Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.B1(C=C)OB([CH:40]=[CH2:41])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:40]=[CH2:41])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 250 %

Procedure:
Intermediate (15a) (11.0 g, 21.8 mmol) was dissolved in 1,2-dimethoxyethane (100 mL, 1 μmol). Tetrakis(triphenylphosphine)palladium(0) (252 mg, 218 μmol) was added and the mixture was stirred under nitrogen for 20 minutes. Water (48 mL, 2.6 mol), 2,4,6-trivinylcyclotriboroxane pyridine complex (2.1 g, 8.7 mmol) and potassium carbonate (3.0 g, 21.8 mmol) were then added and the mixture was heated at 90° C. under nitrogen. After 2 hours, the mixture was cooled to room temperature, diluted with EtOAc, washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (0-50% EtOAc:hexanes) to yield intermediate (15b) (9.8 g). MS m/z: [M+H+] calcd for C26H27FN2O4, 451.2; found 451.0. 1H-NMR (CDCl3): 8.17 (1H, s), 7.79 (1H, d), 7.48 (1H, t), 7.40 (1H, t), 7.28 (1H, s), 7.01(2H, m), 6.86 (1H, t), 6.67 (1H, m), 5.95 (1H, d), 5.41 (2H, s), 5.27 (1H, d), 4.48 (2H, q), 1.38 (3H, t), 1.25 (9H, s).
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2Br.BrCCBr.[Cl:17][Si:18]([CH3:24])([CH3:23])[Si:19](Cl)([CH3:21])[CH3:20]>C1COCC1.O>[Cl:17][Si:18]([CH3:24])([CH3:23])[Si:19]([CH3:21])([CH3:20])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C:3]([CH3:2])=[CH:11]2
Reactant: CC1=Cc2cccc(Br)c2C1
Reactant: C[Si](C)(Cl)[Si](C)(C)Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: O
Solvent: C1CCOC1
Product: CC1=Cc2cccc([Si](C)(C)[Si](C)(C)Cl)c2C1

Procedure:
To 7.97 g (0.332 mol) of magnesium turnings in 80 mL of THF a mixture of 33.4 g (0.160 mol) of 2-methyl-7-bromo-1H-indene, 30.0 g (0.160 mol) of 1,2-dibromoethane and 420 mL of THF was added dropwise with vigorous stirring at such rate that the mixture is refluxed. Further on, this mixture was additionally refluxed for 30 minutes. The obtained solution was added dropwise with vigorous stirring to a solution of 100 g (0.534 mol) of 1,2-dichloro-1,1,2,2-tetramethyldisilane in 100 mL of THF for 2 hours at room temperature (water bath cooling is required). The resulting mixture was stirred for 12 hours at ambient temperature and then evaporated to dryness. To the residue 100 mL of dry ether was added, and the obtained suspension was stirred for 20 minutes and then filtered through glass frit (G3). The precipitate was washed with 2×100 mL of ether. The combined filtrate was evaporated to dryness, the residue was dried and then rectificated in vacuum, b.p. 140° C.-145° C./1 mm Hg. Yield 26.3 g (58%) of the title product. 1H NMR (CD2Cl2): δ 7.22-7.32 (m, 3H, 4,5,6-H), 6.54 (m, 1H, 3-H), 3.39 (s, 2H, 1,1′-H), 2.21 (s, 3H, 2-Me), 0.66 (m, 3H, SiMe), 0.61 (m, 3H, SiMe), 0.59 (m, 3H, SiMe), 0.50 (m, 3H, SiMe). Anal. Calc. for C14H21ClSi2: C, 59.85; H, 7.53%. Found: C, 59.65; H, 7.72%.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:24]1CCN2C(=NCCC2)CC1.C=O.Cl>C1COCC1.C(OCC)(=O)C.O>[CH2:17]([C:11](=[CH2:24])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccccc1)P(=O)(OCC)OCC
Reactant: C1CCC2=NCCCN2CC1
Agent: C=O
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(Cc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
1.0 g of lithium chloride was suspended in 20 ml of THF, and 5 g of ethyl 2-diethylphosphono--3phenylpropionate was dropwise added thereto. The mixture was stirred at room temperature for seven minutes. Then, 3.6 ml of DBU was added thereto and further 11 minutes later, a suspension of 0.72 g of paraformaldehyde in THF (20 ml) was added thereto at 0° C. The mixture was stirred at room temperature overnight. Then, the mixture was neutralized with 1N hydrochloric acid, and water and ethyl acetate were added thereto. The organic layer was separted, and washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1)to obtain 2.4 g of ethyl 2-benzylacrylate as colorless oily substance.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[I-].[K+].[OH-].[K+].[CH3:20][O:21][C:22]([O:34][CH3:35])([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH2:25]Cl>C1(C)C=CC=CC=1.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:15])[CH2:10][CH2:11][N:12]([CH2:25][CH2:24][CH2:23][C:22]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)([O:34][CH3:35])[O:21][CH3:20])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COC(CCCCl)(OC)c1ccc(F)cc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)(OC)c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 3.5 h

