Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7](O)[C:8]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1.Cl>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[CH:6]=[CH:7][C:8]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1
Reactant: OC1Cc2ccc(Br)cc2CNc2ccc(Cl)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1)C=Cc1ccc(Br)cc1CN2
Yield: 87.3 %

Procedure:
To a mixture of 8-Bromo-2-chloro-5,6,11,12-tetrahydro-dibenzo[b,f]azocine-12-ol (0.85 g, 2.5 mmole) in dioxane (10 mL) was added concentrated HCl (1 mL). The reaction was heated to reflux for 24 hours. The reaction mixture was concentrated and the residue obtained was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered and concentrated to give 8-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (0.7 g, 87%). HPLC Rt=4.33 min. m/z=320 (M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].[C:13]([O:22][CH3:23])(=[O:21])[C:14]([CH2:16][C:17](OC)=[O:18])=[CH2:15]>>[CH3:23][O:22][C:13]([CH:14]1[CH2:16][C:17](=[O:18])[N:12]([CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)[CH2:15]1)=[O:21]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: NCC1COc2ccccc2O1
Product: COC(=O)C1CC(=O)N(CC2COc3ccccc3O2)C1

Procedure:
The title compound was prepared using 200 mg (1.21 mmol) of 2,3-dihydro-benzo[1,4]dioxin-2-ylmethylamine and 0.17 mL (1.21 mmol) of dimethyl itaconate according to the procedure for substituted pyrrolidines described in J. Org. Chem. 26 (1961) 1519-1524. Purification by column chromatography (silica gel, heptane/ethyl acetate, 1:2) afforded the pure product.
Reaction SMILES: C(C1C=CC(Br)=CC=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+].[Br:29][C:30]1[C:35]2[CH2:36][CH:37]([CH2:39][OH:40])[O:38][C:34]=2[CH:33]=[CH:32][CH:31]=1.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>>[CH3:51][C:41]1[CH:46]=[CH:45][C:44]([S:47]([O:40][CH2:39][CH:37]2[CH2:36][C:35]3[C:30]([Br:29])=[CH:31][CH:32]=[CH:33][C:34]=3[O:38]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: OCC1Cc2c(Br)cccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C=CCc1ccc(Br)cc1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(Br)cccc3O2)cc1
Yield: 78 %

