Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:18])[N:14]=[CH:15][C:16](I)=[C:11]2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[C:25](=[O:27])=[O:26]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:18])=[N:14][CH:15]=[C:16]([C:25]([OH:27])=[O:26])[C:11]=2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(I)c12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12

Procedure:
To a solution of 7-chloro-4-iodo-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (200 mg) in dry tetrahydrofuran (4 ml) at −40° C. under an atmosphere of nitrogen, was added dropwise, a solution of isopropylmagnesium chloride (2M in tetrahydrofuran, 600 ul) and the solution stirred at −40° C. for 15 minutes. The solution was saturated with a stream of carbon dioxide gas and then diluted with ethyl acetate. The organic was extracted with saturated ammonium chloride followed by 1N sodium hydroxide solution. The combined aqueous was then acidified to pH1 with concentrated hydrochloric acid to afford a precipitate. The precipitate was filtered and washed with water until neutral. The solid was then sucked dry and dried over sodium hydroxide at 50° C. to afford the title compound (86 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[C:11]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cccc2cc[nH]c12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2cccc3cc[nH]c23)cc1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
To a suspension of 7-bromo-1H-indole (196 mg, 0.00100 mol) in 1,4-dioxane (4 mL) and water (1 mL) was added phenylboronic acid (146 mg, 0.00120 mol), potassium carbonate (414 mg, 0.00300 mol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (82 mg, 0.00010 mol). The flask was evacuated and refilled with nitrogen, three times then the mixture was heated at 100° C. overnight. The mixture was diluted with EtOAc (30 mL), washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL), then dried over anhydrous sodium sulfate and the solvent removed in vacuo. The crude material was purified by chromatography over silica gel eluting with hexane/EtOAc to give the title compound (180 mg, 93% yield). 1H NMR (CDCl3, 400 MHz): δ 6.64 (dd, J=3.0, 2.0 Hz, 1H), 7.18-7.26 (m, 3H), 7.41 (t, J=7.5 Hz, 1H), 7.48-7.57 (m, 2H), 7.61-7.70 (m, 3H) and 8.43 (br s, 1H) ppm. LC-MS (ES+.): 194 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-one and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:23]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].N(CCCC)(CCCC)CCCC.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:21][O:20][C:18]([CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:23])=[O:19]
Reactant: COC(=O)CCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: COC(=O)C1CCCCCCC=CCCCCCCCC1=O
Yield: 45.1 %

Procedure:
Under an argon stream, CH2Cl2 solvent (0.1 ml) was placed in a flask beforehand, and thereto were added dropwise, at 0 to 5° C., a mixed solution of dimethyl cis-9-octadecenedioate (141 mg, 0.41 mmol) and Bu3N (230 mg, 1.24 mmol) in CH2Cl2 (1.7 ml) and a solution of TiCl4 (132 μl, 1.20 mmol) in CH2Cl2 (2.0 ml) at the same time over a period of 1 hour by means of a microfeeder. The whole was further mixed at the same temperature for 15 minutes. Water was added to the reaction mixture and the resulting mixture was stirred and then extracted with ether. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the evaporation of the solvent under reduced pressure, the crude product was purified by silica gel chromatography (hexane/ethyl acetate=20/1→10/1) to obtain the aimed product (57 mg, 45%) and a by-product (34-membered ring; 22 mg, 17%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(#N)C>[Br:16][C:7]1[C:2]([F:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)ccn1
Solvent: CC#N
Product: Nc1cc(F)c(Br)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-fluoropyridin-2-amine (400 mg, 3.57 mmol) in acetonitrile (35. 7 mL) was added NBS (648 mg, 3.64 mmol) in three portions at 0° C. The reaction mixture was stirred at 0° C. for 20 min. LCMS showed the reaction complete. After quenched with sat Na2S2O3 and NaHCO3, stirred for 30 min. The reaction mixture was extracted with EtOAc 3 times. Washed by sat NaHCO3, water and brine. Dried and concentrated. The crude material was triturated with ether and taken to the next step without further purification. LCMS (m/z): 192.9 (MH+), 0.32 min.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[N:4]=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:6]2[CH:11]=[CH:10][N:9](COCC[Si](C)(C)C)[C:7]=2[N:8]=1.[F-].O>C1COCC1>[CH3:1][N:2]([CH3:25])[C:3]1[NH:8][C:7]2=[N:9][CH:10]=[CH:11][C:6]2=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: CN(C)c1nc(-c2ccco2)c2ccn(COCC[Si](C)(C)C)c2n1
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1nc(-c2ccco2)c2ccnc-2[nH]1
Yield: 21.2 %

Procedure:
A solution of N,N-dimethyl-4-(2-furyl)-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine (370 mg, 0.97 mmol) in THF (3 mL) was treated with tetrabutylamnonium fluoride (1 ml, 1-M in THF, 1 mmol),refluxed for 36 h, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:9, alumina) to give the title compound (47 mg, 21%) as a yellow solid.