Procedure:
A stirred slurry of 120.0 parts 4-(4-chlorophenyl)piperidin-4-ol hydrochloride and 40.0 parts of potassium iodide in 500 parts of water is warmed to a temperature of about 35° C. under a nitrogen atmosphere. Then, 70.0 parts of potassium hydroxide is added. After further heating to about 55° C., 138.0 parts of 1,1-dimethoxy-1-(4-fluorophenyl)-4-chlorobutane is added. The temperature is then raised to about 102° C. and heating continued for 3.5 hours. After cooling to about 75° C., 785 parts of toluene is added to the reaction mixture and stirred for about 5 minutes. An additional 320 parts of toluene is added and the water and organic layers separated. 102 Parts of methanol is used to rinse the flask and added to the organic layer to provide a solution of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4,4-dimethoxybutyl]-piperidin-4-ol. Then, 59 parts of concentrated hydrochloric acid is added to a stirred solution of the organic layer to precipitate a solid. The solid is filtered, rinsed twice with 550 parts by volume portions of a 10:9:1 acetone-toluene-methanol mixture, twice with 400 parts by volume portions of a 10:1 acetone-methanol mixture, and air-dried. The dried solid is then dissolved in 1950 parts of methanol with gentle heating on a steam bath. The resulting solution is filtered and 300 parts by volume of concentrated ammonium hydroxide is added. Heating is continued to reflux and maintained thereat for about 1 hour. Then, 2520 parts of water is added and the slurry stirred at about 75° C. for 1.5 hours. After cooling to about 25° C., the solid is filtered, washed twice with 600 parts by volume portions of a 3:1 mixture of water-methanol, and air-dried. The resulting product, 4-[4-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone, is obtained in 32.5% yield. This product melts at about 148.5° - 150.5° C., and is represented by the following structural formula. ##STR8##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[C:12]#[N:13])[N:8]([C:14]([NH2:16])=[O:15])[CH2:7][CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:31]3([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:28]=[N:29][CH:30]=2)O1>>[C:12]([C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:14]([NH2:16])=[O:15])=[CH:3][C:2]=1[C:25]1[CH:30]=[N:29][CH:28]=[C:27]([C:31]2([OH:37])[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH:26]=1)#[N:13]
Reactant: N#Cc1nc2c(cc1Br)CCCN2C(N)=O
Reactant: CC1(C)OB(c2cncc(C3(O)CCOCC3)c2)OC1(C)C
Product: N#Cc1nc2c(cc1-c1cncc(C3(O)CCOCC3)c1)CCCN2C(N)=O

Procedure:
6-Bromo-7-cyano-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide is coupled with 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-tetrahydro-pyran-4-ol (which is prepared according to Step 4 of Example 119) to give the titled product using Suzuki Coupling Method VI.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[CH2:11][C:12](=O)[CH3:13]>>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][N:5]2[C:4]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COCc1ccccn1
Reactant: CC(=O)CCl
Product: COc1c(C)cn2ccccc12

Procedure:
This compound is obtained starting with 2-(methoxymethyl)pyridine and chloroacetone, using the Tschitschibabin reaction. The product is isolated in the form of a yellow oil which crystallizes in the freezer.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (1H-imidazol-4-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine as starting material. Product as an oil (20 mg, 62%). LC/MS (Method B) 2.89 min, [M+1]+ 461. Potency class A.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:18][CH3:19])=[O:17])=[N:14][CH:15]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:18][CH3:19])=[O:17])=[N:14][CH:15]=1
Reactant: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](C)O4)[nH]3)c2)cn1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(-c3ccc(C4=NC[C@H](C)O4)[nH]3)c2)cn1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1,1-pyrrol-2-yl}phenoxy)-N-methylpyridine-2-carboxamide (176 mg, 0.38 mmol) synthesized in Example (123b) was dissolved in methylene chloride (5 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.50 mL, 0.50 mmol) was added at −78° C. Subsequently, the temperature was brought back to room temperature, followed by stirring for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with methylene chloride. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (118 mg, yield 69%) as a white solid.
Reaction SMILES: [Br-].[CH3:2][NH:3]CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:25]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:30]=[CH:29][C:28]([C:31]([C:33]2C=CC(C3C=CC=CC=3)=C[CH:34]=2)=O)=[CH:27][CH:26]=1>>[C:25]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:30]=[CH:29][C:28]([CH:31]=[C:33]=[CH:34][NH:3][CH3:2])=[CH:27][CH:26]=1
Reactant: CNCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Agent: [Br-]
Product: CNC=C=Cc1ccc(-c2ccccc2)cc1