Procedure:
Treatment of 2-allyl-5-bromophenol (27.25 g, 0.128 mmol), with 3-chloroperoxybenzoic acid (66.20 g, 0.384 mol, 77%)) followed by potassium carbonate (44.18 g, 0.319 mol) generally according to the procedure described for Intermediate 9 provided (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol as a yellow oil. Treatment of the oil with p-toluenesulfonyl chloride (15.65 g, 0.082 mol) generally according to the procedure described for Intermediate 10 afforded 24.7 g (78%) of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 90-91° C.; Anal. calcd. for C16H15BrO4S: C, 50.14; H, 3.94. Found: C, 50.09; H, 3.82.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.C1(CC([NH:22][CH:23]2[C:56](=[O:57])[N:25]3[C:26]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:27]([CH2:30][S:31][C:32]4[N:33]=[N:34][N:35]([CH2:37][C:38]#[CH:39])[N:36]=4)[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.CO>C(Cl)Cl>[NH2:22][CH:23]1[C:56](=[O:57])[N:25]2[C:26]([C:40]([O:42][CH:43]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:41])=[C:27]([CH2:30][S:31][C:32]3[N:33]=[N:34][N:35]([CH2:37][C:38]#[CH:39])[N:36]=3)[CH2:28][S:29][C@H:24]12
Reactant: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of phosphorus pentachloride (8.5 g) in methylene chloride (130 ml) was cooled to 5° C. and thereto was added pyridine (3.2 g). The mixture was stirred for 30 minutes at room temperature, cooled to 5° C. and thereto was added benzhydryl 7-(2-phenylacetamido)-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (13.0 g) to give a homogeneous solution. The obtained solution was stirred for 30 minutes at 5° C. and added to methanol (65.4 g) precooled to -30° C. The resulting mixture was stirred for 30 minutes without external cooling. The reaction mixture was evaporated and to the residue were added ethyl acetate and water. The mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The ethyl acetate layer was separated, washed with water (×3), dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure to give benzhydryl 7-amino-3-[2-(2-propynyl)-2H-tetrazol-5- yl]thiomethyl-3-cephem-4-carboxylate (7.31 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH:5]=[CH:4][N:3]=[N:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCn1ccnn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCn1ccnn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
3-(1,2,3-triazol-1-yl)propanol (2.5 g, 19.66 mmol) was dissolved in dichloromethane (50 mL), and the solution was cooled to 0° C. Then, triethylamine (5.53 mL, 39.32 mmol) and methane sulfonyl chloride (2.3 mL, 29.5 mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 2 hours, extracted with dichloromethane and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (3.01 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:16][N:17]([CH:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O.CCOC(C)=O>[C:21]([O:20][C:18](=[O:19])[N:17]([C@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:14][CH3:15])[CH2:9][CH2:10]1)=[O:27])[CH3:16])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)C(Cc1ccccc1)C(=O)O
Reactant: COc1ccc(F)cc1C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(F)cc1C1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above product of 4-(5-fluoro-2-methoxy-phenyl)-piperidine (Intermediate 4) was dissolved in N,N-dimethylformamide (10 mL) at 0° C. To the resulting solution, 0.70 g (2.5 mmole) of 2-[N-methyl-N-(tert-butoxycarbonyl)-amino]-3-phenyl-propionic acid in a minimal amount of DMF was added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DAEC) (0.48 g, 2.5 mmole), 1-hydroxybenzotriazole hydrate (HOBT) (0.41 g, 2.5 mmole) and 4-methylmorpholine (NMM) (0.37 mL, 3.4 mmole) and the mixture was stirred overnight (the reaction temperature was slowly allowed to warm up to room temperature). The reaction mixture was diluted with water (50 mL) and EtOAc (50 mL) and the layers separated. The aqueous layer was washed with HCl (1N), saturated NaHCO3, and the combined aqueous layers were extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography, gradient elution with 1:4 EtOAc-hexane to 3:7 EtOAc-hexane to afford (R)-{1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-2-oxo-ethyl}-methyl-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[N:13][NH:14][C:15]2=S)([CH3:4])([CH3:3])[CH3:2].O.[NH2:23][NH2:24]>C(O)C>[C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[N:13][N:14]=[C:15]2[NH:23][NH2:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)NCC(O)COc1cccc2c(=S)[nH]ncc12
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCC(O)COc1cccc2c(NN)nncc12
Yield: 100 %

Procedure:
A stirred mixture of 5-(3-t-butylamino-2-hydroxypropoxy)-1(2H)-phthalazinthione (0.5 g), ethanol (50 ml) and hydrazine hydrate (15 ml) was heated under reflux for 21 hours. Ethanol and excess of hydrazine were removed by evaporation under reduced pressure to give 5-(3-t-butylamino-2-hydroxypropoxy)-1-hydrazinophthalazine (0.5 g, 100%) which was treated with 1.0N sulphuric acid (3.26 ml). Evaporation under reduced pressure gave the crude salt which was crystallised from aqueous methanol to give 5-(3-t-butylamino-2-hydroxypropoxy)-1-hydrazinophthalazine sulphate hydrate (0.45 g, 65%, m.p. 274°-276°, decomposition).
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[N:6]1[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108.9 %

