Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].C(N(C(C)C)C(C)C)C.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:18]=1.[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35]([CH:38]=[CH2:39])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35](/[CH:38]=[CH:39]/[C:13]2[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=2)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: Brc1cncc(OC2CCOCC2)c1
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(/C=C/c2cncc(OC3CCOCC3)c2)C1
Temperature: 110 °C
Yield: 72.3 %

Procedure:
Palladium acetate (0.117 g, 0.52 mmol), 0.678 g (16 mmol) of lithium chloride and 7.25 cm3 (42 mmol) of ethyldiisopropylamine were added in succession to a solution under argon of 1.33 g (5.17 mmol) of 3-bromo-5-(tetrahydropyran-4-yloxy)pyridine and 1.2 g (5.17 mmol) of racemic 3-vinylpyrrolidine-1-carboxylic acid tert-butyl ester in 15 cm3 of dimethylformamide. After 3 hours of heating at 110° C. with stirring, the reaction mixture was stirred for 2 hours at a temperature in the region of 22° C. and then concentrated to dryness under reduced pressure (2.7 kPa). The oily residue was taken up in 50 cm3 of ethyl acetate and the resulting solution was washed in succession with 2 times 25 cm3 of water, 25 cm3 of saturated bicarbonate solution, 2 times 25 cm3 of water and 25 cm3 of saturated sodium chlorine solution and then was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.4 g of brown oil. This residue was purified by chromatography on silica gel [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. Concentration of the fractions under reduced pressure (2.7 kPa) gave 0.44 g of yellow oil which was used without further purification in the remainder of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]=[C:13]=[S:14].Cl.[NH2:16][NH:17][C:18](N)=[NH:19].C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:19][C:18]1[N:12]([C:3]2[C:4]([CH3:11])=[CH:5][C:6]([CH:8]3[CH2:9][CH2:10]3)=[CH:7][C:2]=2[Cl:1])[C:13]([SH:14])=[N:16][N:17]=1
Reactant: N=C(N)NN
Reactant: Cc1cc(C2CC2)cc(Cl)c1N=C=S
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2CC2)cc(Cl)c1-n1c(N)nnc1S
Temperature: 50 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
Compound 3 (935 mg, 4.2 mmol) was dissolved in 5 mL of dimethylformamide, aminoguanidine hydrochloride salt (695 mg, 6.3 mmol) and diisopropyl ethylamine (1.1 mL, 6.3 mmol) were added and the mixture stirred at 50° C. for 18 hours. The mixture was then concentrated and to the resulting residue was added 2M aqueous sodium hydroxide solution (20 mL). The mixture was stirred at 50° C. for 18 hours and then cooled to room temperature. The resulting mixture was then neutralized with aqueous 1N HCl and the precipitate (product) collected to give 5-amino-4-(2-chloro-4-cyclopropyl-6-methylphenyl)-4H-1,2,4-triazole-3-thiol (4). (780 mg, 66% yield)
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[CH:20]1([C:23]([NH2:25])=[O:24])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(OCC)(=O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([OH:19])=[C:5]2[C:10]([CH:11]=[C:2]([NH:25][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])[N:3]=[CH:4]2)=[CH:9][N:8]=1
Reactant: Oc1c(-c2ccccc2Cl)ncc2cc(Cl)ncc12
Reactant: NC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2cnc(-c3ccccc3Cl)c(O)c2cn1)C1CC1
Temperature: 90 °C
Yield: 39.6 %

Procedure:
A mixture of 7-chloro-3-(2-chlorophenyl)-2,6-naphthyridin-4-ol (75 mg, 0.26 mmol), cyclopropanecarboxamide (66 mg, 0.77 mmol), chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-1-pr-1,1′-biphenyl)][2-(2-aminoethyl) Ph]Pd(II) (40 mg, 0.05 mmol), (dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-1-pr-1,1′-biphenyl (28 mg, 0.05 mmol), and cesium carbonate (250 mg, 0.77 mmol) in tetrahydrofuran (2 mL) was heated at 90° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1.0M citric acid in water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (35 mg, 40%). 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.51 (d, J=6.6 Hz, 1H), 8.82 (s, 1H), 8.53 (s, 1H), 7.55 (m, 1H), 7.46 (m, 4H), 2.15-2.04 (m, 1H), 0.88 (m, 4H). LCMS (Method E): RT=3.746 min, M+H+=340.0.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)=[N:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>C(O)(C)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([OH:18])[CH2:16][CH2:17]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OC1CCN(CCCc2noc3cc(F)ccc23)CC1
Yield: 89.3 %

