Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:9][N+:10]([O-])=O>CO.[Ni]>[NH2:10][CH2:9][CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C(c1ccc2c(C(C[N+](=O)[O-])c3ccccc3F)c[nH]c2c1)N1CCOCC1
Agent: [Ni]
Solvent: CO
Product: NCC(c1ccccc1F)c1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Reaction time: 3 h
Yield: 64.7 %

Procedure:
To a spatula full of Raney-Ni in a Parr tube was added a solution of (3-(1-(2-fluorophenyl)-2-nitroethyl)-1H-indol-6-yl)(morpholino)methanone (0.3659 g, 0.921 mmol) in MeOH (30.7 mL). The reaction was shaken under hydrogenation at 53 psi for 3 hr. After flushing with nitrogen, the mixture was filtered through a pad of CELITE® and rinsed with MeOH. The filtrate was concentrated in vacuo to give the desired product (0.270 g, 0.596 mmol, 64.7% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH2:31][CH:27]3[CH2:28][CH2:29][CH2:30][NH:26]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1CCCN1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CCCN3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(pyrrolidin-2-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.96-7.94 (m, 2 H), 7.90 (d, J=7.6 Hz, 1 H), 7.70 (d, J=8.4 Hz, 1 H), 7.61 (t, J=7.6 Hz, 1 H), 7.47-7.45 (m, 2 H), 6.01 (s, 1 H), 5.33-5.25 (m, 2 H), 4.55-4.41 (m, 2 H), 3.96-3.73 (m, 3 H), 3.64 (s, 2 H), 3.38-3.31 (m, 1 H), 3.29-3.27 (m, 1 H), 2.37 (s, 3 H), 2.28-2.21 (m, 1 H), 2.13-1.96 (m, 2 H), 1.89-1.81 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH3:10])=[CH:4][N:3]=1.N#CN.IC1C=CC=C(CC([O-])=[O:23])C=1CC([O-])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:10])=[O:23])=[CH:4][N:3]=1
Reactant: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Reactant: CSCc1ccc(Cl)nc1
Agent: N#CN
Solvent: ClCCl
Product: CS(=O)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
To a solution of sulfide (A) (3.5 g, 17 mmol) and cyanamide (1.4 mg, 34 mmol) in CH2Cl2 (30 mL) at 0° C. was added iodobenzenediacetate (11.0 g, 34 mmol) all at once. The reaction was stirred for 30 min, then allowed to warm to room temperature overnight. The mixture was diluted with CH2Cl2 (50 mL) and washed with H2O. The aqueous layer was extracted with ethyl acetate (4×50 mL), and the combined organic layers were dried over MgSO4 and concentrated. The crude product was triturated with hexanes and purified by chromatography (chromatotron, 60% acetone/hexanes) to furnish the sulfilimine (B) as a yellow gum (0.60 g, 14%). IR (film) 3008, 2924, 2143, 1693 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.8 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 4.5 (d, 1H), 4.3 (d, 1H), 2.9 (s, 3H); LC-MS (ESI): mass calcd for C9H9F3N3S [M+H]+ 248.04. Found 248.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:11]([NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:13])[CH3:12].[F:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32](OC)=[O:33].Cl>C1COCC1>[F:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32](=[O:33])[CH:24]([C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([NH:14][CH:11]([CH3:12])[CH3:13])[S:16][C:17]=2[CH:23]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)Cc1ccc2nc(NC(C)C)sc2c1
Reactant: COC(=O)c1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)c1ccccc1F)c1ccc2nc(NC(C)C)sc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 120.2 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 15.1 mL) in THF (30 mL) was added a solution of methyl 2-(2-(isopropylamino)benzo[d]thiazol-6-yl)acetate (1.60 g, 6.05 mmol) in THF (20 mL) at −78° C. over 40 min. The resulting solution was stirred at −78° C. for 15 min before a solution of methyl 2-fluorobenzoate (1.08 mL, 8.48 mmol) in THF (10 mL) was added over 5 min. The mixture was stirred at −78° C. for 1 hr and then at rt for 3 hr before it was poured into ice-cold water (100 mL). After its pH value was adjusted to 9 with 6 N HCl, the mixture was extracted with AcOEt (3×40 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. Evaporation of solvent under vacuum give the title compound (2.81 g) as an orange yellowish oil. This product was 63% pure by LCMS, but it was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:8]1OCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][NH:14][NH2:15].[OH-].[Na+].O.[CH:19](Cl)(Cl)Cl>>[CH3:13][N:14]1[CH:8]=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=[N:15]1
Reactant: c1ccc(CC2OCCO2)cc1
Reactant: ClC(Cl)Cl
Reactant: CNN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(-c2ccccc2)cn1
Temperature: 70 °C

