Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:19])[C:9]2[C:17]3[C:16]([CH3:18])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23].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+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:16]([CH3:18])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[O:19])=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(C)c23)c1F
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: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncnc(C)c23)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-amide (P-0055, 0.215 g, 0.542 mmol) was dissolved in 40 mL of tetrahydrofuran and Dess-Martin periodinane (0.253 g, 0.597 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and a mixture of 20 mL of saturated aqueous sodium bicarbonate and 4 mL of saturated aqueous sodium thiosulfate was added. The mixture was vigorously stirred until the organic layer turned clear. The aqueous layer was separated and extracted once with ethyl acetate. The combined organic layers were washed with water and brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was suspended in tetrahydrofuran and acetonitrile and sonicated for 15 minutes. The solid material was collected with filtration to provide the desired compound as a white solid (P-0056, 67 mg). LC-MS showed one major peak with 99.7% purity and 1H-NMR(dmso-d6) was consistent with the desired compound. MS(ESI) [M+H+]+=395.0. The filtrate was recovered and purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as an off-white solid (P40056, 51 mg). LC-MS showed one major peak with 99.8% purity. 1H-NMR(dmso-d6) was consistent with the desired compound. MS(ESI) [M+H+]+=395.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:17][NH:18][CH3:19].ClC1C=C(C2(CNC)CCCCC2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][N:18]([CH3:19])[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=CC1(c2ccc(F)c(Cl)c2)CCCCC1
Reactant: CNC
Agent: CNCC1(c2ccc(F)c(Cl)c2)CCCCC1
Product: CN(C)CC1(c2ccc(F)c(Cl)c2)CCCCC1
Yield: 88 %

Procedure:
The title compound was synthesized from 1-(3-chloro-4-fluorophenyl)cyclohexanecarbaldehyde and dimethyl amine using General Procedure H1 and was obtained in 88% yield as an oily solid. The title compound was also synthesized from 1-(1-(3-chloro-4-fluorophenyl)-cyclohexyl)-N-methylmethanamine according to General Procedure C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[ClH:10].[CH2:11](O)[CH3:12]>>[ClH:10].[OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH2:11][CH3:12])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H]1CC(O)CN1
Yield: 95 %

Procedure:
A slurry of 100 g (760 mmol) of 4-hydroxy-L-proline in 600 mL of absolute ethanol was treated with dry hydrogen chloride until homogeneous. The solution was heated to the reflux temperature for 2 h. Upon cooling in the refrigerator, the product was obtained as white needles which were filtered, washed well with ether, and dried under reduced pressure to yield 141 g (95%) of (5): mp 153°-153.5° C. (lit. mp-147°-148° C.). 1H NMR (DMSO d6) δ1.25 (t, 3H, J=7 Hz), 4,20 (q, 2H, J=7 Hz). 13C NMR (D2O) 24.1, 47.1, 63.6, 68.7, 73.8, 79.1, 177.5; IR (KBr) 3320, 1735 cm-1.
Reaction SMILES: ClC1C=CC(CC2C(=O)OC(C)(C)OC2=O)=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl.[CH3:40][O:41][C:42]1[CH:58]=[CH:57][C:45]([CH2:46][CH:47]2[C:52](=[O:53])[O:51]C(C)(C)[O:49][C:48]2=[O:56])=[CH:44][CH:43]=1>>[CH3:40][O:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][CH:47]([C:48]([OH:56])=[O:49])[C:52]([OH:53])=[O:51])=[CH:57][CH:58]=1
Reactant: COc1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1
Agent: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: COc1ccc(CC(C(=O)O)C(=O)O)cc1

Procedure:
The title compound was prepared by substituting 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a) with 5-(4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 7: step a) then following the procedure described for the preparation of 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:27][O:28][Si](C(C)(C)C)(C)C)[C@@H:10]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.C1C=CN=CC=1.F>C1COCC1>[Si:1]([O:8][C@H:9]([CH2:27][OH:28])[C@@H:10]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: *CC(*)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 50 mL polypropylene bottle containing (S)—N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(3-chloro-5-fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (350.00 mg, 618 μmol) was added THF (10 mL) and the mixture was allowed to stir at 0° C. for 5 minutes. At this time, PYRIDINE (2699 μl, 33371 μmol) was added via syringe before the addition of HF-Pyridine, 70% HF 30% pyr (1782 μl, 19775 μmol) via a syringe. The reaction was allowed to stir at this temp for 2 h and then quenched by pouring into sodium bicarbonate (sat 150 ml). The aq. layer was extracted with EtOAc 94×75 mL). The combined organics were washed with HCl (0.1 N, 3×100 mL), bicarbonate (sat, 100 mL), brine and dried with sodium sulfate. The dried solution was filtered and concentrated to give a yellow oil which was purified on a 40 g ISCO column to give the title compound.
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.C(=O)(O)[O-].[Na+].[C:23](#[N:25])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:11]([N:8]1[CH2:9][CH2:10][CH:6]([C:23]#[N:25])[CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Product: N#CC1CCN(Cc2ccccc2)C1

