Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][O:9][CH2:10][O:11][CH3:12])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:5]1[CH:6]=[C:7]([CH2:8][O:9][CH2:10][O:11][CH3:12])[C:2]([CH3:14])=[N:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COCOCc1cc(F)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: COCOCc1cc(F)cnc1C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of 0.10 g of 2-chloro-5-fluoro-3-((methoxymethoxy)methyl)pyridine in 3 mL of dioxane, 0.20 g of potassium carbonate, 68 μL of trimethylboroxin and 56 mg of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was heated under reflux while stirring for 2 hours under a nitrogen atmosphere. Thereto were added 0.20 g of potassium carbonate, 68 μL of trimethylboroxin and 56 mg of tetrakis(triphenylphosphine)palladium(0), and the mixture was heated under reflux while stirring for 2 hours under a nitrogen atmosphere. Thereto were added 0.20 g of potassium carbonate, 68 μL of trimethylboroxin and 56 mg of tetrakis(triphenylphosphine)palladium(0), and the mixture was heated under reflux while stirring for 1 hour under a nitrogen atmosphere. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 93 mg of a colorless oily substance. The substance was purified by basic silica gel column chromatography using an eluent of chloroform to obtain 64 mg of 5-fluoro-3-((methoxymethoxy)methyl)-2-methylpyridine as a colorless oily substance.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20].Cl[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[CH:17]=[CH:18]/[C:19]([O:21][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[O:20]
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Reactant: OCCCCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC
Temperature: 80 °C
Reaction time: 19 h

Procedure:
A solution consisting of 0.72 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5-5) and 5 ml of dimethylformamide was added dropwise to a solution of 1.0 g of (E)-3,4-dimethoxycinnamic acid in 10 ml of dimethylformamide in the course of 10 minutes at room temperature. The reaction mixture was then heated to 80° C., 0.18 g of tetrabutylammonium iodide and 0.71 ml of 6-chlorohexanol were then added in succession and the reaction was then allowed to continue for 19 hours. Thereafter, the reaction mixture was cooled to room temperature and was partitioned between diethyl ether and 1 N hydrochloric acid and the organic phase was washed several times with saturated sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over 150 g of silica gel using 3:2 toluene/ethyl acetate gave 1.35 g of 6-hydroxyhexyl (E)-3,4-dimethoxycinnamate.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(N[S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])C=CC=CC=1>C1COCC1>[C:13]([N:20]1[CH2:25][CH2:24][C:23]([O:26][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[CH:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 90 %

Procedure:
To a stirring solution of diisopropylamine (38.7 mL, 276 mmol) in THF (900 mL) at 0° C. was added dropwise via an addition funnel a solution of n-BuLi in hexanes (1.6 M, 171.5 mL, 276 mmol). After 25 min, the solution was cooled to −78° C. To this solution was added dropwise via an addition funnel a solution of 1-Boc-4-piperidinone (50 g, 250.9 mmol) in THF (300 mL). After 30 min, a solution of N-phenyltrifluoromethanesulfonamide (95.9 g, 268.5 mmol) in THF (300 mL) was added and the solution was warmed to 0° C. After 3 h, the solvents were evaporated in vacuo and the residue was loaded onto a silica gel column with a minimal amount of dichloromethane and eluted with 5% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 74.84 g (90%) of a light yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:25])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][CH2:3][CH:4]([OH:25])[CH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: COCC(=O)CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCC(O)CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
A suspension of Example 126A (850 mg, 2.28 mmol) in ethanol (100 mL) at ambient temperature was treated with sodium borohydride (103 mg, 2.74 mmol), stirred for 30 minutes, treated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to provide 820 mg (96%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[C:3]=1[C:14](OC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[C:3]=1[CH2:14][OH:15]
Reactant: COC(=O)c1c(Cl)cc(Cl)c2ccc(Cl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Yield: 85 %

Procedure:
A solution of methyl 2,4,7-trichloro-1-naphthoate (1.3 g, 4.5 mmoles) in ether (50 ml) was added dropwise (15 minutes) to a well stirred suspension of lithium aluminum hydride (0.25 g, 6 mmoles) in ether (25 ml). After stirring at room temperature for 17 hours the reaction mixture was treated with an additional 0.25 g of lithium aluminum hydride. The mixture was stirred for 3 hours, cooled in an ice-bath, and treated dropwise with 0.5 ml of water, 1.5 ml of 20% (w/v) of aqueous NaOH solution, and 0.5 ml of water. After filtration, the solid was extracted with ether. The combined ether solutions were dried (MgSO4), filtered, and concentrated in vacuo to give 1.0 g of the title compound, mp 107°-112° C.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:17][C@@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22].ClC(OCC(C)C)=O>>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][C@@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CSCC[C@@H](N)C(N)=O
Agent: CC(C)COC(=O)Cl
Product: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(N)=O
Yield: 70 %

