Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]2[C:8]=1[C@@:9]1([CH3:30])[C@H:18]([CH2:19][S:20]2)[C@:17]2([CH3:27])[C@H:12]([C:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]1)(=O)=O.[CH3:33]B1OB(C)OB(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH3:26][O:25][C:23]1[CH:22]=[C:21]2[C:8]([C@@:9]3([CH3:30])[C@H:18]([CH2:19][S:20]2)[C@:17]2([CH3:27])[C@H:12]([C:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]3)=[C:7]([CH3:33])[CH:24]=1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(C)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 100 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
In a sealed tube was placed (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl trifluoromethanesulfonate (Compound No. 32) (0.098 g, 0.20 mmol), trimethylboroxine (0.050 g, 0.40 mmol), K3PO4 (0.085 g, 0.40 mmol), Pd(Ph3P)4 (0.046 g, 0.04 mmol) and dioxane (4 mL). The vessel was degassed for 5 min, then sealed and stirred at 100° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc and washed with brine. The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 95:5) gave (1R,10R,11S,16S)-5-methoxy-1,3,11,15,15-pentamethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 33) (0.060 g, 83%) as a white foam. 1H NMR (CDCl3): δ 6.46 (m, 1H), 6.39 (m, 1H), 3.71 (s, 3H), 2.98-2.80 (m, 3H), 2.50 (s, 3H), 1.95-1.37 (m, 8H), 1.37 (s, 3H), 1.20-1.00 (m, 2H), 0.94 (s, 3H), 0.90 (m, 1H), 0.86 (s, 3H), 0.84 (s, 3H). MS m/z 359 (C23H34OS+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-])=O)[CH:30]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:38]([O-])=O.[H][H].[CH:43](O)=O>[Pd]>[NH:1]1[C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]3)=[O:11])=[CH:4][C:3]=2[N:38]=[CH:43]1
Reactant: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2ccc(-c3cccc([N+](=O)[O-])c3)cc2)CC1
Reactant: [H][H]
Reactant: O=CO
Agent: [Pd]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc(-c3cccc(N)c3)cc2)CC1

Procedure:
Prepared from N-[1-((4-amino-3-nitro-phenyl)-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-3'-nitro-4-biphenylyl-sulphonamide and reduction with catalytically actived hydrogen in the presence of palladium/charcoal in formic acid analogously to Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+]>CN(C=O)C.O>[CH2:17]([N:1]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)[CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 153.2 %

Procedure:
A solution of 4-aminophenylacetonitrile (20 g, 151.3 mmol) in dry DMF (150 ml) was treated with potassium carbonate (50.1 g, 363.1 mmol), benzyl bromide (54.4 g, 318 mmol), and potassium iodide (5 g, 0.2 30.3 mmol). The reaction mixture was stirred at room temperature for 12 h. Water (100 ml) was added to the mixture and the organic was extracted with ether (3×200 ml). The combined organic fraction was washed with brine (200 ml), dried over sodium sulfate and concentrated. The crude product was further purified by flash chromatography (SiO21 20% EtOAc:Hexanes) to give 36.2 g (76%) of the pure product. NMR was consistent with the proposed title structure. Field Desorption Mass Spectrum:M+=312.
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CS(O[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)(=O)=O>CN(C=O)C>[CH2:1]([CH:3]1[C:4](=[O:9])[N:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[C:6](=[O:8])[NH:7]1)[CH3:2]
Reactant: CCC1NC(=O)NC1=O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1NC(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 100 °C

