Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:15]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C=Cc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccc(-c2ccccc2)c1
Yield: 110.6 %

Procedure:
A stirred mixture of 11.0 grams (0.043 mole) of ethyl 3-(3-bromophenyl)-2-propenoate, 5.8 grams (0.047 mole) of phenylboronic acid, 0.25 gram (catalyst) of tetrakis-(triphenylphosphine)palladium(0), and 54.0 mL (0.110 mole) of a 2M solution of aqueous sodium carbonate in 100 mL of toluene was heated at reflux during a two hour period. After this time the reaction mixture was cooled, and the aqueous layer was separated. The toluene layer was washed with two 100 mL portions of water and then with 100 mL of an aqueous solution saturated with sodium chloride. The toluene layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 12.0 grams of ethyl 3-(3-phenylphenyl)-2-propenoate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2.Cl>C(O)(=O)C>[Br:2][C:3]1[C:4]2[NH:9][C:14]3[CH:15]4[CH2:18][CH2:19][N:11]([CH2:12][C:13]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1)[CH2:17][CH2:16]4
Reactant: O=C1CCN2CCC1CC2
Reactant: NNc1ccccc1Br
Agent: Cl
Solvent: CC(=O)O
Product: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Temperature: 105 °C
Reaction time: 18 h

Procedure:
A mixture of (2-bromophenyl)hydrazine hydrochloride (1.5 g, 6.71 mmol; Aldrich) and the product of Example 1A (0.94 g, 6.71 mmol) was combined with a solution of HCl in acetic acid (1.0 M, 20 mL; Aldrich) and stirred at 105° C. for 18 hours. The reaction mixture was concentrated under vacuum. The residue was taken up in toluene (100 mL) and concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure was repeated a second time). The residue was dissolved in dimethyl sulfoxide (20 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4 ) δ ppm 2.05-2.13 (m, 4 H), 3.08 (pent, J=6.9 Hz, 2 H), 3.15 (pent, J=3.6 Hz, 1 H), 3.26 (pent, J=7.2 Hz, 2 H), 4.23 (s, 2 H), 6.88 (t, J=7.8 Hz, 1 H), 7.19 (d, J=7.6 Hz, 1 H), 7.27 (d, J=7.9 Hz, 1 H); MS (APCI) m/z 291/293 (M+H)+.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8](Br)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C([O-])(O)=O.[Na+]>CCO>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]2[N:26]3[C:22]([S:23][CH:24]=[CH:25]3)=[N:21][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccccc2)cc1
Reactant: Nc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccccc3)nc3sccn23)cc1
Yield: 44.1 %

Procedure:
A mixture of the bromoketone of step 3 (2.26 g, 6.4 mmol) and 2-aminothiazole (964 mg, 9.6 mmol) in EtOH (45 mL) was heated to reflux for 18 h. Aqueous NaHCO3 was added to the cooled mixture and the mixture was extracted with Et2O. The Et2O extracts were washed with brine, dried over MgSO4, filtered and concentrated to an oil. Chromatography of the oil on silica gel (eluted with 60 % EtOAc/hexane) gave 1 g (44%) of the title compound: m.p. 190°-192° C. Anal. calcd for C18H14N2O2S2 : C, 61.00; H, 3.98; N, 7.90. Found: C, 60.31; H, 3.96; N, 7.68. 1H NMR (CD3COCD3): δ3.20 (s, 3H), 7.20-7.34 (m, 4H), 7.58-7.61 (m, 2H), 7.77-7.83 (m, 3H), 8.03-8.06 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:11]=2[CH2:12][O:13][Si](C(C)C)(C(C)C)C(C)C)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1([C:10]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][C:11]=2[CH2:12][OH:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CO[Si](C(C)C)(C(C)C)C(C)C)CCCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CO)CCCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a solution of (2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyloxy)triisopropylsilane (276 mg; 0.602 mmol) in tetrahydrofuran (3.5 mL) was added tetrabutylammonium fluoride (0.62 mL; 0.62 mmol; 1.0 M solution in tetrahydrofuran). Reaction was stirred at room temperature for 1.5 hours. Solvent was evaporated under reduced pressure. The residue was purified by 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-30% ethyl acetate in heptane) to yield 169 mg (92.9%) of the title compound as a colorless gum. MS-GC (El): Calc: 302.3, Found: 302 (M). 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (s, 1H), 7.49 (dd, J=8.30 Hz, 1H), 7.40 (d, J=8.30 Hz, 1H), 5.03 (s, 2H), 3.00 (s, 3H), 2.54 (bs, 1H), 2.23 (m, 2H), 2.04 (m, 2H), 1.88-1.55 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](O)=[O:8].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:22][C:18]1[C:3]2[O:4][CH2:5][C@H:6]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7](=[O:8])[NH:1][C:2]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2c(F)cccc2NC1=O
Yield: 42 %