Reaction SMILES: C1([C@H]2COC(C3C=CC=C(C4OC[C@H](C5C=CC=CC=5)N=4)N=3)=N2)C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:38][CH2:39][C@H:40]2[O:44][C@@H:43]([N:45]3[CH:52]=[CH:51][C:49](=[O:50])[NH:48][C:46]3=[O:47])[C@H:42]([OH:53])[C@@H:41]2[OH:54])=[CH:33][CH:32]=1.[C:69]1([N:75]=[C:76]=[O:77])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([C:61]2[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:38][CH2:39][C@H:40]2[O:44][C@@H:43]([N:45]3[CH:52]=[CH:51][C:49](=[O:50])[NH:48][C:46]3=[O:47])[C@H:42]([OH:53])[C@@H:41]2[O:54][C:76](=[O:77])[NH:75][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:35][CH:36]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Cu+2]
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The THF solution (1 ml) containing 2,6-bis[(4S)-phenyl-2-oxazoline-2-yl]pyridine (0.03 mmol, 11.1 mg) and Cu(OTf)2 (II) (0.03 mmol, 11.1 mg) was stirred for 30 minutes at room temperature. After the reaction mixture was cooled to 0° C., the THF solution (1.5 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.3 mmol, 164.0 mg) and the THF solution (1 ml) of phenyl isocyanate (0.3 mmol, 35.7 mg) were added thereto. After the mixture was continuously stirred for 19 hours at 0° C., the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 68:32, and the transformation ratio of the reaction was 81%.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[C@@H:24]([OH:32])[C@H:23]3[OH:33])=[C:15]([NH:34][CH2:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:14]=2)[CH2:9]1)(C)(C)C.[ClH:50]>CO>[ClH:50].[ClH:50].[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[C@@H:24]([OH:32])[C@H:23]3[OH:33])=[C:15]([NH:34][CH2:35][CH:36]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:14]=2)[CH2:9]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
{(R)-1-[9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (ca 4.80 mmol) is dissolved in 1.25 M HCl in MeOH (60 mL). After stirring at room temperature for 3 days, the solvent is removed in vacuo to yield the title compound. MS (ES+) m/e 571.24 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].C(OC(C)C)(C)C>ClCCl>[Cl:13][CH2:14][C:15]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:2][CH:3]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 50 g of methyl 3-phenylpropionate, 51.6 g of chloroacetyl chloride and 250 ml of dichloromethane was cooled to 0° C. Then at 0° to 10° C. with stirring, 122 g of aluminum chloride was added slowly, stirred at a room temperature for 2 hours and allowed to stand overnight. The reaction mixture was poured into an ice-concentrated hydrochloric acid and extracted with chloroform, then the chloroform layer was washed with water, dried and the chloroform was removed by distillation to obtain the residue, then isopropyl ether was added to the residue to effect crystallization. The crystals were collected by filtration, and recrystallized from ethanol to obtain 53.4 g of methyl 3-(4-chloroacetylphenyl)-propionate. Colorless needle-like crystals. Melting point: 90°-92° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][NH:24][OH:25])[CH:17]=3)[C:12]2=[O:26])=[CH:4][CH:3]=1.C[Si]([N:31]=[C:32]=[O:33])(C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([C:32]([NH2:31])=[O:33])[OH:25])[CH:17]=3)[C:12]2=[O:26])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C1c2ccc(OCCNO)cc2CCN1CCCc1ccc(F)cc1
Solvent: C1COCCO1