Procedure:
β-Methylaminoethyltriphenylphosphonium bromide was reacted with di-4-biphenylyl ketone by the method of Example 1 to give 1,1-di(4-biphenylyl-3-methylaminoprop-1-ene ene identical with that described in Example 4.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH:13]([CH3:15])[CH3:14])(=[O:11])[CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[C:16]1([CH2:32]C2C=C(C)C=CC=2S([O-])(=O)=O)([CH2:20]C2C=C(C)C=CC=2S([O-])(=O)=O)[CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[CH2:20]1[C:16]2([CH2:19][CH2:18][CH2:17]2)[CH2:32][C:4]1([C:5]([O:7][CH:8]([CH3:9])[CH3:10])=[O:6])[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CC2(Cc3cc(C)ccc3S(=O)(=O)[O-])CCC2)c1
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC2(CCC2)C1
Temperature: 140 °C
Yield: 138.2 %

Procedure:
A suspension of NaH (60% in mineral oil, 1.394 g, 34.9 mmol) in DMF (35 mL) was treated drop-wise with diisopropyl malonate (5.30 mL, 27.9 mmol) followed by cyclobutane-1,1-diylbis(methylene)bis(4-methylbenzenesulfonate) (5.92 g, 13.94 mmol) and KI (0.231 g, 1.394 mmol) and heated at 140° C. overnight. The mixture was cooled to RT, poured on satd. NH4Cl, extracted with hexane (2×) and the combined organics were washed with H2O, dried over MgSO4 and concentrated to dryness to afford crude diisopropyl spiro[3.3]heptane-2,2-dicarboxylate (5.17 g, 138%) which was carried on without purification.
Reaction SMILES: [CH2:1]([C:3](=[CH:15][CH3:16])[C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][OH:6])[CH3:2].N1C=CN=C1.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)C>[Si:26]([O:6][CH2:5][C@@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])/[C:3](/[CH2:1][CH3:2])=[CH:15]/[CH3:16])([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC=C(CC)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: C/C=C(\CC)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of (S)-tert-butyl 3-ethyl-1-hydroxypent-3-en-2-ylcarbamate (Intermediate 202, 11.855 g, 51.70 mmol) in DCM (120 mL) was added imidazole (5.28 g, 77.55 mmol), DMAP (1.263 g, 10.34 mmol) and TBDMS-Cl (9.35 g, 62.04 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl ether and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (0-50% ethyl acetate/hexanes) afforded the title compound (17.20 g, 97%) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][N:5]1[C@H:9]([CH3:10])[C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:26][O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:26][O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][N:5]2[C@H:9]([CH3:10])[C@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:33]([O:36][CH3:37])=[CH:34][CH:35]=1
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4R,5S)-3-(2-bromo-5-trifluoromethyl-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: C(OC([N:11]1[C@@H:16]([CH2:17][CH3:18])[CH2:15][CH2:14][C@H:13]([N+:19]([O-:21])=[O:20])[C@@H:12]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)C1C=CC=CC=1.[BrH:28]>C(O)(=O)CC>[BrH:28].[CH2:17]([C@@H:16]1[NH:11][C@@H:12]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:13]([N+:19]([O-:21])=[O:20])[CH2:14][CH2:15]1)[CH3:18]
Reactant: CC[C@H]1CC[C@H]([N+](=O)[O-])[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Agent: Br
Solvent: CCC(=O)O
Product: CC[C@H]1CC[C@H]([N+](=O)[O-])[C@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2S,3S,6S)-6-Ethyl-3-nitro-2-phenyl-piperidine-1-carboxylic acid benzyl ester (40 gm; 108 mmol) was dissolved in 80 ml of 30% HBr in propionic acid at room temperature. There was a rapid evolution of gas and the desired product precipitated after 3–5 minutes. The mixture was stirred at room temperature for 16 hours. The tan solids were collected, washed with ether and dried in vacuo to afford 29 gm of the (2S,3S,6S)-6-Ethyl-3-nitro-2-phenyl-piperidine HBr salt. 1H NMR (D2O, 400 MHz) δ 7.4–7.2 (br.m, 5H), 5.25 (m, 1H), 4.95 (d), 3.65 (br.m.), 2.4–2.0 (m), 1.9–1.55 (m), 0.85 (t, 3H) ppm. Mass spectra m/z=235 (p+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.[NH4+].[Cl-].C(OCC)(=O)C>CO.O1CCOCC1.O.[Fe]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([C:4]2[CH:5]=[C:6]([NH:8][CH3:9])[CH:7]=[C:2]([Br:1])[N:3]=2)(=[O:11])=[O:12])=[CH:14][CH:15]=1
Reactant: CNc1cc(Br)nc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CNc1cc(Br)nc(S(=O)(=O)c2ccc(N)cc2)c1
Yield: 87.7 %