Procedure:
A solution of (S)-3-(2-amino-6-fluorophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (2.6 g, 8.27 mmol) and EDCI (1.97 mg, 10.3 mmol) in DMF (40 mL) was stirred at RT for 6 h. The mixture was diluted with EtOAc and washed with H2O. The combined aqueous layers were extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and the filtrate was concentrated to give a residue that was purified by silica gel chromatography to afford (S)-tert-butyl 9-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.03 g, 42%) as an orange solid. MS m/z 319 (M+Na)+
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][C:23]1([CH3:29])[CH2:25][CH:24]1[C:26](Cl)=[O:27]>ClCCl>[CH3:22][C:23]1([CH3:29])[CH2:25][CH:24]1[C:26]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)=[O:27]
Reactant: CC1(C)CC1C(=O)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-amino-1-benzylpiperidine (100 mg, 0.526 mmol) was dissolved into dichloromethane (10 ml) and then added with triethylamine (150 mg, 1.5 mmol) and 2,2-dimethylcyclopropanecarbonylchloride (159 mg, 1.2 mmol), which was further stirred at the room temperature for 14 hours. After the reaction was completed, the resultant was extracted with ethyl acetate and then washed, dried and concentrated according to the conventional manner and purified by using silica gel column chromatography (ethyl acetate, hexane), thus obtained a white crystal of 4-(2,2-dimethylcyclopropanecarbonylamino)-1-benzylpiperidine. The white crystal was dissolved into an ethanol (10 ml)-ethyl acetate (1 ml) mixed solvent, wherein 5% palladium carbon (150 mg) and formic acid (160 mg) were dissolved into the ethanol (10 ml) and applied thereto with dropping, which was stirred at the room temperature over night. After the palladium was filtered, the solvent was distilled out and aqueous solution of 2M sodium hydroxide was added therein to make pH>13, the solution was extracted with dichloromethane and further washed with a saturated saline solution, dried and vacuum concentrated, thus obtained 4-(2,2-dimethylcyclopropanecarbonylamino)piperidine (23:R =2,2-dimethylcyclopropane) (11.2 mg, 11%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([SH:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[O-]CC.[Na+].C(Br)C1C=CC=CC=1>C(O)C>[CH2:12]([S:28][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCCCCCCCCCCCCCCCS
Agent: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCSCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
A solution of 4-nitrobenzyl bromide in ethanol (150.0 g, 0.694 mol in 1.5 L) was brought to reflux. Separately, a solution of 1-hexadecanethiol in ethanol (231 mL, 0.691 mol in 1.5 L) was treated with sodium ethoxide in ethanol (258 mL, 0.691 mol of a 21% solution) over ten minutes, stirred at room temperature for 15 minutes, then warmed to dissolve the precipitate. This was then added to the benzyl bromide solution over twenty minutes, stirred at room temperature for two hours, then allowed to sit undisturbed overnight. The crystallized thioether was collected and combined with the product from a 230 mmol run. This light yellow solid was dissolved in CH2Cl2 (3 L), washed with water (1 L), then dried (Na2SO4), filtered, and spin-evaporated to give 324.5 g of 1 (89.5% yield). The material was a single spot by TLC (19:1 hexanes/EtOAc), and was suitable for further transformation.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:2]1.Cl.Cl[CH2:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25].CC[O-].[Na+]>C(O)C>[CH2:24]([N:23]([CH2:26][CH3:27])[CH2:22][CH2:21][CH2:20][N:13]1[C:12](=[O:17])[CH:11]([CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[NH:15][C:14]1=[O:16])[CH3:25]
Reactant: CCN(CC)CCCCl
Reactant: O=C1NC(=O)C(Cc2c[nH]c3ccccc23)N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)CCCN1C(=O)NC(Cc2c[nH]c3ccccc23)C1=O
Reaction time: 20 h

Procedure:
A mixture of 5-(indol-3-ylmethyl)hydantoin (10 g, 0.04 mole), 3-chloro-N,N-diethylpropylamine hydrochloride (8.2 g, 0.04 mole), NaOC2H5 (0.08 mole) and 500 ml of anhydrous C2H5OH was heated to reflux with stirring for 20 hours. The mixture was filtered and concentrated to dryness. The concentrate was dissolved in CHCl3, filtered and concentrated. The concentrate was crystallized and recrystallized from benzene-petroleum ether. The solid was again recrystallized from xylene and the solvated solid was dried in vacuum, yield 2.5 g, mp 90°.
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][C:5]1[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]2[CH2:14][NH:13][CH2:12][CH2:11][C:9]=2[N:10]=1.NC1N=[C:25]([C:33]2C=CC(F)=CC=2)[C:26]2CNCCC=2N=1.Cl.Cl.C(Br)C=C>>[ClH:2].[ClH:2].[CH2:33]([N:13]1[CH2:12][CH2:11][C:9]2[N:10]=[C:5]([NH2:4])[N:6]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:8]=2[CH2:14]1)[CH:25]=[CH2:26]
Reactant: Nc1nc2c(c(-c3ccc(F)cc3)n1)CNCC2
Agent: Cl
Solvent: C=CCBr
Solvent: O
Product: C=CCN1CCc2nc(N)nc(-c3ccc(F)cc3)c2C1
Yield: 117.4 %

