Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.[Cl-].[OH:15][NH3+:16].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:16][OH:15])[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: [NH3+]O
Reactant: CCCC(=O)c1ccc(SC)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC(=NO)c1ccc(SC)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
9.72 g (50 mmol) of 1-(4-Methylsulfanyl-phenyl)-butane-1-one is dissolved in hot ethanol. Then a solution of hydroxylammonium chloride (3.58 g, 51.5 mmol) and sodium acetate (7.0 g, 85 mmol) in 20 ml of water is added, and the reaction solution is stirred at 100° C. for 4 hrs. After cooling and concentrating, water is added. The crude product is extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (20:80) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 0.98 (t, 3H), 1.54-1.64 (m, 2H), 2.50 (s, 3H), 2.76 (t, 2H), 7.24 (d, 2H), 7.54 (d, 2H), 7.98 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.[Li]CCCC>C1COCC1.C1(C)C=CC=CC=1>[CH3:8][C:4]1[C:3]([CH3:9])=[C:2]([B:10]([OH:15])[OH:11])[CH:7]=[CH:6][N:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nccc(Br)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nccc(B(O)O)c1C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2,3-dimethyl-pyridine (1.38 g) and triisopropyl borate (2.05 mL) in 4 mL dry THF and 14 mL dry toluene was stirred on a dry ice-acetone bath to an internal temperature of −65° C. and 3.56 mL n-BuLi in hexanes was added dropwise over 0.5 h. Stirring continued at −65° C. for additional 2 h, then the bath was removed the mixture allowed to warm to −20° C. Reaction was quenched by addition of 10 mL 2M HCl, then allowed to warm to rt and diluted with more THF. 5M NaOH was added until the mixture reached pH 7, layers formed and the organic layer was collected. Several more extractions with THF were done and the combined organic extracts were dried with brine and Na2SO4 and concentrated under reduced pressure. The product crystallized and two crops were collected, for a total of 304 mg of 2,3-dimethylpyridine-4-boronic acid. LCMS (m/z) 153.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14]Cl)[N+:8]([O-:16])=[C:7]2[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([NH:2][CH3:1])[CH2:14][N+:8]([O-:16])=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[C:6]=2[CH:5]=1
Reactant: CN
Reactant: [O-][n+]1c(CCl)nc2ccc(Cl)cc2c1-c1ccc(O)cc1
Solvent: CO
Product: CNC1=Nc2ccc(Cl)cc2C(c2ccc(O)cc2)=[N+]([O-])C1
Reaction time: 7 h

Procedure:
To a saturated solution of methylamine in 600 ml of methanol in an ice bath was added 19.2 g (0.60 mole) of 6-chloro-2-chloromethyl-4-(4-hydroxyphenyl) quinazoline 3-oxide. The solution was stirred for 7 hr in an ice bath, and 10 hr at room temperature and then evaporated under reduced pressure. The residue was acidified with dilute acetic acid, stirred with ether and filtered to give 19 g of product. Recrystallization for analysis from ethyl acetate gave colorless plates, mp 278°-279° dec.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17](=[O:18])[C:16]3[CH:19]=[CH:20][C:21]([N+:22]([O-])=O)=[C:14]4[C:15]=3[C:10](=[CH:11][CH:12]=[CH:13]4)[C:9]2=[O:25])[CH2:4][CH2:3]1.CO>O.[Pd]>[NH2:22][C:21]1[CH:20]=[CH:19][C:16]2[C:17](=[O:18])[N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:9](=[O:25])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3
Reactant: CN1CCC(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)CC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CN1CCC(N2C(=O)c3cccc4c(N)ccc(c34)C2=O)CC1
Yield: 79.6 %

Procedure:
A mixture of 2,3-dihydro-2-(1-methyl-piperidin-4-yl)-6-nitro-1H-benz[de]isoquinoline-1,3-dione (11.5 g; 33.9 mmol), prepared as in Example 3, in water (150 mL) and methanol (350 mL) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst (1.4 g) for 5 hours. The catalyst was removed by filtration and the filtrate concentrated to a small volume. Isopropanol was added and the solution concentrated. Isopropanol was again added to the residue and the solution reconcentrated. The residue was swirled in ethanol and ether and the solid residue collected on a Buechner funnel. Drying under vacuum gave 6-amino-2,3-dihydro-2-(1-methylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (9.34 g; 27.0 mmol), m.p 345°-348° C.
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].[I-:14].[Na+]>C(#N)C>[C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3]([I:14])[CH3:4]
Reactant: [I-]
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: [Na+]
Solvent: CC#N
Product: CC(I)OC(=O)OC1CCCCC1

