Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH:13]3[O:15][CH:12]3[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.S([O-])(O)(=O)=[O:21].[K+]>C(O)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH:13]([OH:21])[CH:12]([OH:15])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(Cl)s2)CC2OC2C1
Reactant: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1(NC(=O)c2ccc(Cl)s2)CC(O)C(O)C1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 0.76 g (1.84 mmol) methyl 1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-epoxy-cyclopentane-1-carboxylate, 3.0 ml acetic acid and 0.38 g potassium hydrogen sulphate are stirred for 4 h at 40° C. Then the mixture is concentrated by evaporation, dissolved in DMF, acidified with trifluoroacetic acid and purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH:16]=[CH2:17])[C:10]=1[OH:18].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:16][CH3:17])[C:10]=1[OH:18]
Reactant: C=CCc1cccc(Sc2ccccc2Cl)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC=Cc1cccc(Sc2ccccc2Cl)c1O
Temperature: 110 °C
Yield: 98.4 %

Procedure:
A mixture of 2-(2-chlorophenylthio)-6-allylphenol (32 g) and potassium hydroxide (41 g) in methanol (140 ml) was stirred at 110° C., and methanol was distilled off under ordinal pressure. The remaining mixture was further stirred at 100° C. for an hour, cooled to the ambient temperature and then dissolved in water. The aqueous solution was acidified with conc. hydrochloric acid under ice-water cooling. The resultant oily substance was extracted with diethyl ether, and the extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give oily 2-(2-chlorophenylthio)-6-(1-propenyl)phenol (31.5 g). This product was subjected to column chromatography on silica gel (450 g) and eluted with a mixture of benzene and n-hexane (1:10) to give the purified oily product (26.3 g).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Yield: 14 %