Procedure:
The title compound was prepared as described in Example 17 starting with 2-amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride hemihydrate (1.0 g, 3.1 mmol) and allyl bromide (0.3 mL, 3.1 mmol) instead of iodoethane to produce 0.65 g (59%) of 6-allyl-2-amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride. m.p. 241°-243° C. MS: 285 (MH+). IR(KBr): 3305, 3118, 2476, 1651 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[O:15][CH2:14]1)[CH2:7][CH2:6][CH2:5]2.[CH2:19]([NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([OH:15])[CH2:14][N:26]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: c1ccc(CNCCOc2ccccc2OCc2ccccc2)cc1
Reactant: Nc1c(OCC2CO2)cc2c(c1[N+](=O)[O-])CCC2
Product: Nc1c(OCC(O)CN(CCOc2ccccc2OCc2ccccc2)Cc2ccccc2)cc2c(c1[N+](=O)[O-])CCC2

Procedure:
The condensation of 5-amino-6-(2,3-epoxypropoxy)-4-nitroindane and N-benzyl-2-(2-benzyloxyphenoxy)-ethylamine gives 5-amino-6-{3-[N-benzyl-2-(2-benzyloxyphenoxy)-ethylamino]-2-hydroxypropoxy}-4-nitroindane in the form of an oil. This compound, in the form of its hydrochloride, is hydrogenated and hydrogenolytically debenzylated in methanolic solution in the presence of 10% palladium-charcoal to give 4,5-diamino-6-{2-hydroxy-3-[2-(2-hydroxyphenoxy)-ethylamino]-propoxy}-indane hydrochloride; m.p. 193°-195° C.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([CH:11](O)[CH2:12][CH3:13])=[CH:7][CH:6]=1.N1C=CC=CC=1>C(OCC)C>[Br:2][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)[CH2:12][CH3:13]
Reactant: CCC(O)c1ccc(C)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(Br)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
4.5 g (1.6 ml, 16.7 mmol) Phosphorus tribromide were added portion-wise, with stirring to a solution of 4.98 g (33.0 mmol) rac-1-p-tolyl-propan-1-ol and 0.37 ml pyridine in 17 ml anhydrous diethyl ether at 0° C. The reaction mixture was warmed to ambient temperature and the reaction monitored by HPLC to completion. The reaction mixture was poured onto ice-water and the whole was extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4 and evaporated to give rac-1-(1-bromo-propyl)-4-methyl-benzene as a colourless oil that did not require further purification: NMR (CDCl3, ppm): 1.01 (3H, t), 2.28 (2H, m), 2.40 (3H, s), 4.92 (1H, t), 7.20 (4H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:36](B1OC(C)(C)C(C)(C)O1)=[CH2:37].CC(O)=O>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH:36]=[CH2:37])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Temperature: 90 °C
Yield: 85.5 %

Procedure:
To a screw-cap vial equipped with a magnetic stir bar, ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (Example 1, step 3, 971.6 mg, 2.263 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) (Aldrich, 163.8 mg, 0.2082 mmol) and K3PO4 (1017.1 mg, 4.7916 mmol) were added. The vial was sealed with a Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). A solution of vinylboronic acid pinacol ester (561.6 mg, 3.646 mmol) in 1,4-dioxane (10.0 mL) was added via a syringe, followed by deoxygenated water (8.0 mL). The mixture was then heated at 90° C. for 6 h. After the reaction was cooled to room temperature, water (50 mL) was added. AcOH (1.50 mL, 26.4 mmol) was added to adjust the pH to 5. The mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give the title compound as a yellow solid (673.9 mg, 85%). LCMS calc. for C20H17N2O4 (M+H)+: m/z=349.1. found 349.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.CCOCC.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][CH2:6][CH2:7][NH2:8]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cc(Cl)cc(Cl)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: NCCOc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 109.9 %

