoic acid (845 mg, 5.0 mmol) and commercially available 5-cyclopentyl-1,3,4-thiadiazol-2-amine (intermediate 49) (700 mg, 5.0 mmol). To this was added EDC (960 mg, 5 0 mmol) and HOAt (675 mg, 5.0 mmol) followed by 25 ml DCM. The reaction mixture was stirred with a Teflon covered magnetic stir-bar at room temperature for overnight. The product was collected by ethyl acetate and 5% HCl solution work up, and then to purified by column (CH3OH/DCM, 1-10% gradient system), yielding N-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-2-fluorobenzamide (0.61 g, 42%) as solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[C:28]([S:30][CH3:31])[CH:27]=[C:26]([CH:32]([CH3:34])[CH3:33])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:9]=[CH:14][CH:15]=[CH:16][C:17]=3[CH:10]([C:11]([NH:25][C:24]3[C:26]([CH:32]([CH3:34])[CH3:33])=[CH:27][C:28]([S:30][CH3:31])=[CH:29][C:23]=3[CH:20]([CH3:22])[CH3:21])=[O:13])[C:4]=2[CH:3]=1
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Reactant: CSc1cc(C(C)C)c(N)c(C(C)C)c1
Product: CSc1cc(C(C)C)c(NC(=O)C2c3ccccc3COc3ccc(Br)cc32)c(C(C)C)c1
Yield: 76.1 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 46 (Compound H) in place of Compound A and 0.84 g of 2,6-diisopropyl-4-methylthioaniline in place of aniline to obtain 1.25 g of Compound 44.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:21][O:20][C:18](=[O:19])[CH:17]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH3:22]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1b), the alkylation of 4-benzyloxy-phenol [Example 2a)] with methyl (RS)-2-bromopropionate in acetone using cesium carbonate as the base yielded the (RS)-2-(4-Benzyloxy-phenoxy)-propionic acid methyl ester as light yellow oil; MS: m/e=304 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4](C(OCC)=O)=[C:3]1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(O)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cc(C)cn1C
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To 50 grams of a solution of 20% ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate (10 grams, 40 mmoles) in toluene containing 2.4 ml of absolute ethanol (1.9 grams, 41 mmoles) were added, dropwise, over 20 minutes, 8.6 ml of 96% sulfuric acid (15 grams, 160 mmoles, containing 0.63 gram, 35 mmoles of water). During the addition, the temperature of the reaction mixture rose to about 50° C., and the mixture became heterogeneous. The reaction mixture was then heated in an oil bath at 75°-80° C. for 75 minutes with stirring. Gas evolution was observed. The reaction mixture was then diluted with 25 ml of toluene and cooled to 5° C. Then 75 ml of ice water was added in one portion with vigorous stirring. After five minutes, the organic layer was separated and dried with magnesium sulfate. Gas chromatographic analysis indicates the toluene contained 9% ethyl 1,4-dimethylpyrrole-2 -acetate. The toluene was removed by vacuum distillation at 100 mm of mercury followed by vacuum distillation of the residue at 1 mm of mercury to give a fraction which weighed 5.5 grams. This corresponds to a 78% yield of ethyl 1,4-dimethylpyrrole-2-acetate.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](O)(=[O:36])[C:33]#[C:34][CH3:35]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][N:27]3[C:32](=[O:36])[C:33]#[C:34][CH3:35])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4cccnn4)cc3)c12
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cccnn3)cc2)c2c(N)nccn12
Yield: 31.8 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridazin-3-yl)benzamide (intermediate 33) and 2-butynoic acid, to afford the title compound (11 mg, 31.8%). Data: UPLC(C) Rt: 1.92 min; m/z 481.3 (M+H)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[CH2:7][CH2:6]2)[O:4]CC1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: c1csc(C2CCC3(CC2)OCCO3)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(c2nccs2)CC1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A solution of 2-(1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole (0.21 g, 0.93 mmol) in 10 mL of THF/3NHCl (1:1) was stirred for 2 h at 50° C. After cooling to room temperature, the mixture was treated with Na2CO3 to pH 8 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.16 g of 4-(1,3-thiazol-2-yl)cyclohexanone in 95% yield. MS (EI) calcd: (M+H)+=182.1; found: 181.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[CH:5]=[C:4]([NH2:16])[N:3]=1.[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[C:5]([N:17]=[O:18])=[C:4]([NH2:16])[N:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(OCC2CC=CCC2)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(OCC2CC=CCC2)n1
Temperature: 25 °C

Procedure:
