Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]1([CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Mg]Br.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>C1COCC1>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].[C:5]1([CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:15]1([OH:23])[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14]1
Reactant: Cc1ccccc1[Mg]Br
Agent: O=C1Cc2ccccc2C1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccccc1C1(O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of anhydrous cerium chloride (40.60 g, 164.7 mmol) in THF(250 mL) was stirred at room temperature for 2 hours under nitrogen. o-Tolylmagnesium bromide (70.0 mL of 2.0 M solution in diethyl ether, 140.0 mmol) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature overnight (12 h). It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. Kugelrohr distillation (120° C./0.3 mm Hg) yielded 4.0 g of 2-indanone and 10.38 g of 2-(o-tolyl)-2-indanol in solid form. 1H-N.M.R. (CDCl3) d 2.13 (br s, 1H), d 2.52(s, 3H), d 3.36 (d, J=16.2 Hz, 2H), d 3.63 (d, J=16.2 Hz, 2H), d 7.15-7.62 (m, 8H)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:18][CH3:19])=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=[O:20].[Cl:21][CH2:22][CH2:23][C:24]1[O:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[CH:25]=1>>[ClH:21].[CH3:1][N:2]([CH2:22][CH2:23][C:24]1[O:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:18][CH3:19])=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=[O:20]
Reactant: ClCCc1cc2ccccc2o1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2C1=O
Product: COc1cc2c(cc1OC)C(=O)N(CCCN(C)CCc1cc3ccccc3o1)CC2
Product: Cl

Procedure:
Prepared from 2-(N-methyl-3-amino-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 2-(2-chloro-ethyl)-benzo[b]furan analogously to Example 1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH2:13](O)[CH3:14]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:13][CH3:14])=[O:7]
Reactant: CCO
Reactant: O=C(O)CCCCBr
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCCBr

Procedure:
A! Starting from 5-bromopentanoic acid (50 g, 0.276 mole) and thionyl chloride (39 ml, 0.552 mole) in absolute ethanol (500 ml) and following the procedure of Example 13,A!, there were obtained 62.7 g of ethyl 5-bromopentanoate (quantitative yield) which was used as such in the next step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:44])/[CH:16]=[C:17]2\[C:18]([F:43])([F:42])[CH2:19][CH2:20][N:21]([C:28]([C:30]3[S:34][C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:32][C:31]=3[CH3:41])=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]\2=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:45]C(OC(Cl)C)=O>ClCCl>[ClH:45].[F:43][C:18]1([F:42])[CH2:19][CH2:20][N:21]([C:28]([C:30]2[S:34][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32][C:31]=2[CH3:41])=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2/[C:17]/1=[CH:16]/[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:44]
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc21
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NC2CCNCC2)c2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 500 mg of (Z)-N-(1-benzyl-4-piperidyl)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-acetamide in 15 ml of dichloromethane was added 88 μl of 1-chloroethyl chloroformate, and the mixture was stirred for 3.5 hours with heating under refluxing. The solvent was evaporated, and 20 ml of methanol was added to the residue, followed by stirring at 50° C. for two hours. After this was cooled down to room temperature, a saturated aqueous solution of sodium bicarbonate was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluting with methanol-aqueous ammonia). After making into a hydrochloride using a 4N HCl/ethyl acetate solution, the salt was collected by filtration and washed with ethyl acetate to give 273 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-(4-piperidyl)acetamide monohydrochloride as a colorless powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:38]>C(O)C>[ClH:38].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([C:33]([F:36])([F:34])[F:35])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCCCCCCCSc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCCCCCCCSc1ccc(CCC(N)(CO)CO)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 25-1 (910 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (630 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:36][C:35]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:39]4[CH:38]=[C:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH:36]=[CH:35][C:34]=4[O:33][CH3:32])=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: COC(=O)CCc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC)c(-c2cnc(SC)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 45) (307 mg, 0.579 mmol), methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (INTERMEDIATE 2) (185 mg, 0.579 mmol), 1,1bis(di-tert-butylphosphino)ferrocene palladium dichloride (39.4 mg, 0.058 mmol), potassium carbonate (0.724 ml, 1.447 mmol) and THF (5 mL) were sealed in a uw vessel and subject to microwave irradiation at 140° C. for 20 min. The reaction crude was dried over Na2SO4, filtered and purified by preparative TLC (silica gel) developed with EtOAc/hexanes (40% ethyl acetate v/v) to give a brown solid as the titled compound. LCMS calc.=643.16. found=644.17 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[CH3:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[I-].[K+].C(=O)([O-])[O-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:15]2[CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13][CH2:14]2)=[CH:4][N+:3]=1[O-:10]
Reactant: CC1CCNCC1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1CCN(Cc2ccc(Cl)[n+]([O-])c2)CC1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide (222 mg, 1.25 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333) in tetrahydrofuran (2 mL) were added a solution of 4-methylpiperidine (247 mg, 2.49 mmol) in tetrahydrofuran (1.5 mL), a catalytic amount of potassium iodide, and MP-Carbonate (2.55 mmol/g, 1.47 g, 3.74 mmol). The mixture was gently stirred at room temperature for one week. The mixture was filtered (20 μm polyethylene filter), and the beads were washed with several portions of methylene chloride. The filtrate was washed with NaHCO3 (aq. sat.), dried (Na2SO4), and the solvent was evaporated to give a crude product which was purified by column chromatography using chloroform/ethanol, (95:5), as the eluent to give 168 mg (56% yield) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.37 (d, J=1 Hz, 1 H), 7.41 (d, J=8 Hz, 1 H), 7.20 (dd, J=8, 2 Hz, 1 H), 3.41 (s, 2 H), 2.80-2.75 (m, 2 H), 2.00 (dt, J=12, 2 Hz, 2 H), 1.63-1.58 (m, 2 H), 1.45-1.30 (m, 1 H), 1.22 (m, 2 H), 0.92 (d, J=6 Hz, 3 H); MS (ES) m/z 241 (M++1).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>C(#N)C>[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-piperazinecarboxylate (5.51 g, 29.623 mmol) in acetonitrile (60 mL) at 0° C. was treated with diisopropylethylamine and 2-bromobenzyl bromide (7.776 g, 31.105 mmol), warmed to room temperature, stirred for 2 hours, and concentrated. The residue was partitioned between ethyl acetate and aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:36])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:31]([O:33]CC)=[O:32])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:36])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:31]([OH:33])=[O:32])[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(CCCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
To 0.8 mL of an ethanol solution containing 80 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(3-phenylpropyl)piperidine-4-carboxylate, 0.2 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 5 hours. After the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure, water was added, and adjusted to pH 6.8 with 6.0 mol/L hydrochloric acid. The solvent was removed under reduced pressure, and the residue thus obtained was purified by reversed-phase silica gel column chromatography [eluent; acetonitrile:water=3:7] to give 23 mg of 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(3-phenylpropyl)piperidine-4-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]([OH:12])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O>[Si:23]([O:22][CH2:21][CH2:20][O:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1cc(O)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ncc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 94.5 %

Procedure:
Step A To a solution of 4-methoxy-5-nitropyridin-2-ol (0.5 g, 2.9 mmol) in anhydrous DMF (12 mL) were added K2CO3 (0.82 g, 5.9 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (0.7 g, 2.9 mmol) sequentially. The reaction mixture was heated at 70° C. for 2 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 2-(2-(tert-butyldimethylsilyloxy)ethoxy)-4-methoxy-5-nitropyridine as a white solid (0.9 g, 93%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](=[N:15]O)[CH3:14])[CH2:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N.[Ni]>[NH2:15][CH:13]([CH:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:17])[CH2:10]1)[CH3:14]
Reactant: CC(=NO)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Ni]
Agent: N
Product: CC(N)C1CC(=O)N(Cc2ccccc2)C1
Reaction time: 3 h
Yield: 91.6 %