Procedure:
To a solution of 5 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 100 ml of tetrahydrofuran are dropwise added 1.82 ml of pyridine and a solution of 2.86 g of benzoyl chloride in 20 ml of tetrahydrofuran at 0° C. under nitrogen atmosphere. After 20 minutes, the reaction mixture is warmed up to room temperature. After additional 2 hours, the mixture is diluted with ice water and extracted with ethyl acetate. The extract is washed with an aqueous sodium sulfate and condensed under reduced pressure to yield 7.02 g of benzyl α-(3ξ-carbomethoxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]1>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 75.4 %

Procedure:
Using 4-bromobenzotrifluoride (3.15 g, 13.99 mmol) and ethyl isonipecotate (2.2 g, 13.99 mmol), ethyl 1-(4-trifluoromethylphenyl)piperidine-4-carboxylate (3.18 g, yield 74%) as a pale brown crystalline powder was prepared in the same manner as described in Reference Example 21.
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.CN.[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1F)[N:16]([C:22]1[CH:27]=[C:26]([NH:28][CH3:29])[C:25]([F:30])=[CH:24][C:23]=1[F:31])[CH:15]=[C:14]([C:32]([OH:34])=[O:33])[C:13]2=[O:35]>C(OCC)C>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[NH:1][CH3:2])[N:16]([C:22]1[CH:27]=[C:26]([NH:28][CH3:29])[C:25]([F:30])=[CH:24][C:23]=1[F:31])[CH:15]=[C:14]([C:32]([OH:34])=[O:33])[C:13]2=[O:35]
Reactant: c1ccncc1
Reactant: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(C)c32)c(F)cc1F
Agent: CN
Solvent: CCOCC
Product: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC)c(C)c32)c(F)cc1F
Temperature: 40 °C
Reaction time: 72 h
Yield: 24.3 %

Procedure:
Pyridine (300 mg) and a 40% aqueous solution (150 mg) of methylamine were added to 6,7-difluoro-1-(2,4-difluoro-5-methylaminophenyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (80 mg), and the mixture was heated and stirred at 40° C. for 3 days. After the reaction mixture was allowed to cool, diethyl ether was added, followed by stirring. A supernatant liquid was removed, and ethanol (1 ml) was added to the residue to disperse solids therein. The solids were collected by filtration and washed with ethanol and dried to obtain the title compound (20 mg) as a pale yellow powder.
Reaction SMILES: [CH3:1][C@H:2]([N:6]1CCC[C:7]1=[O:11])[C:3]([OH:5])=[O:4].C(I)C.[CH2:15]([S:22]CBr)[C:16]1[CH:21]=[CH:20]C=[CH:18][CH:17]=1>>[CH2:21]([C:16]1([CH2:15][SH:22])[CH2:17][CH2:18][N:6]([C@@H:2]([CH3:1])[C:3]([OH:5])=[O:4])[C:7]1=[O:11])[CH3:20]
Reactant: BrCSCc1ccccc1
Reactant: C[C@@H](C(=O)O)N1CCCC1=O
Solvent: CCI
Product: CCC1(CS)CCN([C@@H](C)C(=O)O)C1=O

Procedure:
Following the procedures of Examples 1C-1E, α(S)-methyl-2-oxo-1-pyrrolidineacetic acid was first alkylated with ethyl iodide and then with benzylmercaptomethyl bromide. Removal of the benzyl group in the usual way and purification by chromatography provided the title compound as a mixture of diastereomers. [α]D25 =-4.04° (c=1, methanol).
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH:6]1([N:12]([C:39](=[O:53])[CH2:40][CH2:41][NH:42][CH2:43][CH2:44][C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=2)[CH2:13][CH2:14][N:15]([CH2:26][CH2:27][C:28]2[C:36]3[S:35][C:34](=[O:37])[NH:33][C:32]=3[C:31]([OH:38])=[CH:30][CH:29]=2)C(=O)OCC2C=CC=CC=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(O)(=O)C.COC(C)(C)C.C(O)C>[BrH:1].[BrH:1].[CH:6]1([N:12]([CH2:13][CH2:14][NH:15][CH2:26][CH2:27][C:28]2[C:36]3[S:35][C:34](=[O:37])[NH:33][C:32]=3[C:31]([OH:38])=[CH:30][CH:29]=2)[C:39](=[O:53])[CH2:40][CH2:41][NH:42][CH2:43][CH2:44][C:45]2[CH:46]=[C:47]([F:52])[CH:48]=[C:49]([F:51])[CH:50]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cc(F)cc(F)c1)C1CCCCC1
Agent: Br
Solvent: CCO
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: O=C(CCNCCc1cc(F)cc(F)c1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCC1
Reaction time: 1 h