Procedure:
32.8 g (0.20 mol) of 2-benzyl-1,3-dioxolane are introduced, at a temperature of between 50° C. and 65° C., into a reactor containing 57.6 g (0.45 mol) of N,N-dimethylchloromethyliminium chloride in solution in 150 ml of chloroform and the solution is then heated for 1 h to 65° C. The chloroform is removed under reduced pressure and 11.5 g (0.25 mol) of monomethylhydrazine in aqueous solution at a concentration of 30% are then introduced at 50° C. The solution is heated for 2 h at 70° C. It is cooled to 20° C. and then neutralised to pH =8 with an aqueous 30% sodium hydroxide solution. 10 ml of water are then added and the required product is then extracted with 2 15-ml portions of methylene chloride. The extraction solvent is removed. A crude product is thus obtained, which was purified by recrystallisation from isopropyl ether. The purified product, 1-methyl-4-phenylpyrazole, identified by 1H NMR and mass spectrometry, has a melting point of 103.6° C. The yield of 1-methyl-4-phenylpyrazole formed, determined by quantitative analysis of the crude product, is 46%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:54])[C@H:15]([NH:24][C:25]([C@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][CH2:40][CH:41]2[C:53]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:47]3[C:42]2=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.[CH3:55][S:56](Cl)(=[O:58])=[O:57].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][CH2:40][CH:41]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=3[C:48]3[C:53]2=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:38])=[O:26])[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:56]([CH3:55])(=[O:58])=[O:57])[CH2:13][CH2:12]2)=[O:54])=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Yield: 86.3 %

Procedure:
Fluoren-9-ylmethyl (3R)-3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino] phenylpiperazinyl)-2-oxoethyl]carbamoyl}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from fluoren-9-ylmethyl (3R)-3-(N-{(1R)-2-[4-(2-aminophenyl)piperazinyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (250 mg, 0.34 mmol) according to the procedure for Preparation III using methanesulfonyl chloride (30 μl, 0.39 mmol) and 2,6-di-tert-butyl-pyridine (80 μl, 0.36 mmol) (Aldrich). The crude product was concentrated in vacuo and purified by flash chromatography (SiO2, 15% EtOAc in CH2Cl2), to afford the desired compound (240 mg). MS (ESI, pos. ion) m/z: 818 (M+H), (ESI, neg. ion) m/z: 816 (M−H). Calc'd for C45H44ClN5O6S: 817.27.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].Cl>O.C(Cl)Cl.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][O:20][CH3:19])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)COC)n2oc(=O)nc2n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
5.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 100 ml. of methylene chloride and 10 ml. of triethylamine. 2.5 g. of methoxyacetyl chloride in 20 ml. of methylene chloride are added dropwise while stirring and cooling to about 5° C. After 1 hour at about 5° C., the mixture is treated with water and adjusted to pH 4 with 3-N hydrochloric acid. The two phases are separated and the aqueous phase is extracted with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}-2-methoxyacetamide having a melting point of 135°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-])=O)=[CH:6]2.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([NH2:13])=[CH:6]2
Reactant: COc1ccc2ncc([N+](=O)[O-])cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(N)cc2c1