Procedure:
To a solution of 5-ethylimidazoline-2,4-dione (1 g) in DMF (40 ml) was added potassium carbonate (2.16 g) followed by tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (2.18 g) and the resulting mixture was heated to 100° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and then was partitioned between dichloromethane and water. The organic layer was collected, dried and evaporated to dryness. The residue was purified by chromatography on silica eluting with a gradient of isohexane to ethyl acetate/isohexane (1:1) to give tert-butyl 4(4-ethyl-2,5-dioxoimidazolidin-1-yl)piperidine-1-carboxylate as a solid. Yield 1.12 g. NMR (CDCl3): 0.95 (t, 3H), 1.5 (s, 9H), 1.9 (m, 2H), 2.35 (m, 2H), 2.7 (m, 2H), 3.8-4.0 (m, 3H), 4.1 (q, 2H), 5.6 (bs, 1H).
Reaction SMILES: [CH2:1]([Sn:5]1([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH:9]=[CH:8][CH:7]=[C:6]1[Li])[CH2:2][CH2:3][CH3:4].C([Sn]1(CCCC)C=CCC=C1)CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:38]([Sn:42]1([CH2:51][CH2:52][CH2:53][CH3:54])[CH:47]=[CH:46][CH:45]([CH2:48][CH2:49]Br)[CH:44]=[CH:43]1)[CH2:39][CH2:40][CH3:41]>C1COCC1.O>[CH2:1]([Sn:5]1([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=[CH:9][CH:8]([CH2:49][CH2:48][CH:45]2[CH:44]=[CH:43][Sn:42]([CH2:51][CH2:52][CH2:53][CH3:54])([CH2:38][CH2:39][CH2:40][CH3:41])[CH:47]=[CH:46]2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn]1(CCCC)C=CC(CCBr)C=C1
Reactant: [Li]C1=CC=CC[Sn]1(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: CCCC[Sn]1(CCCC)C=CCC=C1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn]1(CCCC)C=CC(CCC2C=C[Sn](CCCC)(CCCC)C=C2)C=C1
Reaction time: 16 h

Procedure:
A solution of 1 ,1-dibutyl-1-stannacyclohexadienyllithium prepared from 1,1-dibutyl-1-stannacyclohexa-2,5-diene (0.08 g, 2.67 mmol) and 2.67 mmol of lithium diisopropylamide (LDA) in 20 mL of THF was added to a solution of 1,1 -dibutyl-4-(2-bromoethyl)-1-stannacyclohexa-2,5-diene (1.0 g, 2.46 mmol) in 5 mL THF at -78° C. After stirring approximately 16 hours, 10 mL of water were added and the product was extracted with pentane, dried over MgSO4, and evaporated to dryness. The red residue left contained 1.25 g (81 percent) of crude product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].[CH2:19](N(CC)CC)C.CN(C1C=CC=CN=1)C>C(OCC)(=O)C>[C:12]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[CH:1]=[CH:19][NH:8]2)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc2[nH]ccc12
Yield: 69 %

Procedure:
A suspension of 3.24 g of trans-6-benzyloxy-2-nitro-β-pyrrolindino -styrene (prepared from 2-methyl-3-nitrophenol by a procedure reported in Organic Synthesis, Coll. Vol. 7, 34, 1990) and 648 mg of 10% pd/C catalyst in 30 ml of ethyl acetate was shaken under hydrogen atmosphere and at 50 psi, for 5 hours. To this reaction mixture were added acetic anhydride (1.4 ml), triethylamine (2.1 ml) and dimethylaminopyridine (324 mg). The resultant mixture was stirred for 1 hour at room temperature. The catalyst was removed over a layer of Celite and the filtrate was evaporated under reduced pressure to give an oily residue to which crushed ice was added. The resulting white precipitate was collected by filtration to give 1.2 g (69% yield) of 4-acetoxyindole: mp 97°-98° C.; HNMR (300 MHz, DMSO-d6)δ 2.32 (s,3H), 6.31 (s,1H), 6.71 (d,1H,J=8Hz), 7.05 (t, 1H, J=8 Hz), 7.28 (d,1H,J=8Hz), 7.32 (s,1H), 11.27 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].O1CCOCC1.O.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4ccc(C(F)(F)F)cc4)C3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4ccc(C(F)(F)F)cc4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.4 %

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoate (D199) (24 mg, 0.428 mmol) in a mixture 1,4-dioxane and water (3 ml/1 ml) lithium hydroxide monohydrate (2.7 mg, 0.064 mmol) was added and the mixture was stirred 2 days at room temperature. After solvent evaporation the residue was diluted with water (5 ml) and HCl 1M (15 ml) and extracted with ethylacetate (3×20 ml). Collected organics after solvent evaporation gave the title compound (E73) (15 mg) as racemic mixture.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([CH3:27])=[C:12]([C:23]([O:25]C)=[O:24])[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].Cl.O>C1COCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([CH3:27])=[C:12]([C:23]([OH:25])=[O:24])[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1C)OCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Reaction time: 96 h

Procedure:
Methyl 9-(1,3-benzodioxole-5-yl)-8-methyl-naphtho[1,2-d]-1,3-dioxole-7-carboxylate was dissolved in a mixture of THF (6 ml) and methanol (3 ml). After addition of 1N NaOH (3 ml), the mixture was stirred for 4 days. 1N HCl was added to the reaction mixture, followed by addition of water. The resulting precipitate was collected by filtration to yield the title compound (264 mg). Some portions of the compound was recrystalized from methanol-chloroform to be used for elemental and instrumental analysis.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[CH:12][C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[CH:12][C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(OC)c(C)cc2F)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c(F)cc1C