Procedure:
Hydrogen bromide/acetic acid (33%, 2 mL) was added to a solution of the carbamate of step i) (0.350 g) in acetic acid (2 mL) and the reaction was stirred for 1 h. The solution was diluted with t-butyl methyl ether (20 mL) and the resulting precipitate filtered off, washed with more t-butyl methyl ether (10 mL) and dried to afford a peach coloured solid. The solid was slurried in ethanol (7.5 mL), filtered off and dried to yield the title product (0.22 g) as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:20]2[C:21]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[N:22][N:23]([CH2:33][CH3:34])[C:24]=2[NH:25]C(=O)OC(C)(C)C)[CH2:16][CH2:17][CH:18]=O)=[CH:11][CH:10]=1.BrC1C=CC(C2CCC=NC3N(CC)N=C(C4C=CC=CN=4)C2=3)=CC=1.[Na]>O.C(#N)C.C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:16][CH2:17][CH2:18][NH:25][C:24]3[N:23]([CH2:33][CH3:34])[N:22]=[C:21]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[C:20]2=3)=[CH:11][CH:10]=1
Reactant: CCn1nc(-c2ccccn2)c(C(CCC=O)c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Agent: CCn1nc(-c2ccccn2)c2c1N=CCCC2c1ccc(Br)cc1
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCn1nc(-c2ccccn2)c2c1NCCCC2c1ccc(Br)cc1
Reaction time: 0.67 h
Yield: 76.9 %

Procedure:
TFA (0.800 mL) was added to a solution of tert-butyl (4-(1-(4-bromophenyl)-4-oxobutyl)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (0.0400 g, 0.0780 mmol) and DCM (0.800 mL). After about 40 min, reaction monitor by LC-MS (Table 1, Method g) Rt=2.68 min; m/z 395 and 397 (M+H)+indicated conversion to 4-(4-bromophenyl)-1-ethyl-3-(pyridin-2-yl)-1,4,5,6-tetrahydropyrazolo[3,4-b]azepine. Sodium triacetoxyhydroborate (0.083 g, 0.390 mmol) was added in one portion. After about 45 min, the volatiles were removed under reduced pressure. THF (0.8 mL) and 2 M aqueous HCl (0.8 mL) were added. After about 15 min, saturated aqueous NaHCO3 (5 mL) was added. The solution was extracted with EtOAc (2×5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 50-100% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford an ivory solid. Acetonitrile (0.5 mL) was added. The slurry was diluted with water (4 mL) then sonicated for about 2 min. The organic volatiles were removed under reduced pressure. The mixture was frozen then lyophilized to afford 4-(4-bromophenyl)-1-ethyl-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-b]azepine (0.0239 g, 0.0600 mmol, 77%) as an ivory solid. LC-MS (Table 1, Method h) Rt=2.61 min; m/z 397 and 399 (M+H)+; 1H NMR (400 MHz, DMSO) δ 8.44-8.34 (m, 1H), 7.79-7.75 (m, 1H), 7.70-7.63 (m, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.17-7.11 (m, 1H), 7.05 (d, J=8.4 Hz, 2H), 5.56-5.47 (m, 2H), 4.16-3.94 (m, 2H), 3.33-3.20 (m, 1H), 2.81-2.70 (m, 1H), 2.18-2.07 (m, 1H), 1.92-1.80 (m, 1H), 1.71-1.59 (m, 1H), 1.49-1.35 (m, 1H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=[N:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([Cl:15])=[N:13][CH:12]=[C:11]([CH2:16][O:17][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cnc(Cl)c(OCc2ccccc2)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.9 %