Procedure:
Condensation of BocLeuOH (3.49 g.) and HDMetNH2 (2.0 g.) by the mixed anhydride method using isobutyl chloroformate gave BocLeu-DMetNH2 in 70% yield. De-t-butoxycarbonylation of BocLeu-DMetNH2 (2.74 g.) using hydrogen chloride in ethyl acetate gave HLeu-DMetNH2 in 91% yield. Condensation of BocGlyOSu (2.66 g.) and HLeu-DMetNH2 (1.95 g.) by the active ester method gave BocGly-Leu-DMetNH2 in 92% yield. De-t-butoxycarbonylation of BocGly-Leu-DMetNH2 (2.30 g.) using hydrogen chloride in acetic acid gave HGly-Leu-DMetNH2 in 79% yield.
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([NH:17][CH3:18])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16].S(O)(O)(=O)=O.[NH2:24]N.C(=O)([O-])O.[K+]>CN(C)C=O>[ClH:1].[ClH:1].[NH2:24][NH:4][C:5]([NH:17][CH3:18])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16]
Reactant: NN
Reactant: CNC(=NCCSCc1[nH]cnc1C)NO
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CNC(=NCCSCc1[nH]cnc1C)NN
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A mixture of the isothiourea dihydrochloride from Example 1 (i) (8.3 g), hydrazine sulphate (4.1 g), potassium hydrogen carbonate (12.5 g) and anhydrous dimethyl formamide (100 ml) was stirred at 90° C. for 3 hours. Following cooling and filtration from inorganic material, the filtrate containing the free base was treated with ethanolic hydrogen chloride. The residue was then triturated with isopropanol to give a solid which was recrystallised from aqueous isopropanol to give the title compound (1.94 g), m.p. 234°-235°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1.[ClH:18]>C(O)C.[Fe]>[ClH:18].[ClH:18].[NH2:8][C:6]1[CH:5]=[C:4]([CH3:11])[C:3]([N:12]=[C:13]2[NH:14][CH2:15][CH2:16][NH:17]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1N=C1NCCN1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)cc(C)c1N=C1NCCN1

Procedure:
The 2-(2,6-dimethyl-4-nitrophenylimino)imidazolidine (8.75 g) was reduced with iron and hydrochloric acid in aqueous ethanol according to the process of Example 12. The product was chromatographed on a silica column and eluted with a methanol in methylene chloride gradient. The fractions containing the required compound were evaporated and the residue was treated with ethanolic hydrochloric acid to give 2-(4-amino-2,6-dimethylphenylimino)imidazolidine dihydrochloride. An analytical sample was recrystallised as the mono-hydro-iodide salt, mp 252°-253° C.
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Br[CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18]([OH:20])=[O:19]>C(N(CC)CC)C>[O:15]=[C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([S:4][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=[O:19])[NH:14]1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: O=c1[nH]c(S)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Sc1nc2ccccc2c(=O)[nH]1)c1ccccc1
Yield: 31 %

Procedure:
A methylene chloride solution of 8.9 g (0.05M) of 2-mercapto-4(3H)-quinazolinone, α-bromophenylacetic acid and triethylamine is heated to gentle reflux for 48 hours. A small amount of insoluble material is filtered off and then the solvent is removed. The oily residue is dissolved in water and insoluble material filtered off. The aqueous filtrate is acidified with a dilute HCl solution and the gummy solid is extracted with methylene chloride. The methylene chloride solution is dried over anhydrous magnesium sulfate. After the solvent is removed the residual solid is dissolved in 500 ml hot acetonitrile, and upon cooling the solid is filtered. The filtrate, upon standing, gives 5.0 g (31% yield) of product which has a melting point of 184°-5° C. dec.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:25]O>>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:25])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Temperature: 85 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (13.73 g, 39.6 mmol) in MeOH (300 mL) was added SOCl2 (60 mL). After stirring at 85° C. overnight, most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (300 mL×3). The combined organic extract was washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the corresponding product (gray solid, 12.58 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 9.09 (s, 1H), 8.05 (d, 1H), 7.00-7.14 (m, 4H), 3.94 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])C.[CH2:29]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH2:35])[CH3:30]>C(O)C>[CH2:29]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH:35][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18](=[O:26])[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH:10]=2)=[O:5])[CH3:30]
Reactant: CCOC(=O)c1nc(C#N)c2cc(NC(=O)c3ccc(F)cc3)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(NC(=O)c3ccc(F)cc3)ccc2c1O