Procedure:
The title compound (34 mg, 14%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (225 mg, 0.669 mmol, prepared in example 1), 4-methoxybenzeneboronic acid (125 mg, 0.822 mmol), dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), 2 M sodium carbonate (245 mg in 1.15 mL water), and 1,2-dimethoxyethane (4.5 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 220 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[Cl:12])[CH:7]=O)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:25][C:26]#[N:27])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].[OH-].[Na+]>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.O.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:25](/[C:17]2[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=2)\[C:26]#[N:27])[CH:9]=[CH:10][C:11]=1[Cl:12])([O-:3])=[O:2]
Reactant: COc1cc(CC#N)cc(OC)c1OC
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C(C#N)=C/c2ccc(Cl)c([N+](=O)[O-])c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
5.0 g of 3-nitro-4-chlorobenzaldehyde, 5.6 g of 3,4,5-trimethoxyphenylacetonitrile, 1.3 g of sodium hydroxide and 500 mg of trioctylmethylammonium chloride were dissolved in 10 ml of water and 50 ml of dichloromethane. The mixture was stirred vigorously for 3 hours at room temperature. The ice water was added to the mixture and the mixture was extracted with dichloromethane three times and dried over anhydrous sodium sulfate. The organic layer was concentrated and the residue was crystallized from ethyl acetate to give 4.9 g of the intended compound. The yield was 48.5%.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:9](O)[CH:10]=[CH:11][CH2:12][OH:13].C1CCCCC1>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(C=CC(O)=CC=1)O.O>[CH2:4]([C:5]1([CH3:6])[O:13][CH2:12][CH:11]=[CH:10][CH2:9][O:7]1)[CH2:3][CH:2]([CH3:8])[CH3:1]
Reactant: OCC=CCO
Reactant: CC(=O)CCC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: Oc1ccc(O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)CCC1(C)OCC=CCO1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a one liter flask equipped with heating jacket, agitator and condenser fitted with a Dean-Stark trap was charged 136 grams (1.2 mole) 5-methyl-2-hexanone, 88 grams (1.0 mole) 2-butene-1,4-diol, 160 grams cyclohexane, 2 grams citric acid and 0.3 grams hydroquinone. The mixture was heated with vigorous agitation at reflux (87°- 97°C.) until water no longer continued to be distilled from the reaction mixture (24 hours). The reaction mixture was cooled to room temperature and the citric acid neutralized by washing the reaction mixture with a 5% aqueous solution of sodium hydroxide and then with water. The reaction mixture was then distilled to remove the cyclohexane and the oil vacuum distilled to obtain 152 grams (83% of theoretical) of 4,7-dihydro-2-isopentyl-2-methyl-1,3-dioxepin having a boiling point of 94°C. at a pressure of 9.0 millimeters of mercury (refractive index, ND20 = 1.4523). Analysis for carbonyl content by IR showed 0.0% carbonyl and VPC analysis showed the compound to have a purity of 97.4%.
Reaction SMILES: O1CCCC1.[NH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1.C(N(CC)CC)C.Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>O>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)=[N:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 150 ml of a tetrahydrofuran suspension containing 10 g of trans-4-aminocyclohexanol was added 15 ml of triethylamine, 50 ml of a tetrahydrofuran solution containing 2-chloro-5-nitropyridine was further added thereto under ice-cooling, and then, the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (2:1)) to obtain 8.52 g of trans-4-(5-nitro-2-pyridylamino)cyclohexanol. (2) To 10 ml of a dichloromethane solution containing 1.0 g of the compound obtained in the above (1) was added 1.8 ml of triethylamine, 0.65 ml of methanesulfonyl chloride was further added thereto under ice-cooling, and the mixture was stirred for 1 hour. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. 1.37 g of sodium azide was added to a solution of the residue dissolved in 10 ml of dimethylformamide and the mixture was stirred at 50° C. for 3 days. After cooling, an aqueous saturated sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and then, the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (1:5)) to obtain 758 mg of cis-4-azide-N-(5-nitro-2-pyridyl)cyclohexylamine. (3) A solution comprising 10 ml of tetrahydrofuran-1 ml of water, containing 640 mg of the compound obtained in the above (2) and 704 mg of triphenylphosphine was stirred at room temperature for 2 days. The reaction mixture was concentrated, and the residue was purified by silica gel flash column chromatography (solvent: ethyl acetatemethanol (10:1)) to obtain 531 mg of N-(5-nitro-2-pyridyl)-cis-1,4-cyclohexanediamine (the compound of Reference Example 4 in Table 5).
Reaction SMILES: [NH3:1].CO.[CH2:4]([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[O:25][N:24]=[C:23]([C:26]([O:28]CC)=O)[N:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(C)C>[CH2:4]([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[O:25][N:24]=[C:23]([C:26]([NH2:1])=[O:28])[N:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N
Reactant: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Solvent: CO
Solvent: CC(C)O
Product: NC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Temperature: 40 °C
Yield: 40 %

Procedure:
Ammonia in MeOH solution (2.3 mL, 16.11 mmol) was added to a solution of ethyl 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (600 mg, 1.61 mmol) in isopropanol (8 mL) and the reaction mixture was heated at 40° C. for 1 h. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (0 to 10% MeOH/DCM) to afford 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide (220 mg, 40%). ESI-MS (EI+, m/z): 344.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]4)=[C:29]([O:39][CH3:40])[N:28]=3)=[N:25][N:26]=[C:19]12>CN(C=O)C.C(OCC)(=O)C.[Cl-].[NH4+]>[CH3:40][O:39][C:29]1[N:28]=[C:27]([C:24]2[N:20]3[CH2:21][CH2:22][CH2:23][C:18]([O:10][C:4]4[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=4)([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:19]3=[N:26][N:25]=2)[CH:32]=[CH:31][C:30]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a mixture of 3,4,5-trifluorophenol (0.31 g) and potassium carbonate (0.80 g) in DMF (16 mL) was added ethyl 8-chloro-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (0.80 g) at room temperature, and the mixture was stirred at 100° C. for 30 min. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the mixture was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.42 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[CH2:7]([O:9][C:10](=[O:14])[C@H:11]([CH3:13])[NH2:12])[CH3:8].[OH-].[Na+]>ClC(Cl)C>[CH2:7]([O:9][C:10](=[O:14])[C@H:11]([CH3:13])[NH:12][C:3](=[O:4])[CH2:2][Cl:1])[CH3:8]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@H](C)NC(=O)CCl
Reaction time: 3 h