Procedure:
To a solution of (5-(benzyloxy)-6-chloropyridin-3-yl)methanol (1.76 g) and tert-butyldimethylchlorosilane (1.59 g) in DMF (10 mL) was added imidazole (960 mg), and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.64 g) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:24][C:25](=[O:35])[NH:26][O:27]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:24][C:25]([NH:26][OH:27])=[O:35])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccc1)NOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccc1)NO
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
(5S)-1-((2R)-2-(Cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-phenyl-4,5-dihydro-1H-pyrazole-5-carboxamide (110 mg, 0.23 mmol) was dissolved in methanol (8 mL), and Pearlman's catalyst (37 mg, 0.05 mmol) was added. The resulting mixture was stirred under 1 atm of H2 for 30 min. After 30 min, the mixture was filtered, concentrated, and purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-[(2R)-2-(cyclopentylmethyl)-4-(hydroxyamino)-4-oxobutanoyl]-N-phenyl-4,5-dihydro-1H-pyrazole-5-carboxamide (60 mg, 0.15 mmol, 66% yield) as a white solid. MS: 387 ([M+H]+). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.13 (none, 2H) 1.37-1.68 (m, 5H) 1.72-2.02 (m, 4H) 2.20-2.33 (m, 1H) 2.38-2.50 (m, 1H) 3.05-3.21 (m, 1H) 3.79-3.92 (m, 1H) 7.08-7.15 (m, 2H) 7.28-7.36 (m, 2H) 7.54-7.59 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=2)[N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:3][CH2:4][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:25])(=[O:26])=[O:27])=[CH:20][CH:19]=2)[N:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(CO)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 798 %

Procedure:
To a solution of compound 3c (4 g, 1.04 mmol) in 20 mL of THF was added LiAlH4 (1.26 g, 33.2 mmol). The reaction mixture was stirred for 6 hours at room temperature. EtOAC (30 mL) and water (30 mL) were added successively. The solvent was removed in vacuo and the resulting solid was filtered. The crude product was purified by column chromatography (EtOAc/Hexanes in adequate proportions) to give the compound (2.85 g, 80%) as a white solid. mp 165.9-169.3° C. 1H NMR (300 MHz, DMSO-d6): δ 7.81 (d, J=9 Hz, 2H), 7.48-7.43 (m, 2H), 7.41 (d, J=9 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 2H), 6.59 (s, 1H), 5.26 (t, J=6 Hz, 1H), 4.51 (d, J=6 Hz, 2H), 2.31 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH:14]1([CH2:20][C:21]#[CH:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCCCCC>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:14]1([CH2:20][C:21]#[C:22][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#CCC1CCCCC1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C(#Cc1nccs1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (185 mg, 0.97 mmol) were combined in DME (30 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (8.5 mL, 61 mmol) and PdCl2(PPh3)2 (340 mg, 0.49 mmol) were added and 3-cyclohexyl-1-propyne (2.9 g, 24 mmol) was added dropwise. The reaction was stirred at ambient temperature for 16 h at which time GC/MS analysis indicated that the reaction was complete. The mixture was filtered through Celite.™., and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane, then 98:2 hexane:ethyl acetate to afford 2-(3-cyclohexyl-1-propynyl)-1,3-thiazole (1.14 g, 46% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) Δ7.76 (d, J=3.0 Hz, 1H), 7.27 (d, J=3.0 Hz, 1H), 2.35 (d, J=6 Hz, 2H), 1.89-1.61 (m, 5H), 1.3-1.03 (m, 6H). MS (ESI) 205.9 (M++H).