Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].ICCCC.[Cl-].[Na+]>O1CCCC1>[CH2:16]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCI
Product: CCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.3 g, 1.5 mmole) in 30 mL tetrahydrofuran (THF) was cooled to −78° C. and 2.5 M n-butyllithium solution (0.6 mL) was added dropwise. The reaction mixture was allowed to warm to 0° C. over a one hour period. Iodobutane (0.171 mL) was added at 0° C. and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then poured into 50 mL of a saturated aqueous sodium chloride solution and extracted with three portions of 50 mL of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide a brown oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate/hexanes) to provide 143 mg (37%) of butyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (7) as a pale yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:10][C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH:16][S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[C:6]([CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc(N)cc2C(C)C)cc1
Temperature: 80 °C
Yield: 75.9 %

Procedure:
To a suspension of N-(2,6-diisopropyl-4-nitro-phenyl)-4-methyl-benzenesulfonamide (3.72 g) in ethanol (50 mL) was added stannous(II) chloride dihydrate (11.2 g) and the mixture was heated to 80° C. for 1.5 hour. It was then poured onto ice (300 mL), made strongly basic with solid sodium hydroxide (20 g) and diluted with ethyl acetate (100 mL). The suspension was filtered and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 2.60 g (76%) of the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3): 0.95 (d, 12H), 2.40 (s, 3H), 3.02 (m, 2H), 3.68 (b, 2H), 5.74 (s, 1H), 6.39 (s, 2H), 7.23 (d, 2H), 7.60 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)[CH:19]=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:19]([OH:20])[CH3:25])[CH:21]=[CH:22][CH:23]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)c1cccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
0.085 g (0.26 mmol) of 3-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde is dissolved in 8 ml of tetrahydrofuran under a stream of nitrogen. The medium is cooled to 5° C. before slow addition of 0.30 ml (0.90 mmol) of a methylmagnesium bromide solution (3M in ethyl ether). The medium is subsequently stirred at ambient temperature for 2 hours. Neutralization is carried out by adding, under cold conditions and dropwise, a saturated aqueous ammonium chloride solution and then dilution is carried out with ethyl acetate and water. The organic phase is separated and then the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified by chromatography on silica gel (by solid deposit), elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2). 0.048 g (53%) of the expected product is obtained in the form of a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl-:12].[Na+].S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[N+:1]([C:4]1[CH:9]=[C:8]([Cl:12])[CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: [Cl-]
Reactant: COc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
2-Nitroanisole (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to the reaction mixture. The mixture was heated at 80° C. under inert atmosphere for 4 h. The product was purified by column chromatography to give 2-nitro-4-chloroanosole (55%).
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6]O)[CH2:3][CH2:2]1.C1C=CC(P([N:22]=[N+:23]=[N-:24])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCCCCC.C(Cl)Cl>[CH:1]1([C:4]#[C:5][CH2:6][N:22]=[N+:23]=[N-:24])[CH2:3][CH2:2]1
Reactant: OCC#CC1CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCC#CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Cyclopropyl-prop-2-yn-1-ol (3.28 g, 34.1 mmol) was dissolved in 40 mL toluene, DPPA (11.26 g, 40.9 mmol) was added, followed with DBU (6.24 g, 40.9 mmol) while maintaining temperature with a water bath. The mixture was stirred at room temperature for one hour and was diluted with 100 mL hexane and 15 mL CH2Cl2. The mixture was washed with water four times and once with brine, dried over Na2SO4, filtered and concentrated under rotovap with cold water bath to remove most of organic solvent leaving some toluene (product volatile). The residual oil was used for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][C:13]([CH3:21])=[N:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([CH3:21])=[N:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc2onc(N)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)n(-c2ccc3onc(N)c3c2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of ethyl 1-(3-aminobenzisoxazole-5-yl)-3-methyl-5-pyrazole carboxylate (0.14 g) in THF (5 mL) was added NaOH (10% in water, 5 mL). The reaction was stirred at 60° C. for 2 h, THF was evaporated, HCl (10% in water) was added dropwisely until the pH was between 4-5, partitioned between ethylacetate and water, washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-(3-aminobenzisoxazole-5-yl)-3-methyl-5-pyrazole carboxylic acid (0.11 g). ESI mass spectrum z (rel. intensity) 259 (M+H, 100).
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[NH2+:16])=[CH:13][CH:12]=2)=[C:5]([CH3:20])[CH:4]=1.[N:21]1[C:28]([Cl:29])=[N:27][C:25](Cl)=[N:24][C:22]=1[Cl:23].[OH-].[Na+].P([O-])([O-])([O-])=O>O>[Cl-:23].[Cl:23][C:22]1[N:21]=[C:28]([Cl:29])[N:27]=[C:25]([NH:2][C:3]2[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH2:17])=[NH2+:16])=[CH:18][CH:19]=3)=[C:5]([CH3:20])[CH:4]=2)[N:24]=1
Reactant: Cc1cc(N)ccc1N=Nc1ccc(C(N)=[NH2+])cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Nc2nc(Cl)nc(Cl)n2)ccc1N=Nc1ccc(C(N)=[NH2+])cc1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 5.8 g of 4-(4'-amino-2'-methylphenylazo)benzamidinium chloride in 800 parts of water was added 3.8 g of cyanuric chloride and the pH maintained between 5 and 6 and finally raised to 7 by the addition of 20 g of 1M sodium hydroxide solution. To this solution were then added 8 g of mixed phosphate buffer (equimolar amounts of KH2PO4 and Na2HPO4), followed by 40 g of salt and the precipitate of dichlorotriazine filtered off, mixed with further 1 g of phosphate buffer to ensure stability during drying and dried in vacuo giving 4-(4-[4,6-dichloro-s-triazin-2-ylamino]-2-methyl-phenylazo)benzamidinium chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH2:10]1[CH2:20][C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.B(F)(F)F.CCOCC>>[NH2:1][C:2]1[C:3]2[C:8]3[N:9]=[C:17]4[C:12]([CH:11]=[CH:10][CH:20]=[CH:18]4)=[CH:13][C:14]=3[CH2:15][CH2:16][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2ccccc21
Reactant: N#Cc1ccccc1N
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1cccc2c1-c1nc3ccccc3cc1CC2