Procedure:
A solution of 7.2 g (0.064 mole) of chloroacetyl chloride in 20 ml dichloroethane was added dropwise at 0°-5° C. to a rapidly stirred mixture of 10 g (0.064 mole) of the DL-alanine ethyl ester, hydrochloride prepared above and 10.2 g of 50% aqueous sodium hydroxide (0.128 mole) in 80 ml dichloroethane. The mixture was allowed to come to room temperature after addition was complete. After standing 3 hours the product was isolated by washing with 50 ml of saturated salt solution, dried over magnesium sulfate, followed by evaporation of the solvent. The product, 8.0 g was a solid having a m.p. of 43°-47° C. and was identified by nuclear magnetic resonance (NMR) and infrared (IF) spectroscopy analysis as the title compound.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34](=[O:48])[C@@H:35]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][C:37](O)=[O:38])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:44]([O:43][C:41]([NH:40][C@@H:35]([CH2:36][C:37]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:38])[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:48])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.03 g, 0.078 mmol) in DCM (5 mL) was added (S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (0.118 g, 0.408 mmol) followed by DCC (0.049 g, 0.235 mmol) and DMAP (9.58 mg, 0.078 mmol). The reaction was stirred at rt for 18 hours. Water (15 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 25% ethyl acetate in petroleum ether to provide the purified product (37 mg, 68%) as an off-white semi solid. LC-MS (Method A) RT=2.55 min, (M+H)+=654.4. 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.34 (m, 2H), 7.20-6.98 (m, 6H), 4.82-4.53 (m, 1H), 4.43-4.24 (m, 2H), 4.11 (d, J=14.1 Hz, 1H), 3.58 (t, J=8.8 Hz, 1H), 3.48-3.39 (m, 1H), 3.22-3.07 (m, 3H), 3.02 (dd, J=16.1, 6.5 Hz, 1H), 2.87 (dd, J=15.8, 7.8 Hz, 1H), 2.78-2.63 (m, 2H), 2.38-2.31 (m, 1H), 2.29 (s, 3H), 2.17-2.03 (m, 1H), 1.98-1.86 (m, 1H), 1.78 (br. s., 1H), 1.74-1.58 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H). 19F NMR (376 MHz, DMSO-d6) δ −180.707.
Reaction SMILES: C(C1C=CC=CC=1)(=[O:3])C.C[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:15][C:14]=1[O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:12]>>[F:28][C:27]([F:30])([F:29])[CH2:26][O:25][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:18][C:13]=1[C:11]([OH:12])=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
replacing the methyl moiety of the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid;
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][NH:23][CH2:22][CH2:21][NH:20]3)=[O:18])[CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)C(C)C)(C)C.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:34]([N:23]1[CH2:22][CH2:21][NH:20][CH:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)[CH2:16][CH2:15]2)=[O:18])[CH2:24]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(C1CNCCN1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CN(Cc2ccccc2)CCN1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-4-(piperazin-2-ylcarbonyl)piperazine dihydrochloride (150 mg), N,N-di-iso-propylethylamine (0.189 mL) and dichloromethane (10 ml) was stirred at room temperature under argon. After 5 minutes benzaldehyde (0.04 ml) was added followed by sodium triacetoxyborohydride (153 mg). The mixture was stirred overnight at room temperature and then filtered through a SCX-2 column eluting with methanol and then a 7M solution NH3 in methanol. The basic fraction was concentrated at reduced pressure. The residue was purified using reverse phase HPLC eluting with a mixture of 5-95% acetonitrile in water and then was filtered through a SCX-2 column eluting with methanol and then a 7M solution NH3 in methanol. The basic fraction was concentrated at reduced pressure. This gave 1-benzyl-3-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}piperazine as a colourless gum (125 mg).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:23])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]=[CH2:3].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>C(O)C>[CH2:1]([C:4]1[C:5]([O:23][CH2:24][CH:26]2[O:28][CH2:27]2)=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]=[CH2:3]
Reactant: ClCC1CO1
Reactant: C=CCc1c(O)ccc2c(OCc3ccccc3)cc(=O)oc12
Solvent: CCO
Product: C=CCc1c(OCC2CO2)ccc2c(OCc3ccccc3)cc(=O)oc12
Yield: 82 %

