Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[OH:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:18]([C@H:14]([NH:13][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:12])[C:15]([N:28]1[CH2:29][CH2:30][C@H:26]([OH:25])[CH2:27]1)=[O:17])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O[C@H]1CCNC1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](O)C1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropionic acid (EXAMPLE 42, 50 mg, 0.15 mmol) in DMF (3 mL) was added 3-(S)-hydroxypyrrolidine (13.9 mg, 0.16 mmol), HOBt (20 mg, 0.15 mmol) and DIPEA (51 μL, 0.29 mmol). After 5 min, EDCI (36 mg, 0.19 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 mL) and ethyl acetate (3×20 mL), dried (MgSO4) and concentrated in vacuo. Purification via chromatography on silica gel eluting with methanol/dichloromethane (4:96) gave the title compound as a white solid. m/z (ES+)=413 [M+H]+; RT=3.20 min.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.B(O)O>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cc(-n2ncc3c(OCc4ccccc4)cccc32)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A mixture of 4-[(phenylmethyl)oxy]-1H-indazole (D1) (530 mg, 2.37 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (873 mg, 3.55 mmol), copper acetate (861 mg, 4.74 mmol), triethylamine (0.660 mL, 4.74 mmol) and powdered 4A molecular sieves (2.5 g) in dichloromethane (10 mL) was stirred vigorously under an air atmosphere at ambient temperature. Further quantities of boronic acid, triethylamine and copper acetate were added after 18 hours (0.5 equivalents of each) and 22 hours (1 equivalent of each). After stirring for a further 24 hrs, the mixture was filtered through a plug of silica gel and concentrated. Chromatography (silica gel, elution with 0-20% ethyl acetate in hexane) gave the title compound (D2) as a white solid (309 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[CH:5]=[CH:4][C:3]1=2.O[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CC=C(Sc2ccccc2)c2cc(C(=O)O)ccc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(Sc2ccccc2)=CCC3(C)C)cc1

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid (Compound E19, 150.0 mg, 0.484 mmol), ethyl 4-hydroxybenzoate (88.5 mg, 0.530 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120.6 mg, 0.630 mmol), and 4-N,N-dimethylaminopyridine (77.0 mg, 0.630 mmol) in 5.0 mL DMF was stirred overnight at room temperature. EtOAc (50 mL) was added and the solution washed with H2O and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure and column chromatography (10-15% EtOAc-hexanes) of the residual oil afforded the title compound as a colorless solid.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[C:9]([O:13][C:14]([NH:16][C@@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][C@H:18]1[OH:33])=[O:15])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C=O)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][C@H:18]1[O:33][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyldimethylchlorosilane (6.51 g, 43.2 mmol) was added to a solution of (+/−)(3R,4R)-benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylate (prepared according to a published literature procedure: Fink, Brian, et al., WO 2005/066176, 10.1 g, 28.8 mmol) and imidazole (3.92 g, 57.6 mmol) in DMF (60 mL). The mixture was stirred at room temperature overnight. Ice water was added and the reaction mixture was extracted with ether twice, the combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (330 g column, eluting with 5-20% ethyl acetate/dichloromethane) to give (+/−)-(3R,4R)-benzyl 4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (13.3 g) as a white solid.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][CH2:21][C:22]1[CH:23]=[C:24]([Mg]Br)[CH:25]=[CH:26][CH:27]=1.BrC1C=C(COC2CCCCO2)C=CC=1>C1COCC1>[OH:1][CH:2]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:21][O:20][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)[CH:27]=1)[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=CCCc1ccccc1C(=O)O
Reactant: Br[Mg]c1cccc(COC2CCCCO2)c1
Agent: Brc1cccc(COC2CCCCO2)c1
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1CCC(O)c1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At -10° C., a solution of the aldehyde of Step 4 (5.045 g, 28.3 mmol) in 50 mL of THF was added dropwise to 0.57M 3-((2-tetrahydropyranyloxy)methyl)phenylmagnesium bromide in THF (120 mL, 68.4 mmol, prepared from the bromide of Step 2 and Mg in THF and filtered to remove the excess of Mg) and the mixture was stirred at r.t. for 30 min. At 0° C., 25% aq NH4OAc was added. The title product was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using acetone:toluene:HOAc 5:95:1 and 15:85:1.
Reaction SMILES: [CH:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O-:15][Mn](=O)(=O)=O.[K+].[Cr]([O-])(OC(C)(C)C)(=O)=O>>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][C:12](=[O:14])[CH3:13])[CH2:2][CH2:3]1
Reactant: CC(=O)NC1CCCc2ccccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CC(C)(C)O[Cr](=O)(=O)[O-]
Agent: [K+]
Product: CC(=O)NC1CCC(=O)c2ccccc21