Procedure:
A solution of 1.65 g of 1-chloroethyl cyclohexyl carbonate and 5.0 g of sodium iodide in 50 ml of acetonitrile is stirred at 70° C. for 45 minutes and then concentrated under reduced pressure. The residue is extracted with ether. The extracts are combined and evaporated under reduced pressure to remove the solvent to give the title compound as pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)=[C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[C:6]([CH3:31])=[CH:5]2>[Pd].CCOC(C)=O.CCO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)=[C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[C:6]([CH3:31])=[CH:5]2
Reactant: Cc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1cccc(O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(CCC(=O)O)cc2)c1-c1cccc(O)c1
Reaction time: 14 h
Yield: 434.3 %

Procedure:
A 1:1 EtOAc/EtOH solution (4 mL) of (2E)-3-(4-{[6-hydroxy-2-(3-hydroxyphenyl)-3-methyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (251) (0.041 g, 0.01 mmol, 1 equiv) was treated with 5% Pd—C (0.027 g, 0.02 mmol, 0.1 equiv) and the reaction vessel was equipped with an H2-filled balloon. After 14 h at ambient temperature, the crude mixture was filtered through a pad of Celite. Concentration gave a light pink solid that was purified by radial chromatography (SiO2, 1 mm plate, 90:10; CHCl3/MeOH) to afford the title compound (252) as a pink solid (0.018 g, 44%). 1H NMR (CD3OD, 400 MHz) δ 7.58 (d, J=9.0 Hz, 1H), 7.40 (s, 1H), 7.07-7.03 (m, 2H), 6.95-6.89 (m, 3H), 6.62 (dd, J=8.1, 2.3 Hz, 1H), 6.55-6.52 (m, 2H), 6.43 (d, J=8.5 Hz, 2H), 2.75 (t, J=7.7 Hz, 2H), 2.34 (t, J=7.3 Hz, 2H), 2.17 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([CH:12]([CH3:14])[CH3:13])=[C:6]([CH:11]=1)[O:7][CH2:8][C:9]#[N:10].[CH:17]([O:19][CH2:20]C)=O.[H-].[Na+].IC>COCCOC>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([CH:12]([CH3:14])[CH3:13])=[C:6]([CH:11]=1)[O:7][C:8](=[CH:17][O:19][CH3:20])[C:9]#[N:10]
Reactant: COc1cc(C(C)C)c(OCC#N)cc1Cl
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Product: COC=C(C#N)Oc1cc(Cl)c(OC)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a solution of (5-chloro-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (1.44 g, 6.0 mmol) and ethyl formate (2.2 g, 29.2 mmol) in 7 mL 1,2-dimethoxy ethane at 5° C. was added 95% NaH (0.15 g, 6.0 mmol) in one portion. The mixture was warmed to room temperature. After 1 hour 95% NaH (0.15 g, 6.0 mmol) was added in one portion. After 1 hour 10 mL iodomethane was added and the mixture was allowed to stir for 16 hour. The mixture was concentrated in vacuo, 1N HCl was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (85:15 hexane/ethyl acetate) afforded 2-(5-chloro-2-isopropyl-4-methoxy-phenoxy)-3-methoxy-acrylonitrile (1.41 g, 84%) as a white solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:46][CH2:47][CH2:48][CH3:49])[C@H:32]([OH:45])[C:33]([NH:35][C@H:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:37][CH3:38])=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl.C(OCC)(=O)C>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:46][CH2:47][CH2:48][CH3:49])[C:32](=[O:45])[C:33]([NH:35][C@H:36]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:37][CH3:38])=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)N[C@@H](CC)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)C(=O)N[C@@H](CC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
0.383 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one was added to a solution of 0.285 g of 3(S)-(tert-butoxyformamido)-2(S)-hydroxy-N-(1(S)-phenylpropyl)heptanamide in 20 ml of dichloromethane. The mixture was stirred at room temperature for 30 minutes and then a further 30 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one were added. The mixture was stirred at room temperature for 30 minutes and then diluted with ethyl acetate. The solution was extracted with a solution of 10 g of sodium thiosulphate in 40 ml of saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica gel using 20% ethyl acetate in hexane for the elution to give 200 mg of 3(S)-(tert-butoxyformamido)-2-oxo-N-(1(S)-phenylpropyl)heptanamide, MS: m/e 377.1 [M+H]+.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([CH2:15][OH:16])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])(C)(C)C.ClC(Cl)(Cl)C(=N)O[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1.ClCCl>[CH2:32]([O:16][CH2:15][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:8]1[C:6]([OH:5])=[O:7])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(CO)C2C(=O)OC(C)(C)C)cc1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)O)cc1
Temperature: 0 °C