Procedure:
A solution of 2-[2-(3,5-dichloro-phenoxy)-ethyl]-isoindole-1,3-dione (1.29 g, 3.84 mmol) and hydrazine hydrate (202 mg, 4.05 mmol) in MeOH (16 mL) was heated at reflux for 2 h. The mixture was cooled to room temperature and Et2O was added. The suspension was shaken with 40% aqueous potassium hydroxide. The aqueous solution was extracted with Et2O (3×) and the combined organic layers were dried (K2CO3), filtered, and concentrated to provide the title compound (870 mg). 1HNMR (400 MHz, CDCl3) δ6.95 (m, 1H), 6.80 (m, 2H), 3.95 (m, 2H), 3.07 (t, 2H), 1.70 (bs, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=O)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:16][CH2:15][CH:14](O)[CH2:13]1.[H-].[Na+]>CN1CCCC1=O>[CH3:11][N:12]1[CH2:16][CH2:15][CH:14]([C:2]2[CH:3]=[CH:4][C:5]([N:8]=[O:10])=[CH:6][CH:7]=2)[CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN1CCC(c2ccc(N=O)cc2)C1

Procedure:
4-Fluoronitrobenzene and 1-methylpyrrolidin-3-ol were allowed to undergo the reaction in 1-methylpyrrolidone in the presence of sodium hydride. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-(1-methylpyrrolidin-3-yl)oxoaniline. F: 193.
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH:6]=[CH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCCCCC(O)CCCC(CC=Cc1cccc(C(=O)O)c1)C(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(O)CCCC(CCCc1cccc(C(=O)O)c1)C(C)=O

Procedure:
3-(4-Acetyl-8-hydroxy-1-tridecenyl)benzoic acid (7.2 g., 0.02 mole) in ethanol (75 ml.) is hydrogenated over 1.5 g. of a 5% Pd on charcoal catalyst at 1 atmosphere pressure and room temperature. When the theoretical amount (0.02 mole) of hydrogen has been absorbed, the catalyst is filtered off, the solvent evaporated, and the residue chromatographed on silica gel with 4% methanol in chloroform as the eluant. The title compound is obtained as a colorless, viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:31]([C:33]2[O:34][C:35]3[CH:41]=[CH:40][C:39]([C:42]([NH:44][CH2:45][CH3:46])=[O:43])=[CH:38][C:36]=3[N:37]=2)[OH:32])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[C:15]([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([C:31]([C:33]2[O:34][C:35]3[CH:41]=[CH:40][C:39]([C:42]([NH:44][CH2:45][CH3:46])=[O:43])=[CH:38][C:36]=3[N:37]=2)=[O:32])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:21])[C:15]([C:47]2[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)c1ccc2oc(C(O)C(Cc3ccccc3)NC(=O)Cn3c(-c4ccc(F)cc4)ncc(NC(=O)OCc4ccccc4)c3=O)nc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CS(C)=O
Product: CCNC(=O)c1ccc2oc(C(=O)C(Cc3ccccc3)NC(=O)Cn3c(-c4ccc(F)cc4)ncc(NC(=O)OCc4ccccc4)c3=O)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of the objective compound (448 mg, 0.623 mmol) of Step (2) in DMSO (5 mL) was added Dess-Martin periodinane (446 mg, 1.05 mmol) and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution (5 mL) containing sodium thiosulfate in a concentration of 0.22 g/mL, and the mixture was stirred at room temperature and extracted with ethyl acetate. The insoluble material in the extract was collected by filtration and the filtrate was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue and the insoluble material obtained earlier were combined, and separated and purified by silica gel column chromatography (50:1 chloroform:methanol) to give the title compound as pale-yellow crystals (268 mg, 60%).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:16]([CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])([O-:18])=[O:17]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[C:19]([CH3:24])([N+:16]([O-:18])=[O:17])[CH2:4][C:5]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([O:14][CH3:15])[CH:10]=2)[NH:7][CH:6]=1
Reactant: COc1ccc2[nH]cc(CN(C)C)c2c1
Reactant: COC(=O)C(C)[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(Cc1c[nH]c2ccc(OC)cc12)[N+](=O)[O-]
Yield: 38.3 %

Procedure:
A solution of commercially available 5-methoxy gramine (6.24 g) and commercially available methyl 2-nitro-propionate (4.07 g) in a mixture of toluene (50 ml) and N,N-dimethylformamide (2 ml) is refluxed for one day while bubbling argon through the reaction mixture. The solvent is evaporated, the residue is taken up in dichloromethane (300 ml), is washed subsequently with 2 M aqueous HCl, 2 M aqueous NaOH, and water, is dried and concentrated. Column chromatography of the residue (toluene-acetone, 98:2→95:5) gives the title compound (3.42 g, 38%). M.p. 109-110° C. (from ethyl acetate-light petroleum).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCCCBr
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCOc1cccc(O)c1
Temperature: 90 °C
Yield: 34 %

Procedure:
A mixture of 11 g of resorcinol, 8.8 g of methyl 5-bromopentanoate, and 13.8 g of potassium carbonate in 150 mL of dimethylformamide was heated in an oil bath at 90° C. for 24 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic phase was washed with water, washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether providing the title intermediate in 34% yield, NMR.