Procedure:
A mixture of EXAMPLE 1G (1.5 g) and tetrabutlyammonium cyanide (3.15 gm) in acetonitrile (25 mL) was heated at 65° C. for 24 hours, poured into saturated aqueous sodium bicarbonate, and extracted with toluene. The extract was washed with distilled water, dried over anhydrous sodium sulfate, and concentrated. 1H NMR (300 MHz, CDCl3) δ 7.33 (s, 5H), 3.42 (m, 2H), 2.89 (m, 1H), 2.72 (m, 1H), 1.68 (b, 3H), 1.45 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:29][CH2:28][CH2:27][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:25])[C:14]2=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCCl)cc2c1=O

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (0.56 g), 1-bromo-2-chloroethane (0.7 ml) and potassium carbonate (2.32 g) were stirred in DMF (20 ml) at 50° C. for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated to give 3-[7-(2-chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide as a cream coloured solid (0.57 g); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.86 (m, 1H), 4.00 (t, 2H), 4.40 (m, 2H), 6.73 (d, 1H), 7.23 (d, 1H), 7.47 (d, 1H), 7.49 (d, 1H), 7.68 (s, 1H), 7.73 (m, 2H), 7.88 (d, 1H), 8.44 (d, 1H); Mass Spectrum: M+Na+ 419.
Reaction SMILES: CC(O[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])C=O)=[O:7])(C)C.CC(OC([NH:23][C@@H:24]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:25]=[O:26])=O)(C)C>>[CH:9]1([NH:8][C:6](=[O:7])[CH:25]([OH:26])[C@@H:24]([NH2:23])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCCC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Product: CC(C)C[C@H](N)C(O)C(=O)NC1CCCC1
Yield: 34 %

Procedure:
The same procedure as in Reference Example 11 was repeated except that the (S)-2-[N-(2-methyl-2-propyloxycarbonyl)amino]hexanal was replaced by 18.64 g of (S)-2-[N-(2-methyl-2-propyloxycarbonyl)amino]-4-methylpentanal, whereby 6.72 g of the captioned (2RS,3S)-N-cyclopentyl-3-amino-2-hydroxy-5-methylhexanamide was obtained in a yield of 34%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:17][N:18]=[C:19]=[S:20].[H-].[Na+].O>O1CCCC1.C(OCC)C.CCCCCC>[CH3:17][NH:18][C:19]([C:10]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])=[S:20]
Reactant: CN=C=S
Reactant: O=C1CCCCC1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=S)C1(c2cccc([N+](=O)[O-])c2)CCCCC1=O
Reaction time: 0.22 h

Procedure:
A solution of (±)-2-(3-nitrophenyl)cyclohexanone (1 g,4.5 mmol) and methyl isothiocyanate at 20° C. in tetrahydrofuran (15 ml) was treated with sodium hydride (120 mg, 5 mmol) added in one portion. The mixture was stirred vigorously. After 13 minutes, water (20 ml) was added and the mixture extracted with ethyl acetate (2×20ml). The combined organic extracts were dried over magnesium sulphate. Concentration in vacuo (30° C., 14 mmHg) afforded a crude oil (0.95 g) which was purified by flash chromatography over silica gel, eluting with toluene/acetone: 96/4 and trituration with equal portions of hexane and diethyl ether to give (±)-N-methyl-2-oxo-1-(3-nitrophenyl)-cyclohexanecarbothioamide (0.1 g, 0.35mmol) m.p. 128°-132° C.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:15]([O:22][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: Clc1nc(SCc2ccccc2)ns1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2nc(SCc3ccccc3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Into 3 ml of N,N-dimethylformamide were dissolved 243 mg of 5-chloro-3-benzylthio-1,2,4-thiadiazole and 108 mg of benzyl alcohol, 48 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 17 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 146 mg of 5-benzyloxy-3-benzylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (31)).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl>[N:31]1([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]2[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[CH:8][C:7]=3[N:16]=[C:4]2[CH2:1][CH2:2][CH3:3])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A solution of 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoic acid (3.0 g, 9.2 mmol) in anhydrous dichloromethane (50 mL) was cooled to 0° C. Oxalyl chloride (1.44 mL, 16.6 mmol) was added dropwise over a period of 15 minutes. The resulting solution was allowed to warm to ambient temperature and stirred for one hour and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), and morpholine (2.41 mL, 27.6 mmol) was added. The reaction was stirred overnight, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 3.6 g of 1-(6-morpholin-4-yl-6-oxohexyl)-2-propyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([SH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1>O>[CH2:6]([S:13][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccnc1SCc1ccccc1
Temperature: 55 °C
Reaction time: 0.42 h
Yield: 37.4 %