Procedure:
1-Cyano-7-(4-fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (70 mg, 0.2636 mmol) was dissolved/suspended in ethanol (4 mL) and 3-Amino-2,2-dimethyl-propionic acid ethyl ester (115 mg, 0.791 mmol) was added via syringe. The reaction was brought to reflux and maintained for 70 h. The reaction was cooled, concentrated and purified by medium pressure liquid chromatography (15 to 50% ethyl acetate in hexanes) to give the product as a white solid which was used immediately in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])[N:6]=1.[ClH:13].[CH3:14]O>>[ClH:13].[ClH:13].[CH3:14][O:11][C:10](=[O:12])[C@H:8]([CH2:7][C:5]1[N:6]=[C:2]([NH2:1])[S:3][CH:4]=1)[NH2:9]
Reactant: CO
Reactant: Nc1nc(C[C@H](N)C(=O)O)cs1
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1csc(N)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
3-(2-Amino-4-thiazolyl)-L-alanine containing methanol, 26.3 kg (76 mol) and 72 L of methanol are charged into a reactor and stirred at 5° C., followed by 16.9 kg of anhydrous hydrogen chloride gas and stirred at 25° C. for 5 hours. The solution is heated to reflux and then cooled to 5° C. and held for 1 hour. The product is filtered and dried under vacuum at 50° C. to give 17.7 kg of 3-(2-amino-4-thiazolyl)-L-alanine methyl ester dihydrochloride as an off-white solid, 99% pure by HPLC; IR (mineral oil): 3410 (sh), 1749 (sh), 1631 (sh), 1225 (m) cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[N:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Brc1ccc2nccn2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1ccc2ncc(Br)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-bromo-imidazo[1,2-a]pyridine (1 eq, 96 mmol, 19 g) in acetic acid (200 ml) under an inert atmosphere of argon is added dropwise bromine (1 eq, 96 mmol, 4.9 ml). After stirring at room temperature for 1 hour, the reaction mixture is filtered to afford the title compound as a beige solid; [M+H]+=275/277/278
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:25](Br)=[N:24][C:23]3[C:18]2=[N:19][C:20]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:21][C:22]=3[NH2:27])[CH:11]=1)(=[O:8])[O:5]CC)[CH3:2].C([O-])(=[S:35])C.[K+]>CN(C=O)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:25]([SH:35])=[N:24][C:23]3[C:18]2=[N:19][C:20]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:21][C:22]=3[NH2:27])[CH:11]=1)(=[O:8])[OH:5])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOP(=O)(Cc1cccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)c1)OCC
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(O)Cc1cccc(Cn2c(S)nc3c(N)nc(OCCOC)nc32)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of (3-(6-Amino-8-bromo-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-phosphonic acid diethyl ester (50) (180 mg, 0.34 mmol) in DMF (2 ml) was added potassium thioacetate (778 mg, 6.8 mmol). The reaction mixture stirred at 100° C. for 24 h. After cooling to rt, the reaction mixture was filtered and purified by reversed phase prep-HPLC using a linear gradient of acetronitrile in water from 5% to 95%. 1H NMR (DMSO, 300 MHz): (1.08 (t, 3H), (3.00 (d, 2H), (3.25 (s, 3H), (3.58 (t, 2H), (3.77-3.84 (m, 2H), (4.29 (t, 2H), (5.23 (s, 2H), (6.87 (bs, 2H), (7.16-7.28 (m, 4H); 31P NMR (DMSO, 300 MHz): (23.20; MS: 454.1 (M+H)+, 452.0 (M−1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]([NH:11][CH:12]1[C:28](=[O:29])[N:14]2[C:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([CH3:20])[CH2:17][S:18](=[O:19])[C@H:13]12)=[O:10].C(O)(=O)C>[W].ClCCl>[Br:1][CH2:20][C:16]1[CH2:17][S:18](=[O:19])[C@@H:13]2[CH:12]([NH:11][CH:9]=[O:10])[C:28](=[O:29])[N:14]2[C:15]=1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC=O)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC=O)C(=O)N12
Temperature: 0 °C
Yield: 28.5 %