Procedure:
A mixture of 6-methoxy-3-nitroquinoline (Magnus, P. et al., J. Am. Chem. Soc. 119, 5591, 1997; 0.17 g, 0.83 mmol) and Pd/C (10%, 80 mg) in EtOAc (15 mL) was hydrogenated with a hydrogen balloon to give 6-methoxyquinolin-3-amine in quantitative yield. LC/MS (m/z): 175.1 (MH+), Rt 1.54 minutes.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16]>C1COCC1>[C:11]([CH:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[C:13]([O:14][CH2:15][CH3:16])=[O:17])#[N:12]
Reactant: CCOC(=O)OCC
Reactant: N#CCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium hydride (4.2 g, 177.7 mmol) in THF was added 4-fluoro phenyl acetonitrile (10 g, 74.0 mmol) at −10° C. The reaction mixture was stirred for 15 min at the same temperature. Diethyl carbonate (10.5 g, 88.0 mmol) was added to the reaction mixture and the reaction mixture was allowed to come to room temperature and heated to 40° C. (Caution: Reaction will start suddenly and exothermic). The heating path was removed immediately once the reaction was started and the reaction mixture was cooled under ice/acetone. The solution was allowed to come to room temperature and stirred for 1 h. The reaction mass was cooled to 0° C. and quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water (50 mL), brine solution (50 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give ethyl 2-cyano-2-(4-fluorophenyl)acetate as crude compound as crude compound (10 g). The crude compound was taken to the next step without further purification. LC-MS (M−H)+=206.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.44 (2H, m), 7.11 (2H, m), 4.69 (1H, s), 4.27-4.22 (2H, q, J=7.2 Hz). 1.26 (3H, m)
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]3[NH:16][CH:17]=[C:18]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[C:10]=23)[CH2:4]1.Br[CH2:26][CH2:27][F:28].CCN(C(C)C)C(C)C.O>CN(C=O)C>[ClH:1].[Br:15][C:14]1[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][CH2:26][CH2:27][F:28])[CH2:4]2)=[C:10]2[C:18]([NH:19][C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])=[CH:17][NH:16][C:11]2=[N:12][CH:13]=1
Reactant: FCCBr
Reactant: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NCCF)C3)c12)C1CC1
Temperature: 80 °C
Yield: 15.8 %

Procedure:
(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.112 g, 0.248 mmol; Example 29, Step C), 1-bromo-2-fluoroethane (0.0222 mL, 0.298 mmol) and DIEA (0.173 mL, 0.993 mmol, d 0.742) were placed in DMF (2 mL) and heated to 80° C. for 36 hours. The reaction was then cooled to room temperature, poured into water, and extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 40M+, 5-50% water:ACN). The product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(5-bromo-4-(3-(2-fluoroethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.018 g, 15% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.23 (s, 1H), 7.26 (s, 1H), 4.69-4.67 (m, 1H), 4.56-4.55 (m, 1H), 3.84-3.81 (m, 1H), 3.57-3.54 (m, 1H), 3.42-3.16 (m, 5H), 2.22-2.19 (m, 1H), 1.80-1.73 (m, 3H), 1.57-1.55 (m, 1H), 0.90-0.80 (m, 4H). LCMS (APCI+) m/z 424, 426 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[CH2:5][CH2:6][CH2:7][N:8]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:9](=O)[O:10]C1C=CC=CC=1>C(O)C>[NH2:2][N:3]1[CH2:5][CH2:6][CH2:7][N:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]1=[O:10]
Reactant: O=C(Oc1ccccc1)N(CCCCl)c1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN1CCCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (5.3 mL) was added to a solution of 3-(4-fluorophenylamino)propan-1-ol (2.37 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added to the residue, followed by extraction with ethyl acetate (100 mL). Heptane (100 mL) was added to the resulting extract, and the solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1) to obtain (3-chloropropyl)-(4-fluorophenyl)amine. Triethylamine (5.4 mL) and phenyl chlorocarbonate (1.9 mL) were added to a solution of (3-chloropropyl)-(4-fluorophenyl)amine (2.40 g) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (3.93 g). Hydrazine monohydrate (0.40 mL) was added to a solution of phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (500 mg) in ethanol (10 mL) at room temperature. The reaction solution was stirred at room temperature for one hour, stirred at 60° C. for one hour and heated under reflux for seven hours. Hydrazine monohydrate (0.40 mL) was added to the reaction solution, and the reaction solution was heated under reflux for 13 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 265 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][C:9]([CH3:27])([CH3:26])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](ON1C(=O)CCC1=O)=[O:17])=[O:11]>>[CH3:8][C:9]([CH3:27])([CH3:26])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:17])=[O:11]
Reactant: CC(C)(C)C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)C(=O)O
Product: CC(C)(C)C(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 27.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (504 mg, 4.8 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2,2-dimethylpropanoate (1.1 g, 4.0 mmol) were reacted to provide 305 mg (28% yield) of the title compound (24) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.78 (m, 1H), 6.40 (br s, 1H), 6.11 (t, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.93 (m, 1H), 1.44 (2d, 3H), 1.20 (s, 9H). MS (ESI) m/z 278.05 (M+H)+; 295.06 (M+NH4)+; 300.04 (M+Na)+; 276.04 (M−H)−.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:20][CH:21]=[C:22]([CH:30]=O)[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1.O>CO>[CH3:2][O:3][N:4]=[CH:30][C:22]1[C:23]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[NH:20][CH:21]=1
Reactant: O=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CON=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 77 %