Procedure:
1-Benzyl-4-(1-hydroxyiminoethyl)-2-oxopyrrolidine (16.81 g, 0.072 mole), was hydrogenated in saturated methanolic ammonia (200 mL) at 50 psi and 25° with Raney nickel (5 g) for 23 hours. Additional Raney nickel (5 g) was added and hydrogenation continued for three hours. The reaction was Celite filtered and the solvent was removed under reduced pressure to give 4-(1-aminoethyl)-1-benzyl-2-oxopyrrolidine (14.4 g, 91%) as a brown oil which solidified on standing to a brown solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li].C[Li].C(OCC)C.C(NC(C)C)(C)C.[S:23]([NH:33][C@@H:34]1[CH2:39][O:38][C:36](=[O:37])[CH2:35]1)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[CH2:40]([C@H:35]1[C@H:34]([NH:33][S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH2:39][O:38][C:36]1=[O:37])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H]2COC(=O)C2)cc1
Agent: [Li]
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N[C@@H]2COC(=O)[C@H]2Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of lithium diisopropylamine (LDA) in THF was generated by adding 1.5 M methyllithium in diethyl ether (30 mL, 45.0 mmol) to a solution of diisopropylamine (6.4 mL, 45.7 mmol) in 100 mL THF at 0° C. under nitrogen and stirring for 10 min. The solution was then cooled to −78° C., and a solution of (3S)-3-(tosylamino)butano-4-lactone (5.36 g, 21.1 mmol) in 30 mL THF was added dropwise. The resulting yellow solution was stirred for 1 hour at −78° C., and then benzyl bromide (10 mL, 84.1 mmol) was added rapidly. Stirring at −78° C. was continued for 2 hours, and the reaction was quenched with 20 mL sat. aq. NH4Cl solution and allowed to warm to room temperature. The mixture was acidified with 1 M HCl and extracted three times with methylene chloride. The combined organic extracts were dried over Na2SO4 and evaporated to give an orange semisolid that was purified by chromatography (silica gel, hexane/ethyl acetate 3:2) to yield 2.22 g (8.70 mmol, 41%) recovered starting material and 3.37 g (9.76 mmol; 46%) of 4. No diastereomeric addition product could be detected. For further purification 4 can be recrystallized from toluene to give colorless needles. mp. 108.5-109° C., 1H-NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 7.20 (m, 3H), 6.92 (dd, J=7.7, 1.7 Hz, 2H), 4.97 (d, J=5.5 Hz, 1H), 4.27 (dd, J=7.2, 9.8 Hz, 1H), 3.98 (dd, J=7.2, 9.8 Hz, 1H), 3.65 (m, 1H), 3.00 (m, 1H), 2.77 (m, 2H), 2.46 (s, 3H), 13C-NMR (75.5 MHz, CDCl3) δ 144.27 (C), 138.00 (C), 135.83 (C), 129.89 (CH), 128.97 (CH), 128.88 (CH), 127.10 (CH) 71.25 (CH2) 53.21 (CH), 46.54 (CH), 33.54 (CH2) 21.50 (CH3), EI MS m/e 345.1027 calc. for C18H19NO4S 345.1035.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[S:18][C:19]1[CH:26]=[CH:25][C:24]([S:27][C:28]([F:31])([F:30])[F:29])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([CH:21]([OH:22])[C:20]2[CH:23]=[C:24]([S:27][C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:26][C:19]=2[S:18][C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[F:10])[CH2:3][CH2:4]1
Reactant: O=Cc1cc(SC(F)(F)F)ccc1Sc1cc(F)ccc1F
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C(O)c2cc(SC(F)(F)F)ccc2Sc2cc(F)ccc2F)CC1
Yield: 98.9 %