Procedure:
To a solution of 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester (110 mg, 0.275 mmoL) in 3.9 mL cyclohexane and 1.95 mL of dichloromethane was added benzyl trichloracetimidate (0.1 mL, 0.55 mmoL). The solution was cooled to 0° C. and trifluoromethane sulfonic acid (0.008 mL, 0.091 mmoL) was added in. After 2.5 hours the reaction was filtered and the cake was washed with a 2:1 solution of cyclohexane and dichloromethane, the solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate. The solution was washed sequentially with dilute sodium bicarbonate and brine. The organic layer was dried over anhyrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (silica: 30% ethyl acetate in hexanes to 5% methanol in dichloromethane) to yield 3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid; MS: (M+H)+ =434, (M-H)- =432.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:23])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of (5-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (Step 100.3) (10.7 g, 51.4 mmol), NBS (10.1 g, 56.7 mmol, 1.1 equiv), AIBN (843 mg, 5.14 mmol, 0.1 equiv) in CCl4 (500 mL) was stirred for 1 h at reflux. NBS (1.8 g, 10.1 mmol, 0.2 equiv) was added and the mixture was stirred at reflux for additional 30 min. The reaction mixture was filtered hot and the filtrate was concentrated. Trituration of the residue in CH3CN afforded of 12.88 g of impure (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (intermediate 100.2). (R)-3-Hydroxypyrrolidine (181 mg, 2.1 mmol, 1.2 equiv) was added to a mixture of intermediate 100.2 (500 mg, 1.75 mmol) and Cs2CO3 (684 mg, 2.1 mmol, 1.2 equiv) in DMF (5 ml). The reaction mixture was stirred for 24 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 (150 mL) and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) to afford 212 mg of the title compound as a white solid. Title compound: ESI-MS: 294.3 [M+H]+; tR=1.95 min (System 1); TLC: Rf=0.14 (DCM/MeOH, 9:1).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC>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>[C:38]([C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12)(=[O:40])[CH3:39]
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 100 °C
Yield: 27 %

Procedure:
To a sealable flask containing 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.10 g, 0.20 mmol) in 1,4-dioxane (5 mL) was added tributyl(1-ethoxyvinyl)tin (0.079 g, 0.22 mmol) followed by Pd(PPh3)4 (0.07 g, 0.06 mmol). The mixture was flushed with N2, and the tube was sealed and heated to 100° C. After 16 h of heating, the mixture was cooled to rt, and the solvent was removed in vacuo. The residue was dissolved in DMF and was filtered through a pad of celite to remove any remaining solids. The DMF solution was purified by prep HPLC to give the title compound as an off-white solid (0.025 g). LCMS: m/e 463.38 (M+H)+, ret time 1.88 min (method 2). 1H NMR (500 MHz, CDCl3) δ ppm 11.02 (s, 1H) 8.35 (s, 1H) 8.31 (d, J=2.75 Hz, 1H) 7.52-7.62 (m, 5H) 3.81-3.85 (m, 2H) 3.61-3.65 (m, 2H) 3.39-3.43 (m, 2H) 3.31-3.35 (m, 2H) 2.80-2.83 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:4][S:3]1.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[O:1]=[C:2]1[S:6][C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:32](=[O:33])[N:17]3[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]4[S:25][CH:26]=[N:27][N:28]=4)[CH2:20][S:21][C@H:16]23)=[O:10])=[CH:4][S:3]1
Reactant: CON=C(C(=O)O)c1csc(=O)s1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(=O)s1

Procedure:
2-(2-Oxo-1,3-dithiol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 0.2 g.) was allowed to react with 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.2 g.) in a similar manner to that of Example 1 and crystallized with diisoporpyl ether to give the captioned compound (0.15 g.), mp. 80° to 90° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C(C)=CC=CC=1.Cl>[CH3:10][CH:9]([NH:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1)[CH3:11]
Reactant: C1CNCCN1
Reactant: CC(C)Nc1nccnc1Cl
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(C)Nc1nccnc1N1CCNCC1

Procedure:
A solution of 2-chloro-3-(1-methylethylamino)pyrazine (PREPARATION 24, 1.6 g) and piperazine (4.3 g) in xylene (10 ml) is refluxed for 26 hr. The mixture is cooled to 0° and diluted with concentrated hydrochloric acid (8 ml). The xylene is decanted and ether is added and also decanted from the salts. The salts are diluted with excess aqueous sodium hydroxide (5%) and dichloromethane. The phases are separated. The aqueous phase is extracted three more times with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated to give a liquid mixture which is flash chromatographed on silica gel eluting with methanol/chloroform (5/95). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.27, 1.83, 3.04, 4.12, 4.78, 7.49 and 7.72 δ.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][O:13][CH3:14])=[NH:11])[N:3]=1.[CH3:15][O:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])(=[O:19])=[O:18].O>N1C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][C:10]([NH:11][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([O:16][CH3:15])(=[O:19])=[O:18])(=[O:28])=[O:27])=[N:12][O:13][CH3:14])[N:5]=1
Reactant: COS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CONC(=N)Nc1nc(C)cc(C)n1
Solvent: c1ccncc1
Solvent: O
Product: CON=C(Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1S(=O)(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.7 %