Product: NC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (3.0 g, 8.4 mmol) in dioxane (100 mL) is added trimethylsilyl isocyanate (1.06 g, 9.2 mmol). The reaction is stirred at room temperature for 24 hours and subsequently poured into H20 (350 mL). The resulting suspension is extracted with EtOAc (1×500 mL) and the organic phase washed with 2M HCl (1×250 mL), H2O (5×500 mL), saturated NaCl solution (2×500 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is triturated with hexanes, and recrystallized from EtOAc to give 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-aminocarbonyl-N-hydroxyamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 138°-140°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1>C(O)C.[Pd]>[NH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2cc(N)ccc2n1

Procedure:
2-Methyl-6-nitroquinoline (18.8 g) was stirred under a hydrogen atmosphere at 206.8 kPa (30 p.s.i.) for 2 hours in ethanol solution containing 5% Pd/C. The catalyst was then removed by filtration, the filtrate evaporated to small volume in vacuo, and the resultant precipitate collected by filtration, washed with ethanol and ether, and dried to give the title compound, yield 13.2 g, m.p. 188°-189°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([OH:30])=O)[CH2:23]2)=[CH:18][CH:17]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:30])[CH2:23]2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N4CC(C(=O)O)CC4=O)cc3)c2cc1OC
Reactant: Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N4CC(C(=O)Nc5ccccc5)CC4=O)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-5-oxopyrrolidine-3-carboxylic acid (Step 3, 120 mg, 0.29 mmol), aniline (55 mg, 0.59 mmol), HOBt (58 mg, 0.43 mmol) in 6 mL of DMF was added EDC (82 mg, 0.43 mmol) at RT. The reaction was stirred at RT for 16 h. The mixture was diluted with 50 mL of EtOAc, and the resulting solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel column chromatography (30% to 100% EtOAc/hexane then to 5% MeOH/EtOAc) to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 484.5 (M+H). Calc'd Exact Mass for C28H25N3O5: 483.52.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([O-])([OH:12])=[O:11]>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(Br)c1
Product: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To an ice cold conc. sulphuric acid (400 mL) was added fuming nitric acid (200 mL) and to this solution was added 3-bromobenzaldehyde (i) (100 g, 0.540 mol) dropwise within 15 min. The reaction mixture was stirred for 10 min at same temperature at which time TLC showed complete reaction. The reaction mixture was quenched in ice water and filtered to afford a mixture of products which was purified by flash column chromatography eluting with EtOAc/hexane (1-5%) to give 5-bromo-2-nitrobenzaldehyde (ii) as white solid (60 g, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
1-tert-Butoxycarbonylpiperidin-4-one (2.50 g), indoline (1.50 g) and acetic acid (0.73 mL) were dissolved in 1,2-dichloroethane (75 mL), and sodium triacetoxyborohydride (5.32 g) was added thereto. The mixture was stirred at room temperature for 12 hr. The reaction mixture was added to iced water and the mixture was extracted with chloroform. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 1-tert-butoxycarbonyl-4-(1-indolinyl)piperidine (2.82 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].C(=O)(O)[O-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O.O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of (S)-(+)-2-amino-1-propanol (200 g, 2.66 mol) in purified water (400 mL) was added sodium bicarbonate (246 g, 2.93 mol). To this mixture was added benzyl chloroformate (500 g, 2.93 mol) in tetrahydrofuran (800 mL) at an internal temperature of 20° C. or below. Subsequently, the resulting reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, the reaction mixture was then extracted with ethyl acetate. The organic layer was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated under reduced pressure. The residue was crystallized from petroleum ether to give the target product as a white solid (403 g, yield 72.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[C:29]([NH:33][NH2:34])([CH3:32])([CH3:31])[CH3:30]>C(O)(=O)C>[C:29]([N:33]1[C:14]2[CH2:15][CH:16]3[N:11]([S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[CH:12]([CH2:19][CH2:18][CH2:17]3)[C:13]=2[CH:21]=[N:34]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)NN