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2-fluoro-5-methoxy-4-methyl-phenyl)-methanone (Example 384) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-fluoro-5-methoxy-4-methyl-phenyl)-methanone as a white solid. MS (M+H)+, 438.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[CH:19]([CH3:21])[CH3:20])=[CH:6][N:5]=[C:4]([S:22][CH3:23])[N:3]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[CH:19]([CH3:21])[CH3:20])=[CH:6][N:5]=[C:4]([S:22][CH3:23])[N:3]=1)[CH3:25]
Reactant: COc1cc(Cc2cnc(SC)nc2Cl)c(C(C)C)cc1OC
Reactant: CCN
Product: CCNc1nc(SC)ncc1Cc1cc(OC)c(OC)cc1C(C)C
Temperature: 50 °C
Yield: 63 %

Procedure:
To a glass pressure vessel containing 4-chloro-5-(2-isopropyl-4,5-dimethoxy-benzyl)-2-methylsulfanyl-pyrimidine (0.212 g, 0.6 mmol) was added 5.0 mL ethyl amine via a cold finger condenser. The vessel was capped and warmed to 50° C. After 16 hours the solution was cooled to room temperature, evaporated and taken up in H2O. The mixture was extracted with ethyl acetate, washed with H2O and then washed with brine. The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo. Purification via flash chromatography (4:1 hexane/ethyl acetate) afforded ethyl-[5-(2-isopropyl-4,5-dimethoxy-benzyl)-2-methylsulfanyl-pyrimidin-4-yl]-amine (0.136 g, 63%) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].C(N(CC)CC)C.[CH2:26]([CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29]>C(OCC)C.ClCCl>[CH2:26]([CH:30]1[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][NH:38][C:13](=[O:17])[C:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[O:15])[CH2:34][CH2:35]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCC1CCN(CCN)CC1
Reactant: CC(C)n1ccc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCC1CCN(CCNC(=O)C(=O)c2cn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 2.4 %

Procedure:
To a solution of N-isopropyl indole (100 mg, 0.63 mmol) in diethyl ether (2 mL) at 0° C. was drop-wise added oxalyl chloride (60 mL, 0.73 mmol). The mixture was allowed to warm to room temperature over a period of three hours and then concentrated in vacuo to give a yellow solid. To the yellow solid was added dichloromethane (2 mL), triethyl amine (0.525 mL, 3.77 mmol), and a solution of the crude 2-(4-butylpiperidin-1-yl)ethanamine (150 mg) in triethyl amine (0.525 mL, 3.77 mmol) and dichloromethane (1 mL). The mixture was stirred at room temperature for 66 hours, then washed with saturated aqueous sodium bicarbonate (1×5 mL) and water (1×5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil, which was purified by silica chromatography on a Biotage (2-10% MeOH/CH2Cl2) to give a yellow gum (6 mg, 2% yield): 1H NMR (400 MHz, CDCl3): δ 9.11 (s, 1H), 8.46 (m, 1H), 7.92 (t, 1H), 7.43 (m, 1H), 7.33 (m, 2H) 4.71 (m, 1H), 3.47 (q, 2H), 2.45 (d, 2H), 2.54 (t, 2H), 1.98 (t, 2H), 1.65 (m, 2H), 1.61 (d, 6H), 1.25 (m, 9H), 0.89 (t, 3H); MS (ESI) m/z: Calculated for C24H35N3O2: 397.3. Found: 398.3 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1Cl.[H-].[Na+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: N#Cc1ccc2sc(S)nc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)nc2c1
Yield: 99.4 %