Procedure:
Similarly, oxidation of N-(1,2,3,4-tetrahydro-1-naphthyl)acetamide with ceric ammonium nitrate, K2S2O8 /catalytic AgNO3, KMnO4 /catalytic ceric ammonium nitrate, t-butyl chromate, Na2Cr2O7, ceric sulfate, chromyl chloride and H2O2 /V2O5, respectively, under standard conditions and the general workup conditions described in Example 1, also affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:5]([NH:7][CH2:8][C:9]([CH3:15])([CH3:14])[CH2:10][N:11]([CH3:13])[CH3:12])=[O:6].[Cl-].[NH4+].O>C(O)C.C(O)(=O)C.[Fe]>[NH2:19][C:18]1[CH:17]=[CH:16][C:4]([C:5]([NH:7][CH2:8][C:9]([CH3:14])([CH3:15])[CH2:10][N:11]([CH3:13])[CH3:12])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: CN(C)CC(C)(C)CNC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CC(C)(C)CNC(=O)c1ccc(N)c(Cl)c1

Procedure:
3-chloro-N-(3-dimethylamino-2,2-dimethyl-propyl)-4-nitro-benzamide (2.29 g, 7.67 mmol), iron powder (2.45 g, 43.79 mmol) and ammonium chloride (781 mg, 14.60 mmol) were heated in ethanol (50 mL) and water (18 mL) at reflux for one hour. A few drops of acetic acid were added and heating continued for a further hour. The reaction mixture was cooled, filtered and the filtrate concentrated. This residue was partitioned between saturated NaHCO3 (aq.) and DCM. The organic phase was washed with brine, dried with MgSO4 and concentrated. Column chromatography gave the title compound as an orange crystalline solid. (850 mg, 39%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.[C:20]([OH:23])(=O)[CH3:21].[N+:24]([O-])([OH:26])=[O:25]>C(OC(=O)C)(=O)C>[C:20]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]=1[N+:24]([O-:26])=[O:25])(=[O:23])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(OCCOc2ccccc2)cc1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(OCCOc2ccccc2)cc1[N+](=O)[O-]
Yield: 90 %

Procedure:
1-Nitro-4-(2-phenoxy-ethoxy)-benzene is reduced and the resulting amine is heated in acetic anhydride and glacial acetic acid and nitrated with 70% strength nitric acid. 1-Acetamido-2-nitro-4-(2-phenoxy-ethoxy)-benzene is obtained in 90% yield (melting point: 104° to 106° C.). The amide is hydrolysed with potassium hydroxide in ethanol and the desired nitroamine is obtained in 98% yield (melting point 121° to 123° C.).
Reaction SMILES: [ClH:1].NC(=O)[C@@H](N[C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])C1C=CC=CC=1.Cl.[NH2:35][C@H:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37]([O:39][CH3:40])=[O:38]>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:35][C@H:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:37]([O:39][CH3:40])=[O:38])=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: COC(=O)[C@H](N)c1ccccc1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Agent: Cl
Product: COC(=O)[C@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 51.1 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with (R)-methyl 2-amino-2-phenylacetate, hydrochloride salt (Aldrich, 30 mg, 0.10 mmol) in a manner similar to that which is described in Step C of Example 1 to give (R)-methyl 2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate, hydrochloride salt (25 mg, 51% yield). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 9.03 (d, 1H, J=7.0 Hz), 7.96 (d, 1H, J=7.0 Hz), 7.77-7.88 (m, 3H), 7.42 (m, 7H), 6.71 (d, 1H, J=7.5 Hz), 6.12 (s, 1H), 5.44 (d, 1H, J=7.0 Hz), 3.63 (s, 3H), 3.44-3.38 (m, 2H); MS (ESI+) m/z 453.29 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:28](Cl)(=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:30]([O:29][C:28]([N:18]1[CH2:17][CH2:16][N:15]([C:7]2[N:6]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:20][CH2:19]1)=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCOc1nc(N2CCNCC2)nc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=CCOc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12