Procedure:
A solution of a Grignard reagent is prepared by a reaction of 12.0 g of 4-chloro-1-methylpiperidine with 2.4 g of magnesium in 70 ml of tetrahydrofuran and is treated dropwise for 10 minutes with a solution of 21.2 g of 2-(2,5-difluorophenylthio)-5(trifluoromethylthio)benzaldehyde in 40 ml of tetrahydrofuran. The mixture is refluxed for 5 hours and, after cooling, decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is washed with water, dried with potassium carbonate and evaporated. There are obtained 26.9 g of crude oily α-(1-methyl-4-piperidyl)-2-(2,5-difluorophenylthio)-5-(trifluoromethylthio)benzyl alcohol which is used in this state for further reaction.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:10])[O:4][N:3]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:25]1([S:31]([O:1][C:2]2[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[S:10])[O:4][N:3]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Oc1cc(CCC(=S)OC(c2ccccc2)c2ccccc2)on1
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1cc(CCC(=S)OC(c2ccccc2)c2ccccc2)on1)c1ccccc1

Procedure:
This benzhydryl 3-hydroxyisoxazol-5-ylmethylthioacetate was reacted with benzenesulphonyl chloride in the presence of triethylamine to give benzhydryl 3-benzenesulphonyloxyisoxazol-5-ylmethylthioacetate, which was treated with trifluoroacetic acid to afford the title compound as crystals.
Reaction SMILES: [CH2:1]([N:8]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C@@H:9]([CH3:13])[CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>C1COCC1>[CH2:1]([N:8]([C@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[C@H:9]([CH2:10][CH2:11][O:12][CH3:24])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: C[C@@H](CCO)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC[C@H](C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
(3S)-3-[Benzyl-[(1S)-1-phenylethyl]amino]butan-1-ol (17.54 g, 61.9 mmol) is dissolved in anhydrous THF (186 mL) and cooled to 0° C. under an argon atmosphere. Sodium hydride (4.95 g, 60% suspension in mineral oil, 123.8 mmol) is added portionwise over 10 min. The mixture is stirred at 0° C. for 15 min, and then allowed to warm to RT. Methyl iodide (10.54 g, 74.28 mmol) is added dropwise over 30 min. After stirring for 30 additional min, the reaction is quenched by the addition of a saturated solution of NH4Cl in water. The layers are separated and the aqueous layer is extracted with diethyl ether (2×100 mL). The combined organic layers are dried over MgSO4, concentrated, and the crude is purified by normal phase chromatography (two 120 g silica-gel cartridges, 10% of methyl tert-butyl ether in hexanes) to afford the title compound as a colorless oil (14.96 g, 81%). LC-ES/MS m/z 298 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.CN1CCOCC1.[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C:25](O)=[O:26].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:25](=[O:26])[CH2:24][N:20]1[CH2:21][CH2:22][CH2:23][C:19]1=[O:18]
Reactant: O=C(O)CN1CCCC1=O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Temperature: -25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
To a solution of L-proline methyl ester hydrochloride (8.28 g) in DMF (100 ml) were added N-methylmorpholine (5.50 ml), 2-oxo-1-pyrrolidine acetic acid (7.15 g) and HOBt (10.12 g) under ice-cooling. The mixture was cooled to -25° C., added with DCC (10.32 g), and stirred at room temperature for 16 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 12.94 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-proline methyl ester.
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.O1C2C=CC=CC=2N=[CH:12]1.S1C2C=CC=CC=2N=C1>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=[CH:2][CH:3]=1
Reactant: c1ccc2ocnc2c1
Reactant: c1ccc2nccnc2c1
Agent: c1ccc2scnc2c1
Product: c1ccc2ncccc2c1

Procedure:
quinoxaline; benzoxazole; or benzothiazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1.[N:19]1([CH2:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>Cl.C(O)(C)C>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[N:7][C:2]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:25]([CH2:24][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:26]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: NC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: NC(=O)c1ccccc1Nc1nc(Nc2cccc(CN3CCCC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
2-[(2,5-Dichloro-4-pyrimidinyl)amino]benzamide (200 mg, 0.6 mmol) and 3-(1-pyrrolidinylmethyl)aniline (134mg, 0.75 mmol) were combined in a vessel with 5 mL isopropanol and 2 drops of 12N HCl. The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction was cooled to room temperature and the solid was filtered off and washed with isopropanol to give 178 mg (65% yield) of an orange solid as the HCl salt. MS: M(C22H23ClN6O)=422.92, (M+H)+=423 and 425.