Procedure:
The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-5-carbonitrile (243) (960 mg, 5.0 mmol), 1,2,3-trichloro-5-nitrobenzene (Acros, 1.13 g, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 262 (1.9 g, 99%) was obtained as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([C:12]1[N:13]=[C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=1)[C:9]([OH:11])=O.CN(CC1C=CC=CC=1)C.ClC(OCCCC)=O.[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH2:59])[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1>O1CCCC1.C(N(CC)CC)C>[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH:59][C:9](=[O:11])[CH:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[C:12]4[N:13]=[C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=4)[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1
Reactant: CS(=O)(=O)Nc1nc(C(OC2CCCCO2)C(=O)O)cs1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CCCCOC(=O)Cl
Agent: CN(C)Cc1ccccc1
Agent: CS(=O)(=O)N=c1[nH]c(C(OC2CCCCO2)C(=O)O)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC3CCCCO3)c3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (350 mg.), triethylamine (96 mg.), N,N-dimethylbenzylamine (half drop) and tetrahydrofuran (7 ml.) was dropwise added a mixture of butyl chloroformate (130 mg.) and tetrahydrofuran (1 ml.) over 1 minute at -15° C., and then the mixture was stirred for 30 minutes at -15° to -10° C. To the mixture was added all at once a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (224 mg.), triethylamine (80 mg.) and 50% tetrahydrofuran aqueous solution (10 ml.) which was cooled at 0° C., and the mixture was stirred for 30 minutes under ice-cooling and further stirred for 2 hours at room temperature. After the reaction, the reaction mixture was concentrated. The residue was adjusted to pH 8 with 5% sodium bicarbonate aqueous solution and washed with ethyl acetate. Thus obtained aqueous layer was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and dried to give pale brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (270 mg.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>>[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([C:33]([N:8]2[CH2:13][CH2:12][C@H:11]([N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C@H:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9]2)=[O:34])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Reactant: CN1CCNCC1
Product: CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=500.2 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-phenyl-piperidin-4-one, N-methyl-piperazine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH:13]([O:15][CH3:16])[CH2:12][CH2:11][NH:10]1.CO[CH2:19][CH:20]1CCC(C2C=CC=CC=2OC)[NH:21]1.COCC1CCC(C2C=CC=CC=2OC)N1CCN>>[NH2:21][CH2:20][CH2:19][N:10]1[CH2:11][CH2:12][CH:13]([O:15][CH3:16])[CH2:14][CH:9]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1C1CC(OC)CCN1
Reactant: COCC1CCC(c2ccccc2OC)N1
Agent: COCC1CCC(c2ccccc2OC)N1CCN
Product: COc1ccccc1C1CC(OC)CCN1CCN

Procedure:
2-(2-Methoxyphenyl)-4-methoxypiperidine was converted to the title compound in two steps by the same procedures as the transformation of 2-methoxymethyl-5-(2-methoxyphenyl)-tetrahydropyrrole to 2-methoxymethyl-5-(2-methoxyphenyl)-1-(2-aminoethyl)-tetrahydropyrrole as described above in Preparations 23 and 24. 1H NMR (CDCl3, 400 MHz) δ:3.80 (3H, S, OMe), 3.31 (3H, s, OMe).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10](Br)=[N:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using compound 1a (0.20 g, 0.84 mmol) and phenylboronic acid (0.20 g, 1.68 mmol) according to Method B. Yellow solid. Yield: 0.10 g, 57%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.19 (s, 2H), 6.94 (t, J=1.3 Hz, 1H), 7.13 (s, 1H), 7.48-7.50 (m, 4H), 7.60 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.97-7.99 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 119.0, 120.6, 126.9, 128.8, 130.0, 130.4, 135.7, 137.3, 138.6, 148.6, 157.7; MS (ESI): m/z=236.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].[C:22](=[O:25])([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:25][CH3:22])[CH:4]=2)=[C:16]([CH:20]=1)[C:17]([O:19][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)=[O:18]
Reactant: COc1cccc(CBr)c1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(COC(=O)c2cc(Br)ccc2OCc2cccc(OC)c2)c1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
Neat 1-(bromomethyl)-3-methoxybenzene (510 mg, 2.53 mmol) was added in one charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (250 mg, 1.15 mmol) and potassium carbonate (318 mg, 2.304 mmol) in acetone (40 ml) under nitrogen at 20° C. The reaction mixture was stirred at 55° C. for 16 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted by ethyl acetate (3×30 ml) and evaporated in vacuo to yield the title compound as an off-white solid. 430 mg.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13]C)[CH:9]=[CH:10][C:11]=2[CH:12]=1>Br>[OH:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([CH:2]([CH3:1])[C:15]([OH:17])=[O:16])[CH:4]=[CH:5]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: Br
Product: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reaction time: 0.5 h

Procedure:
A mixture of Naproxen (500 grams, 2.774 mmol) and 48% HBr (1500 ml) was refluxed for 10 Hours, poured onto ice water (3000 ml) and stirred for 30 minutes. Crude 36 was filtered, dried (380 grams, 81%) and used as such for next stage.