Procedure:
A solution of 5 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone and 1.4 g of sodium borohydride in 50 ml of isopropanol was stirred at ambient temperature for twenty hrs. The reaction mixture was quenched with methanol and concentrated. The residue was stirred with water and extracted with ether. The organic extracts were washed with water (2x), saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give 4.5 g (90%) of product. Recrystallization from ether gave the analytical sample, mp 88°-89° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CN(CCC2CCNCC2)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(2-(dibenzylamino)ethyl)piperidine-1-carboxylate (5.0 g, 12.25 mmol, 1 eq) was dissolved in dichloromethane (100 ml) and cooled to 0° C. TFA (25 ml) was added dropwise at that temperature and then stirring was carried out for 1 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was concentrated under reduced pressure. The crude product was used in the next stage without being purified further.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[N:35]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCOCC1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][CH2:42][CH2:41][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: NCCN1CCOCC1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(NCCN3CCOCC3)n2)c1F)c1ccoc1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), [2-(4-morpholinyl)ethyl]amine (137 mg, 1.056 mmol) in 1,4-dioxane (2 mL), the title compound was obtained as a white foam (35 mg, 25.6%. 1H NMR (400 MHz, DMSO-d6) ppm 1.62-1.83 (m, 2H), 2.01 (dd, J=12.76, 2.15 Hz, 2H), 2.35-2.47 (m, 7H), 3.23-3.32 (m, 2H), 3.47 (td, J=11.56, 1.89 Hz, 2H), 3.57 (t, J=4.42 Hz, 4H), 3.93 (dt, J=9.35, 2.27 Hz, 2H), 5.81-6.11 (m, 1H), 6.64 (s, 1H), 7.13 (t, J=5.31 Hz, 1H), 7.24 (d, J=5.56 Hz, 2H), 7.44 (dt, J=9.66, 3.76 Hz, 1H), 7.79 (s, 1H), 8.09 (d, J=5.30 Hz, 1H), 8.23 (s, 1H), 10.32 (d, J=1.01 Hz, 1H); MS (ESI): 615.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[CH:3]=[C:4]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])=[CH:23][CH:22]=1
Reactant: NCc1ccc(Br)cc1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(Br)cc3)c2)nc1
Temperature: 60 °C
Yield: 86.6 %

Procedure:
A mixture of 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine (2.0 g, 7.6 mmol), 4-bromobenzyl amine (1.6 g, 8.4 mmol), DIPEA (2.63 mL, 15.3 mmol) and acetonitrile (25.4 mL) were sealed in a reaction vessel and heated to 60° Celsius for 24 h. The mixture was cooled to RT, transferred to a round bottomed flask and concentrated to dryness. The crude mixture was heated to 70° Celsius in a minimum amount of i-PrOH until homogeneous and cooled to RT. The resulting mixture was filtered to collect the yellow solids which were dried to afford the title compound (2.82 g, 86%). MS (ESI): mass calcd. for C20H18BrN3O3, 427.053; m/z found, 428.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1(C=CC(O)=CC=1)O.C1C(=O)N([Br:38])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[C:16]([Br:38])=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2c3sc(C)cc3C(C)C2C1
Reactant: O=C1CCC(=O)N1Br
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC2c3sc(C)c(Br)c3C(C)C2C1
Yield: 17 %