Procedure:
N-(4,6-Dimethylpyrimidin-2-yl) N'-methoxyguanidine (9.75 g) was a dissolved in pyridine (200 ml), and 2-methoxysulfonylbenzenesulfonyl chloride (13.5 g) was added to the solution. The mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and extracted with methylene chloride. The organic layer was washed with a 1N aqueous solution of hydrochloric acid, and dried over anhydrous sodium sulfate. Methylene chloride was evaporated under reduced pressure, and the residue was recrystallized from methanol to give 10 g of the desired N-(4,6-dimethylpyrimidin-2-yl) N'-(2-methoxysulfonylbenzenesulfonyl) N"-methoxyguanidine represented by the following formula. mp. 130°-138° C. ##STR21##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH:20]=[CH2:21])=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][C:14]=3[C:22]([F:24])([F:25])[F:23])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C=CCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: [Pd]
Solvent: CO
Product: CCCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21

Procedure:
A mixture of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (27 mg, 0.07 mmol) and palladium on carbon (10 mg, 10 wt %; Aldrich) in methanol (1 mL) was subjected to 1 atmosphere of hydrogen for 50 min. The reaction was then filtered, concentrated, and the resulting residue was purified by radial chromatography (30% ethyl acetate in hexanes) to give the desired product as a clear residue (25 mg, 91%).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].[CH3:6][C@H:7]1[C:25](=[O:26])[O:24][C@H:9]2[CH2:10][C@:11]3([CH3:23])[O:13][C@H:12]3[C@@H:14]3[O:16][C@@H:15]3[C:17]3[C:21](=[O:22])[O:20][C@@H:19]([C@H:8]12)[CH:18]=3.CN(C1C=CC=CN=1)C>CC(C)=O>[OH:16][CH:14]1[CH:15]([S:4][CH2:3][CH:2]([CH3:5])[CH3:1])[C:17]2=[CH:18][CH:19]([O:20][C:21]2=[O:22])[CH:8]2[CH:9]([O:24][C:25](=[O:26])[CH:7]2[CH3:6])[CH2:10][C:11]2([CH3:23])[CH:12]1[O:13]2
Reactant: C[C@H]1C(=O)O[C@H]2C[C@]3(C)O[C@H]3[C@@H]3O[C@@H]3C3=C[C@@H](OC3=O)[C@@H]21
Reactant: CC(C)CS
Agent: CN(C)c1ccccn1
Solvent: CC(C)=O
Product: CC(C)CSC1C2=CC(OC2=O)C2C(CC3(C)OC3C1O)OC(=O)C2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
2-methyl-1-propanethiol (500 μmol; 54 μl) is added to a solution of dihydromikanolide (100 μmol; 30 mg) and dimethylaminopyridine (10 μmol; 1.2 mg) in acetone (1 ml). The reaction mass is stirred for two hours at ambient temperature then the solvent is evaporated off under reduced pressure. The residue is taken up in ether then the precipitate formed is filtered, washed with ether and dried under vacuum. 25 mg of product is obtained in the form of a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
1-(4-Nitrophenyl)piperazine (2.79 g, 13.5 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.25 ml, 16.2 mmol) was added and the reaction was cooled to 0° C. Methanesulfonyl chloride (1.15 ml, 14.9 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (×3) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-1-methylsulfonylpiperazine as a yellow solid (3.83 g, quantitative yield). GC/MS (EI, M+) m/z=285.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1sccc1N
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NC(=O)c1ccc(C(C)(C)C)cc1
Yield: 85.5 %

Procedure:
A solution of methyl 3-amino-2-thiophenecarboxylate (400 mg, 2.54 mmol) and pyridine (0.226 mL, 2.80 mmol) in methylene chloride (12 mL) was treated with 4-tert-butylbenzoyl chloride (0.500 mL, 2.54 mmol). After consumption of the starting material, the mixture was concentrated in vacuo and the residue dissolved in ethyl acetate and water. The organic layer was washed once with water, once with saturated sodium chloride solution, dried (magnesium sulfate), and filtered. Concentration and purification of the residue by flash chromatography (silica gel, hexanes/ethyl acetate) yielded 689 mg (85%) of the title compound.