Procedure:
Reaction of 8-allyl-4-benzyloxy-7-hydroxycoumarin (12.33 g; 0.04 mole) with epichlorhydrin (25 ml) as described in Example 2(a) gave 11.97 g (82%) of product of m.p. (ethanol) 118°-121° C., νmax (mull) 1715, 1618, 1565 cm-1 (Found; C, 72.45; H, 5.53; C22H20O5 requires; C, 72.51; H, 5.53%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=[O:13].[N+:22]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([C:30]#[N:31])=[O:29])([O-:24])=[O:23]>O1CCCC1>[N+:22]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([C:30]#[N:31])=[O:29])([O-:24])=[O:23].[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:12](=[O:13])[CH2:11][C:28]([C:27]1[CH:32]=[CH:33][CH:34]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1)=[O:29]
Reactant: CC(=O)c1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1c(Cl)cccc1Cl)c1cccc([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of lithium bis(trimethylsilyl)amide (1.0 molar in tetrahydrofuran, 11 mL, 1.1 mole equivalent) cooled at −70 under nitrogen was added dropwise a solution of 2,6 dichloroacetophenone (965 mg, 1.0 molar equivalent) in anhydrous tetrahydrofuran. The resulting mixture was stirred at −20° C. for 2 h. The reaction mixture was re-cooled to −70° C., and a solution of 3-nitrobenzoylcyanide (900 mg, 1.0 molar equivalent) in tetrahydrofuran was added dropwise. The 3-nitrobenzoylcyanide was prepared according to the procedures of S. Yamaguchi et. al. in, Bull. Chem. Soc. Jpn. 1989, 62,3036–3037. The mixture was allowed to warm to room temp over 1 h and was stirred at room temperature for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The crude solid product was purified by column chromatography over silica gel using hexanes and ethyl acetate to give the desired 1-(2,6-dichlorophenyl)-3-(3-nitrophenyl)-1,3 propanedione. NMR 300 MHz (CDCL3) 8.75 (m, 1H), 8.40 (m, 1H), 8.28 (m, 1H), 7.69 (t, 1H), 7.39 (m, 2H), 6.43 (s, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH:29]3[CH3:35])=[O:27])[N:9]=2)[CH:7]=1.[CH3:40]C1(C)CNCCN1C(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:27])[N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][C:29]3([CH3:40])[CH3:35])[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Reactant: CC1CN(C)CCN1C(=O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Product: CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)C(C)(C)C1

Procedure:
Using synthetic method analoguous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from tert-butyl 2,2-dimethylpiperazine-1-carboxylate. LCMS (Method 25) [M+H]+=573.2, RT=0.97 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.2, 6.9 Hz), 8.69-8.68 (m, 2H), 8.27 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.56 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.5, 6.9 Hz), 7.03 (t, 1H, 73.1 Hz), 5.17 (s, 2H), 3.48-3.42 (m, 2H), 2.28-2.22 (m, 2H), 2.17 (s, 3H), 2.08 (s, 2H), 1.39 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([C:14]=1[O:15][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ccccc2n1C
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1c(C(=O)OCC)n(C)c2ccccc12

Procedure:
Prepared by the procedure described in Example 1 from 3-hydroxy-1-methyl-1H-indole-2-carboxylic acid ethyl ester and ethyl bromoacetate. The crude oil product obtained after evaporation was used for further synthesis without additional purification.