Procedure:
To a stirred solution of 35 ml of ethanol, 1 ml of water, and 2.0 g (0.025 mole) of 85% KOH pellets was added 3.2 g (0.025 mole) of benzyl mercaptan. To this mixture was added 4 g (0.025 mole) of 2-chloro-3-nitropyridine. After complete addition (20 minutes), the reaction mixture was warmed to 55° C. and held at that temperature for 25 minutes. It was then allowed to cool to room temperature over the next hour. The solid was filtered off (KCl) and the ethanol was removed from the filtrate. The residue was treated with 40 ml of acetone by warming, cooling and then filtering to remove more KCl. The filtrate was evaporated to leave an oil which solidified. The solid was recrystallized from 40 ml of ethanol to give 2.3 g of crystals, having a melting point of 57-59° C. The infrared spectrum was consistent with the structure. A second crop of 1.3 g of impure product was also obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8](=[CH2:19])[CH2:9][CH:10]([C:15](OC)=[O:16])[C:11](OC)=[O:12].C([O-])(=O)CC([O-])=O>C(OCC)C>[Br:7][C:8](=[CH2:19])[CH2:9][CH:10]([CH2:15][OH:16])[CH2:11][OH:12]
Reactant: C=C(Br)CC(C(=O)OC)C(=O)OC
Agent: O=C([O-])CC(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C=C(Br)CC(CO)CO
Temperature: -78 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
Lithium aluminum hydride (1.9 g, 7.65 mmol) was slurried in anhydrous diethyl ether (50 ml) and cooled to −78° C. in a dry ice/acetone bath. A solution of the product from step A (0.639 g, 16.84 mmol) in dry ether (26 ml) was then added dropwise. After the malonate was added, the solution was allowed warm to room temperature and stirring was continued for 3 hours. The reaction was quenched with brine (50 ml), extracted with ethyl acetate (3×25 ml) and dried over MgSO4. The solvent was removed in vacuo to give the desired product (1.3 g, 86%) which was used for the next step without further purification. 1H-NMR (300 MHz, CDCl3) δ 5.66 (d, J=1.2 Hz, 1 H), 5.48 (d, J=1.5 Hz, 1H), 3.86 (m, 2 H), 3.73 (m, 2 H), 2.51 (d, J=7.5 Hz, 2 H), 2.40 (br s, 2 H), 2.15 (m, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2([CH2:4][CH2:3][CH2:2][N:34]3[CH2:33][CH2:32][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[CH2:36][CH2:35]3)[C:13]3[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=3)[CH2:7][O:6]2)=[CH:17][CH:18]=1
Reactant: N#Cc1ccc2c(c1)COC2(CCCCl)c1ccc(F)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1ccccc1N1CCN(CCCC2(c3ccc(F)cc3)OCc3cc(C#N)ccc32)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-(3-chloropropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (2.5 g, 7.9 mmol), 1-(2-methoxyphenyl)piperazine (2.0 g, 10.4 mmol), potassium carbonate (3 g, 22 mmol) and methyl isobutyl ketone (200 mL) was boiled under reflux for 16 h. After cooling to room temperature the organic phase was washed with water (200 mL), the solvents were evaporated in vacuo and the remaining oil purified by column chromatography (ethyl acetate/heptane/triethylamine 75:20:5). The title compound crystallised from diethyl ether 1.5 g (40 %): mp 147-49° C.; 1H NMR (DMSO-d6) δ 1.30-1.65 (m, 2H), 2.10-2.30 (m, 2H), 2.40 (t, 2H), 2.50-2.70 (m, 4H), 2.90-3.20 (m, 4H), 3.85 (s, 3H), 5.20 (m, 2H), 6.70-7.10 (m, 6H), 7.30-7.55 (m, 4H), 7.60 (d, 1H); MS m/z, 472 (MH+, 100), 262 (14), 109 (19).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].C([NH:22][CH2:23][CH2:24]O)(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:24][CH2:23][NH2:22])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCN)c([N+](=O)[O-])c1
Yield: 38.6 %