Procedure:
2-amino-1-cyano-benzene (2.0 g, 16.9 mmol), α-tetralone (3, 4-dihydro-[2H]-naphthalene-1-one) (Aldrich Chemicals) (2.7 g, 18.5 mmol) and boron trifluoride diethyl etherate (1M, 2.3 ml, 18.8 mmol) were treated according to the general procedure described herein to give the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[N:11]1[C:19]2[C:14]3[C:15](=[CH:20][CH:21]=[CH:22][C:13]=3[C:12]=1S)[CH:16]=[CH:17][CH:18]=2>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][NH:10][C:12]2[C:13]3[CH:22]=[CH:21][CH:20]=[C:15]4[C:14]=3[C:19](=[CH:18][CH:17]=[CH:16]4)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: NOCCCn1ccnc1
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NOCCCn1ccnc1)=N2
Yield: 51.3 %

Procedure:
A mixture consisting of 2.33 grams of 3-(1H-imidazol-1-yl)propoxyamine, 2.84 grams of benz(cd)indol-2-thiol, 4.9 grams of mercuric acetate, and 150 ml of ethanol as stirred and heated under reflux by the conditions of Example 55. The crude product was purified by the chromatographic procedure of Example 46. The resultant orange syrup was recrystallized from ethyl acetate-hexane to give 2.3 grams of the title compound; mp 102° C.-104° C.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2.[SH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[C:34]([CH2:33][CH2:32][S:31][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2)([OH:36])=[O:35]
Reactant: O=C(O)CCS
Reactant: COc1ccc2nc(COc3ccc4c(c3)C(O)c3ccccc3CO4)ccc2c1
Product: COc1ccc2nc(COc3ccc4c(c3)C(SCCC(=O)O)c3ccccc3CO4)ccc2c1