Procedure:
0.078 g (0.00021 mol) of [2-bromo-6-(4-nitrobenzenesulphonyl) -pyridin-4-yl]-methylamine was dissolved in a mixture of 1.5 ml of methanol and 1.5 ml of dioxane, treated with 0.078 g of iron powder and a solution of 0.078 g of NH4Cl in 2.5 ml of water and heated at reflux for 2 hrs. Therafter, the reaction mixture was poured into a mixture of ethyl acetate and water, suction filtered and the organic phase was extracted with water and sat. sodium chloride solution and dried over MgSO4. After removal of the solvent the residue was chromatographed on silical gel with ethyl acetate/hexane 1:3. There was obtained 0.063 g (88%) of [2-(4-aminobenzenesulphonyl)-6-bromopyridin-4-yl]-methylamine as yellowish crystals; m.p.: 158-160° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1.C(N(CC)CC)C>O>[C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([NH:2][C:25](=[O:26])[CH2:24][C:23](=[O:27])[CH3:22])[CH:4]=1)(=[O:16])[CH3:15]
Reactant: COc1ccc(CCNC(C)=O)cc1N
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(C)=O)cc1NC(=O)CC(C)=O
Temperature: 82.5 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
N-[-2-(3-amino-4-methoxyphenyl)ethyl]acetamide hydrochloride (19 g) was mixed with 40 mL N,N-dimethylformamide and 18 g of diketene followed by slow addition of 3 mL of triethylamine. The mixture was stirred at 80-85° C. for 30 minutes and then poured into 300 mL of water. The aqueous solution was extracted with chloroform (2×200 mL) and the solvent was removed by rotary evaporation to yield 21.9 g (96.5%) of N-[5-(2-acetylaminoethyl)-2-methoxyphenyl]-3-oxo-butyramide as a light yellow oil. 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=O.O.ON1C2C=CC=CC=2N=N1.[N:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:5][C:6](=[O:8])[N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)C(CC(=O)O)Cc1ccc(OC)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: COC(=O)C(CC(=O)N1CCN(c2ccncc2)CC1)Cc1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
To a solution of 2-(4-methoxybenzyl)succinic acid 1-methyl ester (3 g) in acetonitrile (60 ml) were added HOBt (1-hydroxy-1H-benzotriazole monohydrate) (1.84 g) and 1-ethyl-3-(3-dimethylamgnopropyl)carbodiide hydrochloride (2.76 g) and the solution was stirred for 10 minutes. To the solution was added 1-(4-pyridyl)-piperazine (1.96 g) and the solution was stirred for 30 minutes at room temperature. The reaction mixture was concentrated and the concentrate was made basic with an aqueous solution of sodium hydrogen carbonate to give an alkaline solution, which was extracted with ethyl acetate twice. The extract was washed with saturated brine and dried over Na2SO4. The solution was concentrated under reduced pressure and recrystallized from ethyl acetate/hexane to give the titled compound (4.25 g) as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[O:14][CH2:15][C:16](=[O:23])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[C:26]([CH:33]=O)=[CH:25]1.[OH-].[Na+]>C(O)C.Cl>[NH:24]1[C:32]2=[N:31][CH:30]=[CH:29][CH:28]=[C:27]2[C:26]([CH:33]=[C:15]2[O:14][C:13]([NH:12][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][OH:11])=[CH:7][C:2]=3[F:1])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:25]1
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCO)cc2F)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCCO)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 60.5 %

Procedure:
To a solution of ethyl 2-{[2-fluoro-4-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.017 g, 0.052 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0075 g, 0.051 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.052 mL, 0.10 mmol) was added at ambient temperature. The mixture was refluxed for 8.5 h. Cooled with ice bath, 2M sodium hydroxide solution (0.047 mL, 0.094 mmol) was added dropwise to neutralize, and ethanol (0.5 mL) was added and refluxed for further 16 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.014 g, y. 59%).
Reaction SMILES: O[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:7]1[C:2]2[O:19][C:17](=[O:18])[CH2:16][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1cccc(Oc2cccc(Cl)c2)c1O
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2cccc(Oc3cccc(Cl)c3)c2O1
Yield: 88.2 %

Procedure:
A solution of 2-[2-hydroxy-3-(3-chlorophenoxy)phenyl]acetic acid (2 g) in acetic anhydride (10 ml) was treated in a similar manner to that of Example 6-(7) to give 7-(3-chlorophenoxy)-2,3-dihydrobenzofuran-2-one (1.65 g). mp 105°-106° C.