Procedure:
To a stirred solution of methyl 3-nitro-4-hydroxybenzoate (1.98 g, 10.04 mmol), N-Boc ethanolamine (1.63 g, 10.11 mmol) and PPh3 (3.43 g, 13.08 mmol) in THF (40 mL) was added DIAD (2.57 mL, 13.05 mmol), and the reaction mixture was then heated under reflux overnight. The resulting mixture was evaporated to give a gum. The residual crude gum was dissolved in CH2Cl2 (30 mL) and TEA (30 mL), and the mixture was stirred for 1 hr at room temp. The mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, and dried over Na2SO4. The solvent was evaporated in vacuo to give the oily residue, which was purified by column chromatography on silica-gel with CHCl3 then CHCl3—MeOH (20:1, v/v) as eluent to give 930 mg (27% for 2 steps ) methyl 3-nitro-4-(2-aminoethoxy)benzoate as gum. 1H-NMR (CDCl3) d 3.16-3.19 (m, 1 H), 3.53-3.57 (m, 1 H), 3.90 and 3.94 (s, 3 H), 3.95-3.98 (m, 1 H), 4.21-4.24 (m, 1 H), 6.89-6.91 and 7.11-7.13 (m, 1 H), 8.03-8.19 and 8.21 (m, 1 H), 8.52 and 8.86 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12]Br)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][C:15]([NH2:17])=[O:16]>CN(C)C=O>[NH2:17][C:15]1[O:16][CH:12]=[C:10]([C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:14]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC)c1coc(N)n1
Yield: 26 %

Procedure:
A solution of 50.4 g (0.2 mol) of ethyl 2-methoxyimino-4-bromoacetoacetate [M. Ochiai et al., Chem. Pharm. Bull. 25, 3115 (1977)] and 60.1 g (1 mol) of urea in 200 ml of dimethylformamide is heated to 100° C. for 30 minutes. Thereafter, the mixture is evaporated, the residue is taken up in 800 ml of water, neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract is chromatographed on silica gel with acetonitrile/methylene chloride (1:1). There is obtained ethyl 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetate in a yield of 26%; melting point 120° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccc(F)cc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncc(F)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.24-7.35 (m, 2H), 7.37 (s, 1 H), 7.92-8.02 (m, 2H), 8.17 (ddd, J=9.4, 2.8, 1.7 Hz, 1H), 8.61 (d, J=3.1 Hz, 1H), 8.96 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH:11]1([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C1C[O:30]CC1>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[OH:30])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(CC1CCCC1)OCc1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(OCc1ccccc1)C(O)C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A 1.0 M sodium hexamethyldisilazide solution in THF (27.5 ml, 27.5 mmol) was added to anhydrous THF (30 ml), and the mixture was cooled to −78° C. An anhydrous THF solution (20 ml) of benzyl cyclopentylacetate (5.0 g, 22.90 mmol) was added dropwise to the mixture over 30 min, and the mixture was stirred for additional 30 min. Subsequently, an anhydrous THF solution (20 ml) of n-benzyl-benzenesulfonyloxaziridine (7.18 g, 27.5 mmol) was added dropwise to the mixture at −78° C. over one hr, and the mixture was stirred for additional one hr. The reaction mixture was quenched with saturated ammonium chloride and was extracted with ether. The organic layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=94:6) to give the title compound as a light yellow oil (3.2 g, yield 60%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[C:16]([CH3:26])[CH:15]=2)[CH2:13][CH2:12]1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.O>CO>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:13][CH2:12]4)=[CH:15][C:16]=3[CH3:26])[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cc(C2CC2)ccc1N1CCNCC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2CC2)ccc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 15 and using 4-bromo-2-methylaniline (3 g), N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (5.65 g) and cyclopropylboronic acid (721 mg), 1-(4-cyclopropyl-2-methylphenyl)piperazine (640 mg) was obtained. To a solution (7 mL) of 6-bromonicotinic acid (132 mg) in methanol were added 1-(4-cyclopropyl-2-methylphenyl)piperazine (150 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (217 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (260 mg).