Procedure:
A solution of the product from step k) (110 mg, 0.42 mmol) in AcOH (1 ml) and CHCl3 (1 ml) was treated with hydroquinone (5 mg) and NBS (77.8 mg, 0.437 mmol) at 40° C. for 3 hours in the dark. Next, the reaction mixture was carefully quenched with sat. NaHCO3 (5 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried (MgSO4) and purified by preparative TLC hexanes:EtOAc (1:1) to give the subtitle compound (24.2 mg, 17%). MS calculated for C14H18BrNO2S+H 344, observed 344, 346.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH:15](O)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.N12CCCN=C1CCCCC2>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10](=[CH:15][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 1.86 g (7.6 mmol) of the resulting 1-(t-butoxycarbonyl)-3-(1-hydroxyethyl)-4-piperidone in 20 ml of methylene chloride, 0.77 g (7.6 mmol) of triethylamine were added. To the resulting mixture, 0.88 g (7.6 mmol) of methanesulfonyl chloride were added under ice cooling, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and the solid so precipitated was filtered off, followed by concentration by evaporation under reduced pressure. The concentrate was then dissolved in 20 ml of chloroform. To the resulting solution, 1.16 g (7.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added at room temperature, followed by stirring at the same temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=19/1), whereby 1.32 g (yield: 77.2%) of the title compound was obtained as a colorless oil.
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.C(N(CC)CC)C.Cl[C:20](OC(Cl)(Cl)Cl)=[O:21]>ClCCl>[Br:11][C:6]1[CH:5]=[N:4][C:3]2[NH:2][C:20](=[O:21])[O:10][CH2:9][C:8]=2[CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ncc(Br)cc1CO
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Nc2ncc(Br)cc2CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-amino-5-bromo-3-hydroxymethylpyridine hydrobromide (Apollo, Cheshire, UK, 0.528 mmol) in dichloromethane (1.25 ml) and triethylamine (1.162 mmol) was cooled with an ice-bath. Was added to the RM trichloromethyl chloroformate (0.317 mmol) in dichloromethane and the RM was stirred for 30 min at 0° C. and 1 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and separated by flash chromatography (heptane/EtOAc 0% to 80%). The fractions containing product were evaporated together to give the title compound as a yellow solid. (HPLC: tR 2.16 min (Method A); M+H=229, 231 MS-ES)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1ccc(Br)cc1=O

Procedure:
5.0 g (28.7 mmol) of 4-bromopyridin-2(1H)-one and 5.3 g (31.6 mmol) of ethyl bromoacetate were reacted according to General Method 4B. Yield: 6.2 g (83% of theory)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:22][CH:21]=1>[Cl-].[Na+].O>[F:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[CH:22][CH:21]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(OCc3cccc(F)c3)cc2)CC1
Temperature: 80 °C

Procedure:
1-(Bromomethyl)-3-fluorobenzene (0.436 ml) and potassium carbonate (670 mg) were added to an acetonitrile (15 ml) solution containing tert-butyl 4-[(4-hydroxyphenyl)sulfanyl]piperidine-1-carboxylate (1.00 g), followed by heating at 80° C. for 2 hours. The reaction solution was cooled, saturated brine was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=8:1 (v/v)) to obtain tert-butyl 4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine-1-carboxylate (1.50 g) as colorless powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:17][S:18]([O:9][CH2:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[CH3:1])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCCCC1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCCCC1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-methyl-2-piperidine-methanol (Aldrich, 0.27 mL, 2.1 mmol) in 10 mL tetrahydrofuran (THF) at 0° C. was added triethylamine (0.87 mL, 6.22 mmol) followed by methanesulfonyl chloride (0.24 mL, 3.1 mmol). The mixture was stirred at 0° C. for 10 min then the ice-bath was removed and the reaction mixture was stirred at 23° C. for an additional 1.5 h. The reaction mixture was filtered though Celite with THF and concentrated under reduced pressure. This crude material was used directly in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4C=CC=CC=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)[CH3:40].C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([N:29]([CH2:39][CH3:40])[CH2:30][CH3:31])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:15]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Product: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 100 %

Procedure:
Following a procedure similar to that for the preparation of 1k, intermediate 1j (48 mg, 0.113 mmol), acetaldehyde (39.6 mg, 0.90 mmol) and NaBH(OAc)3 (216.2 mg, 1.02 mmol) yielded 56 mg (100%) of intermediate 3a. MS (ESI) 483.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5](=[O:20])(=[O:19])[C@@H:6]2[C@@H:16]([Cl:17])[C:15](=[O:18])[N:7]2[C:8]=1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10].C(N(CC)CC)C.[SH:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1>C(#N)C>[C:11]([C:9]([C:8]1[N:7]2[C:15](=[O:18])[C@H:16]([Cl:17])[C@H:6]2[S:5](=[O:20])(=[O:19])[CH2:4][C:3]=1[CH2:2][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cn1nnnc1S
Reactant: CC(C)(C)C(=O)C1=C(CBr)CS(=O)(=O)[C@@H]2[C@@H](Cl)C(=O)N12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)C(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2S(=O)(=O)C1
Yield: 49.3 %