Procedure:
To a solution of 4-[(2-propen-1-yl)oxy]-2-(1-piperazinyl)quinazoline (1.80 g) in dry methylene chloride (18 ml) is added triethylamine (1.88 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (1.04 ml) in dry methylene chloride (3 ml). The mixture is stirred under ice-cooling for 2 hours. The reaction mixture is diluted with chloroform, washed with diluted hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(2-propen-1-yl)oxy]quinazoline (1.76 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH:8]2[CH2:15][C:11]3[S:12][CH:13]=[CH:14][C:10]=3[C:9]2=O)=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[C:8]3[CH2:15][C:11]4[S:12][CH:13]=[CH:14][C:10]=4[C:9]=3[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(F)cc1)C1Cc2sccc2C1=O
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Fc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
5-(4-Fluoro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.1 mmol), hydrazine monohydrate (0.15 mL, 3.1 mmol), glacial acetic acid (0.5 mL) and ethanol (10 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(4-Fluoro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.7 mmol) as yellow solid in 81% yield.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:9](=[O:14])[NH:10][CH:11]=[CH:12][CH:13]=1.ClC(Cl)(Cl)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>ClCCl>[CH3:7][C:8]1[C:9](=[O:14])[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: Cc1ccc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccn(CC(F)(F)F)c1=O
Reaction time: 2 h
Yield: 55.9 %

Procedure:
Cesium carbonate (11.4 g, 34.9 mmol) was added to a solution of 3-methylpyridin-2(1H)-one (3.81 g, 34.9 mmol) and 2,2,2-trifluoroethyl trichloromethanesulfonate (9.81 g, 34.9 mmol) in dichloromethane (80 mL). After 2 h, water was added. The mixture was extracted with ether (3×), and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane 25%→methanol/dichloromethane) gave the title compound (3.73 g). MS192.3 (M+1).
Reaction SMILES: CCCCCC.[H-].[Na+].COP([CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(OC)=O.[CH:26]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:29]=1[C:30]([O:32][CH3:33])=[O:31])=O>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])/[CH:15]=[CH:26]/[C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[C:29]=1[C:30]([O:32][CH3:33])=[O:31])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1c(C=O)cccc1C(F)(F)F
Reactant: COP(=O)(CC(=O)OCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1c(/C=C/C(=O)OCc2ccccc2)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.6 %

Procedure:
To a suspension of hexane-washed sodium hydride (0.42 g of 60% suspension in mineral oil, 10.52 mmol) in 120 mL of THF at 0° C. was added benzyl 2-(dimethoxyphosphoryl)acetate (2.72 g, 10.52 mmol) dropwise in 10 mL of THF. The resulting mixture was stirred 5 min at 0° C. and then was allowed to warm to ambient temperature and stirred for 20 min. To this solution was added methyl 2-formyl-6-(trifluoromethyl)benzoate (2.22 g, 9.56 mmol) dropwise in 10 mL of THF. The resulting solution was stirred at ambient temperature for 1 h. The reaction mixture was quenched with 1N HCl (100 mL) and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 3.4 g (97%) of the title compound which was sufficiently pure to be used without purification. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=7.9 Hz), 7.72-7.67 (m, 2H), 7.55 (t, 1H, J=7.9 Hz), 7.38-7.30 (m, 5H), 6.47 (d, 1H, J=15.8 Hz), 5.23 (s, 2H), 3.94 (s, 3H). LRMS (ESI): 387.17 (M+H+Na)+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([OH:19])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([Cl:22])=[O:19])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1c2ccccc2CCc2ccccc21
Solvent: c1ccccc1
Product: O=C(Cl)CC1c2ccccc2CCc2ccccc21

Procedure:
A mixture of 160 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid and 230 ml of thionyl chloride is heated to boiling under reflux for 2.5 hours. After concentration of the mixture in vacuo, the residue is treated twice with 300 ml of dry benzene each time and in each case evaporated to dryness. 10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid chloride is obtained as a red-brown oil.
Reaction SMILES: [ClH:1].CO[C:4](=[O:32])[CH:5]([NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH2:17])=[N:12][CH:11]=[CH:10]2.[CH3:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[ClH:1].[NH2:17][C:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][CH:5]([NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[C:4]([N:37]3[CH2:38][CH2:39][CH:34]([CH3:33])[CH2:35][CH2:36]3)=[O:32])=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: CC1CCNCC1
Reactant: COC(=O)C(Cc1ccc2c(N)nccc2c1)NS(=O)(=O)c1ccc2ccccc2c1
Agent: Cl
Product: CC1CCN(C(=O)C(Cc2ccc3c(N)nccc3c2)NS(=O)(=O)c2ccc3ccccc3c2)CC1