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)n1ncc2c1CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a suspension of the enol-ketone (9-[(4-chlorophenyl)sulfonyl]-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one, 34 mg, 0.10 mmol), sodium acetate (41 mg, 0.5 mmol) and glacial acetic acid (0.8 mL) in a vial was added the tert-butylhydrazine hydrochloride (31 mg, 0.25 mmol) with good stirring. The vial was capped and the reaction mixture was stirred evenly and heated to 100° C. Upon complete consumption of the enol-ketone (2-18 h, LC-MS), the reaction mixture was evaporated under a stream of nitrogen while being warmed in a 90° C. bath. The brown residue was dissolved with dichloromethane and water. The organic phase was washed with 5% NaHSO4 (3×), 5% NaHCO3 (2×), and brine (2×), dried (Na2SO4), applied to a silica gel column and eluted (0-10% EtOAc in dichloromethane) to yield the product upon evaporation. MS (ES) m/e 306.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:15])([F:14])[C:10](Br)([F:12])[F:11].CS(C)=O>[Cu].O>[F:14][C:9]1([F:15])[C:10]([F:12])([F:11])[C:2]2[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)(F)Br)c(Cl)c1
Agent: [Cu]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
Into a pressure bottle were placed 3.0 g (0.0085 mole) 3-chloro-4-(2-bromo-1,1,2,2-tetrafluoroethoxy)nitrobenzene, 2.7 g (0.043 mole) copper powder (200 mesh), and 40 ml of dimethyl sulfoxide. The pressure bottle was sealed, and the reaction mixture stirred at 190°-195° C. for 6.5 hours. The pressure bottle was cooled to room temperature, opened, and the contents poured into a separatory funnel. Approximately 200 ml of water was added to the separatory funnel, and the mixture was extracted with three 150 ml portions of diethyl ether. The extracts were combined and washed first with 200 ml of a 2N hydrochloric acid solution, then with 200 ml of a saturated aqueous sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, leaving an oil. The reaction described above was repeated one additional time. The residual oils from the two experiments were combined and upon standing formed crystals of 2,2,3,3-tetrafluoro-2,3-dihydro-5-nitrobenzofuran.
Reaction SMILES: [N:1]#[N:2].[C:3]1([S:13]([NH:16][C@H:17]([C:25](O)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.P(Br)(Br)Br>>[N:1]#[N:2].[C:3]1([S:13]([NH:16][C@H:17]([C:25]([NH2:1])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)O
Agent: BrP(Br)Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N#N
Solvent: ClP(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(N)=O

Procedure:
An N2 -naphthalenesulfonyl-L-argininamide is prepared by reaction of a corresponding N2 -naphthalenesulfonyl-L-arginyl halide and an amine. The N2 -naphthalenesulfonyl-L-arginyl halide is prepared by reacting a corresponding N2 -naphthalenesulfonyl-L-arginine with a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, etc.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].CC(N1CCCC(C(C)=O)=C1)C>>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1
Reactant: CC(=O)C1=CNCCC1
Reactant: CC(C)CCBr
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: CC(=O)C1=CN(CCC(C)C)CCC1

Procedure:
Methyl 1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone was prepared from 3-acetyl-1,4,5,6-tetrahydropyridine and 1-bromo-3-methylbutane according to the procedure of Part (b) of Example 1. The product distilled as a pale yellow oil (b.pt. 103-106 °C./0.1 mm Hg).