Procedure:
27 g of N-bromosuccinimide were added portionwise to an ice-cold solution of 30 g of t-butyl 7-formamido-3-methyl-3-cephem-4-carboxylate-1-oxide in 1600 ml of a 1:1 mixture of acetic acid and dichloromethane under exposure to light of two tungsten lamps of 150 W over 3 hours. After a total exposure of 4 hours, the reaction mixture was then washed 3 times with water, a saturated solution of sodium bicarbonate and again with water. The organic phase was treated with activated carbon, dried over magnesium sulfate and evaporated to dryness after filtration. The residue was subjected to preparative high pressure chromatography using a 4:1 mixture of dichloromethane and acetone as eluent to obtain by evaporation to dryness of the suitable fractions 10.7 g of t-butyl 3-bromomethyl-7-formamido-3-cephem-4-carboxylate-1-oxide having the following characteristics:
Reaction SMILES: [OH:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:28]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:31]=[N:30][N:29]=1>CN(C=O)C>[CH3:19][N:18]1[CH2:17][CH2:16][C@@:14]23[C:15]4[C:2]([O:1][C:28]5[N:32]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:31]=[N:30][N:29]=5)=[CH:3][CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]3
Reactant: CN1CC[C@]23CC(=O)CC[C@H]2[C@H]1Cc1cccc(O)c13
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CC[C@]23CC(=O)CC[C@H]2[C@H]1Cc1cccc(Oc2nnnn2-c2ccccc2)c13
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.5 %

Procedure:
A mixture of 1.57 g (5.79 mmol) 4-hydroxy-N-methylmorphinan-6-one, 1.57 g (11.36 mmol) dry K2CO3 and 1.15 g (6.37 mml) 5-chloro-1-phenyl-1H-tetrazole din 30 ml dry DMF was stirred under argon for 24 h at room temperature. Then the reaction mixture was filtered, washed with CHCl3 and the filtrate was evaporated in vacuo (70° bath temperature). The oily residue was dissolved in CHCl3 and extracted with 2×20 ml 5% tartaric acid. The aqueous layer was rendered alkaline with conc. NaOH and extracted with CHcl3. The organic layer was washed with brine, dried and evaporated to give 2.2 g of an oil, which was crystallized with EtOAc/Et2O to yield 2.05 g (85%) of N-methyl-4-(1-phenyl-1H-5-tetrazolyloxy) morphinen-6-one, m.p. 172°-174°, [α]D26 -37.4° (c 1.35, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:40])[NH:17]3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)c(F)cc2F)C1(F)F
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)c(F)cc2F)C1(F)F
Yield: 83.1 %

Procedure:
The reaction of (R)-5-[5-(3-chloro-phenylethynyl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (622 mg, 1.14 mmol) with Lawesson's reagent (572 mg, 1.41 mmol) in 1,4-dioxane (40 ml) yielded the (R)-5-[5-(3-chloro-phenylethynyl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (432 mg, 67% yield) as a light brown gum.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C@H:6]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[Br:22][C:10]1[C:11]([NH2:14])=[N:12][CH:13]=[C:8]([C@@H:6]2[CH2:5][CH2:4][O:3][C@H:2]([CH3:1])[CH2:7]2)[N:9]=1
Reactant: C[C@@H]1C[C@H](c2cnc(N)cn2)CCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[C@@H]1C[C@H](c2cnc(N)c(Br)n2)CCO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
To a solution of 5-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine (40 mg, 0.207 mmol) in acetonitrile (3 mL) was added NBS (35.0 mg, 0.197 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. After quenched with NaHCO3, the reaction mixture was extracted with EtOAc three times. The organic layers were combined and washed with water, and brine. Dried over Na2SO4, filtered and concentrated to afford 47 mg of 3-bromo-5-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine, which was used as it was. LCMS (m/z): 274 (MH+), 0.64 min. For 5-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine, following the above method, 3-bromo-5-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine was obtained. LCMS (m/z): 274 (MH+), 0.65 min. The absolute stereochemistry of the products were assigned arbitrarily.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](Cl)[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Na+].[Na+].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:21]1[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]1)[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClC1CCc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CCc3cc(Br)ccc32)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
5-Bromo-1-chloro-2,3-dihydro-1H-indene (10 g, 43 mmol) was dissolved in 80 mL of acetonitrile, and sodium carbonate (4.8 g, 45 mmol) was added followed by tert-butyl piperazin-1-carboxylate (9.7 g, 52 mmol). The mixture was stirred at 60° C. overnight. The insoluble substance was removed by filtration and the filtrate was concentrated. The residue was separated by silica gel column using ethyl acetate/hexanes (1:2 to 1:1) as the eluent to obtain 12 g (72% yield) of the subtitle compound. MS (M+1)=381.11, 383.11.