Procedure:
Compound 11a was saponified and subsequently coupled with 4-methylpiperidine using the procedure described for 4 to give 11b. 1H-NMR 200 MHz (CD3OD) δ: 0.15-3.24 (12H, m), 3.75-4.24 (2H, m), 4.57-4.72 (1H, m), 6.71-7.91 (10H, m), 8.11-8.19 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1([P:18](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[Br-:9].[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][PH3+:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C[PH3+])cc1
Product: [Br-]
Temperature: 25 °C
Yield: 161.3 %

Procedure:
p-Nitrobenzylbromide (54.0 g, 0.25 mol) and triphenylphosphine (65.6 g, 0.25 mol) were dissolved in 150 mL of dry benzene in a flask equipped with a drying tube. The solution was heated on a steam bath with swirling until a majority of product had precipitated (5 min), and then was allowed to cool to near ambient temperature with occasional agitation. Filtration of the precipitate and washing with 3×200 mL anhydrous ether yielded 100.8 g of the desired product as an off-white powder. The filtrate was flash evaporated to 50 mL and heated on a steam bath for 5 min, then chilled overnight to provide an additional 11.4 g of product (93.8% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]1)(=[O:24])=[O:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:23])=[O:24])[CH2:26][CH2:27]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)N1CCN(CCO)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OCCN2CCN(S(C)(=O)=O)CC2)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 2-(4-Methanesulfonyl-piperazin-1-yl)-ethanol.
Reaction SMILES: [Si]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13]/[C:14](=[C:19](\[CH:24]([CH3:26])[CH3:25])/[C:20]([O:22][CH3:23])=[O:21])/[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.CCCCCC.C(OCC)(=O)C>O1CCCC1>[CH3:18][O:17][C:15](=[O:16])/[C:14](/[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:28][CH:27]=1)=[C:19](/[CH:24]([CH3:25])[CH3:26])\[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)/C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)=C(\C(=O)OC)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)C(C)C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of dimethyl 2-[4-(t-butyldimethylsilyloxy)benzyl]-3-isopropylmaleate (823 mg, 2.02 mmol) in tetrahydrofuran (13 mL) was added a 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (2.1 mL, 2.1 mmol) at room temperature, and the mixture was left standing at room temperature for 1 h. The reaction mixture was directly concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 2:1) to give 592 mg of 2-(4-hydroxybenzyl)-3-isopropylmaleic acid dimethyl ester as a solid (quantitative).
Reaction SMILES: [I-].[OH:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5](=O)[CH2:6][N+]1C=CC=CC=1.[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=O)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1.C([O-])(=O)C.[NH4+:42].C(O)(=O)C>O>[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[C:27]([C:28]2[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[CH:6]=[C:5]([C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=2[OH:2])[N:42]=1
Reactant: [NH4+]
Reactant: CN(C)c1ccc(C=CC(=O)c2ccccc2O)cc1
Reactant: O=C(C[n+]1ccccc1)c1ccccc1O
Agent: CC(=O)[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1ccc(-c2cc(-c3ccccc3O)nc(-c3ccccc3O)c2)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
1.63 g (5 mmol) of 2-hydroxyphenacyl-pyridinium iodide, 0.53 g (2 mmol) of 1-(2-hydroxyphenyl)-3-(4-dimethylaminophenyl)-2-propen-1-one and 4 g of ammonium acetate were added to 4 ml of acetic acid, and the mixture was subjected to refluxing under heating for 5 hours. After being cooled to room temperature, the reaction mixture was poured to 50 ml of water and extracted two times with 30 ml each of chloroform. The chloroform was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography with chloroform as the eluent to obtain 0.61 g (yield: 79%) of 2,6-bis(2-hydroxyphenyl)-4-(4-dimethylaminophenyl)pyridine. (Incidentally in case where the reaction residue was subjected to re-crystallization from 30 ml of ethanol, the 2,6-bisphenolpyridine product was recovered at a yield of 64%.)