Procedure:
0.83 g (9.58 mmol) of O-methylhydroxylamine hydrochloride and 1.56 ml (11.2 mmol) of triethylamine were added to a solution of 0.85 mg (3.2 mmol) of 2-(4-fluorophenyl)-4-formyl-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in Example 1(iii) above] in 17 ml of methanol. The resulting mixture was heated under reflux for 30 minutes, after which water was added to the reaction mixture which was then extracted with ethyl acetate. The organic extract was washed with water and concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 728 mg (yield 77%) of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+:11].CC1C=C(F)C=CC=1[N+]([O-])=O>O>[CH:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([O-:9])[CH:4]=1.[K+:11]
Reactant: Oc1ccc(Cl)cc1Cl
Agent: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: [O-]c1ccc(Cl)cc1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Potassium 2,4-dichlorophenate is prepared by dissolving 6.5 g. (0.04 mole) of 2,4-dichlorophenol and 2.6 g. (0.04 mole) of 85% potassium hydroxide in 30 ml. of methanol and removing the solvent under reduced pressure. The solid residue is dissolved in 60 ml. of sulfolane and 6.2 g. (0.04 mole) of 3-methyl-4-nitrofluorobenzene is added. The resulting solution is heated at 85° C. for 3 hours then at 150° C. for one hour, cooled, diluted with water and extracted with ether/benzene. The extract is dried and the solvent removed. The residue is dissolved in hot isopropanol and on cooling 8.2 g. (69%) of 2,4-dichloro-3'-methyl-4'-nitrodiphenyl ether (m.p. 72.5°-73.5° C.) separated and is isolated by filtration.
Reaction SMILES: [OH:1][C:2]12[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=[O:17])[CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH:18]([O:20][CH2:21][CH3:22])=[CH2:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCCCC.C(OCC)C>[CH2:18]([O:20][CH:21]([O:1][C:2]12[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=[O:17])[CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH3:22])[CH3:19]
Reactant: C=COCC
Reactant: CC1CC(=O)C2CCCCCCCCC2(O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(C)OC12CCCCCCCCC1C(=O)CC(C)C2
Yield: 67.6 %

Procedure:
A mixture of 119 mg (0.5 mmol) of (30) and 384 μl (4 mmol) ethyl vinyl ether was stirred at 25° C. in the presence of 25 mg (0.1 mmol) pyridinium p-toluenesulfonate (PPTS) for 2 hours (94% conversion). Flash chromatography of the reaction mixture, using SiO2 (14 g) and n-pentane/diethyl ether=95:5 as eluent, afforded 105 mg (61%) of (31) as a ˜1:1 mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: C=Cc1ccc(N)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A cooled solution of 2-Fluoro-4-vinylaniline (20-1, 0.96 g, 7 mmol) in pyridine (10 mL) at 0° C. was treated with methanesulfonyl chloride (0.644 mL, 8.4 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:3) as eluant to afford N-(2-Fluoro-4-vinylphenyl)methanesulfonamide (20-2, LJO-325, 1.372 g, 91%) as a white solid.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.OC1C=CC([N:16]2[C:20](=[O:21])[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:28])[NH:17]2)=CC=1>>[OH:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][C:1]=1[N:16]1[C:20](=[O:21])[N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](=[O:28])[NH:17]1
Reactant: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(O)c(-n2[nH]c(=O)n(-c3ccccc3)c2=O)c1

Procedure:
Compound 32 was prepared from p-cresol in the same manner of compound 27, and was obtained as white solids (60%).