A solution of 2,6-diamino-4-cyclohex-3-enylmethyloxypyrimidine (0.5 g, 2.27 mmol) in 30% acetic acid solution was heated to 80° C., and sodium nitrite solution (0.22 g, 3.19 mmol, in 10 ml H2O) was added dropwise over 1 h until excess oxidant was in evidence (starch-iodide paper). The reaction mixture was cooled to room temperature and the resultant violet crystals were collected, washed thoroughly with water and dried (0.52 g, 92%), m.p. 237° C.; δH (200 MHz, d6-DMSO) 1.51-2.19 (7H, m, C6H7), 4.51 (2H, d, OCH2, J=5.66 Hz), 5.82 (2H, br s, C2H2), 7.95 (2H, br s, NH2), 8.15 (1H, br s, NH), 10.21 (1H, br s, NH); m/z (+EI) 249 (M+, 22%), 155 (M+-C7H11, 60), 138 (M+-C7H11O, 100), 69 (24).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[S:22][CH:21]=[C:20]([CH3:23])[C:18]=2[N:19]=1>C1COCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[S:22][CH:21]=[C:20]([CH3:23])[C:18]=2[N:19]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Cl)nc3c(C)csc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A stirred suspension of NaH (16 mg, 0.4 mmol) in dry THF (2 mL) was added 2,4,6-trimethyl phenol and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (87 mg, 0.4 mmol) in dry THF (2 mL) at 0° C. and slowly warmed up to room temperature. After stirring the reaction for 2 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1) to give the product as a white solid (136 mg, 90%):
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[C:9]=1[CH2:18][CH2:19][CH3:20].[C:21]([C:26]1[O:27][C:28]2[C:33]([C:34](=[O:36])[CH:35]=1)=[CH:32][CH:31]=[C:30]([OH:37])[C:29]=2[CH2:38][CH2:39][CH3:40])([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Ca+2].[Cl-]>CN(C)C=O>[C:21]([C:26]1[O:27][C:28]2[C:33]([C:34](=[O:36])[CH:35]=1)=[CH:32][CH:31]=[C:30]([O:37][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[C:9]=1[CH2:18][CH2:19][CH3:20])[C:29]=2[CH2:38][CH2:39][CH3:40])([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OCC)oc12
Reactant: CCCc1c(OCCCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCOc2ccc3c(=O)cc(C(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Reaction time: 18 h
Yield: 44.4 %

Procedure:
4.67 g (13.6 mmole) of 1-bromo-5-[2-n-propyl-3-hydroxy-4-acetylphenoxy]-pentane, 2.39 g (8.65 mmole) of 2-carboethoxy-7-hydroxy-8-n-propylchromone, and 2.76 g (20 mmole) of anhydrous potassium carbonate were dissolved in 100 ml dimethylformamide in a 250 ml single neck round bottom flask equipped with a magnetic stirring bar and a drying tube charged with calcium chloride. The contents of the flask were stirred at 70° for 18 hours. After cooling, the reaction solution was filtered and the dimethylformamide removed by rotary evaporation. The residual dark red oil was dissolved in 50% ethyl acetate/hexane and purified by chromatography to give 2.07 g (44%) of the title compound, mp 90°-91°. Calc: C, 69.13; H, 7.11; Found: C, 69.44; H, 7.44.
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH3:41])[C@H:3]([NH:12][C:13](=[O:40])[C@H:14]([CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[C@@H:15]([N:17]([CH:25]=[O:26])[O:18]C1CCCCO1)[CH3:16])[C:4](=[O:11])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1>C(O)(=O)C>[CH3:41][C:2]([CH3:1])([CH3:42])[C@H:3]([NH:12][C:13](=[O:40])[C@H:14]([CH2:27][CH:28]1[CH2:29][CH2:30][CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)[C@@H:15]([N:17]([CH:25]=[O:26])[OH:18])[CH3:16])[C:4](=[O:11])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1
Reactant: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)N[C@H](C(=O)Nc1nccs1)C(C)(C)C)N(C=O)OC1CCCCO1
Solvent: CC(=O)O
Product: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)N[C@H](C(=O)Nc1nccs1)C(C)(C)C)N(O)C=O
Temperature: 40 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
A mixture of (2R,3S)-3-(formyl-tetrahydropyranyloxyamino)-2-(4-phenylcyclohexylmethyl)butanoic acid [(1S)-2,2-dimethyl-1-(1,3-thiazol-2-ylcarbamoyl)-1-propyl]amide (0.12 g, 0.20 mmol) in 80% acetic acid (10 mL) is heated at 40° C. for 18 h. The mixture is concentrated in vauco, the residue is taken up in ethanol and concentrated in vacuo. Repeating the ethanol treatment several times and addition of water is followed by stirring at 25° C. for 18 h. The resulting solid is filtered, washed with water, and dried to give 0.083 g (80%) of (2R,3S)-3-(formyl-hydroxyamino)-2-(4-phenylcyclohexylmethyl)butanoic acid [(1S)-2,2-dimethyl-1-(1,3-thiazol-2-ylcarbamoyl)-1-propyl]amide as a white solid, m.p. 213-214° C.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:28])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][CH2:3][CH3:4].Cl.[NH2:30][OH:31].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:5][C:6](=[O:28])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([C:18]([NH:30][OH:31])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CC1c2ccc(C#N)c(C)c2CCN1C(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCOC(=O)CC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A flask was charged with 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-cyano-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 18; 590 mg; 1.53 mmol), hydroxylamine hydrochloride (637 mg; 9.16 mmol) (769 mg; 9.16 mmol) followed by ethanol (15 ml) and the resulting suspension was stirred at 80° C. overnight. More hydroxylamine hydrochloride and sodium bicarbonate (3 equivalents of each) were added and the mixture stirred at 80° C. for ca. 14 h. The mixture was cooled to room temperature, and the precipitate was filtered off and the residue washed with ethanol. The combined filtrate and washings were evaporated in vacuo and the residue partitioned between water and ether. The phases were separated and the aqueous phase extracted twice with ether. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound (547 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[C:16]([C:17](O)=[O:18])[N:12]3[C@:11]([CH3:32])([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[C:10]2=[O:33])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[C:49]([O:53][C:54](=[O:57])[CH2:55][NH2:56])([CH3:52])([CH3:51])[CH3:50]>C(Cl)Cl.CN(C=O)C>[C:49]([O:53][C:54](=[O:57])[CH2:55][NH:56][C:17]([C:16]1[N:12]2[C@:11]([CH3:32])([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:31])[F:30])=[CH:23][CH:22]=3)[C:10](=[O:33])[N:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]2=[N:14][CH:15]=1)=[O:18])([CH3:52])([CH3:51])[CH3:50]
Reactant: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Reactant: CC(C)(C)OC(=O)CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1cnc2n1[C@](C)(Cc1ccc(OC(F)(F)F)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
To a solution of (R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (0.500 g, 1.0 mmol) in CH2Cl2 (15 mL) was added oxalyl chloride (0.194 mL, 2.2 mmol), followed by slow addition of DMF (0.05 mL). The reaction was stirred for 90 min. The volatiles were removed in vacuo, and the residue dissolved in THF (15 mL). To this cloudy solution was added diisopropylethylamine (0.88 mL, 5.0 mmol) followed by glycine tert-butyl ester (0.30 mL, 2.2 mmol). The reaction was stirred for another 14 h. The volatiles were removed in vacuo at 40° C. The reaction mixture was diluted with ethyl acetate and washed with 1 N aqueous HCl (×2), 10% aqueous Na2CO3 (×2) and brine (×2). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford {[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-acetic acid tert-butyl ester (0.483 g) as a colorless foam.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:27])[CH:19]([NH:20][C:21](=[S:26])[CH2:22][CH2:23][C:24]#[N:25])[C@H:16]3[S:15][CH2:14][C:13]=2[O:28][CH3:29])=[O:11])=CC=1)([O-])=O.O1CCCC1.Cl>CO.[Pd].C(O)C>[C:24]([CH2:23][CH2:22][C:21]([NH:20][CH:19]1[C:18](=[O:27])[N:17]2[C:12]([C:10]([OH:11])=[O:9])=[C:13]([O:28][CH3:29])[CH2:14][S:15][C@H:16]12)=[S:26])#[N:25]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: COC1=C(C(=O)O)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1
Reaction time: 3 h

Procedure:
To a solution of 1 g. of 7-cyanomethylthioacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 60 ml. of tetrahydrofuran and 100 ml. of methanol containing 5 drops of 1N hydrochloric acid is added 1 g. of prereduced 5% palladium on charcoal in 40 ml. of ethanol. The mixture is hydrogenated for 3 hours at room temperature at 50 psi. The catalyst is filtered and washed with tetrahydrofuran and water. The filtrate and washings are combined, solvent is removed in vacuo and the residue is taken up in an ethyl acetate water mixture. The pH of the aqueous layer is adjusted to 7.5 and the ethyl acetate is removed. Fresh ethyl acetate is added and the pH is adjusted to 2.5. The ethyl acetate layer is removed, washed with water and dried over sodium sulfate. Removal of the solvent in vacuo yields the product 7-cyanomethylthioacetamido-3-methoxy-3-cephem-4-carboxylic acid as a foam.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([C:30]([O:32]C)=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[C:13](=[O:34])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:35])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([C:30]([OH:32])=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[C:13](=[O:34])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:35])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of the product of Step D (22 mg, 0.047 mmol) in MeOH (5 mL) was added 1N NaOH (2 mL). The reaction mixture was stirred 0.5 hours, and was then concentrated in vacuo. The residue was taken up in water and acidified to pH=2 with 1N HCl. Next, the aqueous layer was partitioned with chloroform and extracted 3 times. The combined organic layers were dried (MgSO4), filtered and the filtrate concentrated in vacuo to yield 15 mg (65%) of the title compound (Rf =0.40, hexane/ethyl acetate/acetic acid (75:23.5:1.5)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
A solution of 4-nitrobenzenethiol (Aldrich, 2.5 g; 16.1 mmol) in acetone (110 ml) was treated with potassium carbonate (2.22 g; 16.1 mmol) and ethyl 4-bromobutanoate (Aldrich, 3.43 g; 17.6 mmol). After stirring at RT for 18 hours, the mixture was filtered and the solid washed with acetone. The organic fractions were combined and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of Et2O to give the title compound as an off-white solid (4.0 g, 92%).