Procedure:
A solution of 3-bromomethyl-4-tert-butylcarbonyl-7α-chloro-3-cephem 1,1-dioxide (65 mg), prepared as in Example 6, in dry acetonitrile (5 ml) was treated with triethylamine (0.025 ml) and 5-mercapto-1-methyl-1,2,3,4-tetrazole (26 mg). An immediate reaction took place (TLC monitoring). The solvent was removed in vacuo and the residue purified by flash-chromatography, thereby obtaining the title product as a white powder (35 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14](Br)=[CH:13][N:12]=2)[CH2:7]1.N.[CH3:24][N:25](C)C=O>ClCCl.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:24]#[N:25])=[CH:13][N:12]=2)[CH2:7]1
Reactant: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: N
Agent: [C-]#N
Solvent: ClCCl
Product: N#Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 65 °C
Yield: 36 %

Procedure:
Add zinc cyanide (104 mg, 0.88 mmol) and tetrakis(triphenylphosphine) palladium(0) (209 mg, 0.18 mmol) to a stirred solution of (S)-(2,4-dichlorobenzyl)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-amine (359 mg, 0.89 mmol) in N,N-dimethylformamide (5 mL). Heat at 65° C. for 4 hours. Cool to room temperature and add 2 M aqueous ammonia solution (30 mL). Extract with ethyl acetate (3×50 mL), extract the combined organic layers with water (5×50 mL) followed by saturated aqueous sodium chloride (50 mL). Concentrate to give a residue. Dissolve the residue in dichloromethane, filter, and concentrate to give a residue. Chromatograph the residue on silica gel to give the title compound as a white solid (111 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 8.50 (2H, m), 7.32-7.40 (2H, m), 7.20-7.27 (1H, m), 3.86-3.94 (2H, m), 3.75-3.83 (2H, m), 3.63-3.71 (1H, m), 3.48-3.55 (2H, m), 2.20 (1H, m), 1.95 (1H, m); MS (ES): m/z=348 [M+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:44][O:45][C:46]([CH3:62])([CH3:61])[C:47]([NH:49][NH:50][C:51](=[O:60])[C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[C:54]([OH:59])[CH:53]=1)=[O:48]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[O:45][C:46]([C:47](=[O:48])[NH:49][NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][C:55]([OH:58])=[C:54]([OH:59])[CH:53]=2)([CH3:61])[CH3:62])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(-c4ccc(O)c(O)c4)nc4ccnn34)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reaction time: 24 h
Yield: 91.3 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (625 mg) and 500 mg of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 10 ml of dimethylacetamide and left at room temperature for 24 hours. Thereafter, the solvent is evaporated at 30° C. in a vacuum. The residue is triturated with 30 ml of water, whereby it becomes solid. It is filtered off under suction, washed with water and dried at 0.1 mmHg/40° C. and there are obtained 800 mg of beige (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]-acetamido]-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[Cl:19][C:20]1[N:24]=[C:23](Cl)[S:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:23]3[S:22][N:21]=[C:20]([Cl:19])[N:24]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: Clc1nsc(Cl)n1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nc(Cl)ns3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.0 g, 4.0 mmol) and 3,5-dichloro-1,2,4 thiadiazole (0.45 mL, 4.8 mmol) in DMF (24 mL) was added cesium carbonate (2.61 g, 8 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with H2O, acidified to pH 3 with aqueous HCl (1N). The mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (silica, Ethyl acetate) affording the title compound (1.25 g, 85%) as a white solid: 1H NMR (CDCl3) δ7.48 (d, 1H), 7.19 (d, 1H), 5.68 (dd, 1H), 5.18 (s, 1H), 4.18 (q, 2H), 3.10 (dd, 1H), 2.45 (dd, 1H), 2.39 (s, 3H), 1.25 (t, 3H). MS found: (M+H)+=369.