Procedure:
11-Hydroxy-2-(6-methoxyquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:11]Br>O>[Br:11][CH2:9][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: BrBr
Solvent: O
Product: CCOC(=O)C(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-methyl-3-oxobutanoate (5.05 g, 35.0 mmol) in water (10 mL) at 0° C. was added bromine (1.81 mL, 35.0 mmol) dropwise over 2 h. The resulting solution was stirred at rt for 16 h. The reaction mixture was extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated to give ethyl 4-bromo-2-methyl-3-oxobutanoate. 1HNMR (500 MHz, CDCl3), δ4.322-4.274 (m, 2H), 2.455 (s, 2H), 1.991 (s, 3H), 1.337-1.309 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22](Br)[CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:20]([CH3:25])[CH:19]=1
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: Cc1cc(Br)cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
Prepared from (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3,5-dibromotoluene according to Procedure B. White solid: mp 231-233° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.66 (s, 1H), 7.58-7.56 (m, 2H), 7.50 (s, 1H), 7.37 (s, 1H), 6.95 (d, 1H, J=8.67 Hz), 2.37 (s, 3H), 1.67 (s, 6H); (ESI) m/z 344/346 ([M−H]−, 100%); Anal. Calc. For C17H16BrNO2: C, 58.98; H, 4.66, N, 4.05. Found: C, 58.82; H, 4.62; N, 3.94.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[CH:22]=[C:21]2[C:10]([CH2:11][C:12]3[CH:16]=[CH:15][N:14]([CH2:17][CH:18](O)[CH3:19])[C:13]=32)=[CH:9][CH:8]=1.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.CN(C)C=O.O>[N:30]([CH:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[CH2:11][C:10]3[C:21]([C:13]1=2)=[CH:22][C:7]([CH3:6])=[CH:8][CH:9]=3)=[N+:31]=[N-:32]
Reactant: Cc1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2c(c1)-c1c(ccn1CC(C)N=[N+]=[N-])C2
Yield: 67.7 %

Procedure:
0.67 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 0.98 g of (RS)-1-(7-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 2.4 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.56 g of sodium azide and the reaction mixture was heated to 60° for 16 hours while stirring. After cooling, the solution was poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 737 mg (68%) of (RS)-1-(2-azido-propyl)-7-methyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18](O)[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>ClC1C=CC=CC=1.ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([Cl:28])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: N#Cc1ncc2c(c1Cl)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (2.0 g, 4.66 mmol) and phosphorus pentachloride (2.9 g, 14.0 mmol) in chlorobenzene (6 mL) was heated at 105° C. for 1 hour. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo to afford a residue. The resultant residue was dissolved in dichloromethane (300 mL) and the solution was treated with ice/water (300 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (300 mL). The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with methanol and dried to afford the title compound as a tan solid (1.1 g, 53%). 1H NMR (300 MHz, DMSO-d6): 9.70 (s, 1H), 9.06 (d, J=2.2 Hz, 1H), 8.98 (d, J=2.2 Hz, 1H), 8.27-8.22 (m, 2H), 7.77-7.76 (m, 1H), 7.67-7.60 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][CH:22]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][CH2:22][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: C1CCNCC1
Solvent: CO
Product: c1ccc(CN2CCN(Cc3ccccc3)C(CCN3CCCCC3)C2)cc1
Reaction time: 0.5 h

Procedure:
In methanol (10 mL) were dissolved 1,4-dibenzyl-2-(formylmethyl)piperazine (600 mg) and piperidine (200 mg). After stirring for 30 minutes, the solvent was concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL), followed by the addition of sodium borohydride (147 mg). The resulting mixture was stirred. Five hours later, the solvent was distilled off under reduced pressure. Chloroform was added to the residue and the mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=10:1→5:1), whereby the title compound (640 mg) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:23].FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[F:23]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCNCC2)cc1F

Procedure:
tert-Butyl 4-(4-amino-3-fluorobenzoyl)piperazine-1-carboxylate (0.649 mmol, 210 mg) was stirred with dichloromethane (˜2 mL) and trifluoroacetic acid (˜0.5 mL) overnight. The mixture was purified by SCX chromatography to give the intermediate (4-amino-3-fluorophenyl)(piperazin-1-yl)methanone. 2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.649 mmol, 219 mg), potassium carbonate (0.649 mmol, 90 mg) and acetonitrile (5 mL) were added to the intermediate (4-amino-3-fluorophenyl)(piperazin-1-yl)methanone and the mixture was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was stirred in dichloromethane, filtered and the filtrate was purified by silica chromatography (eluting with dichloromethane increasing to ethyl acetate) to afford the title compound (46 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>CC(C)=O>[CH3:28][O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCCCOc1ccc([N+](=O)[O-])cc1
Yield: 65.2 %

Procedure:
To a mixture of 4-nitrophenol (150 g, 1.079 moles), potassium carbonate (600 g, 4.341 moles) and sodium iodide (10 g, 66.7 mmol) in anhydrous acetone (2.1 L) was added methyl 6-bromohexanoate (156 g, 746.41 mmol) and heated to reflux for 48 hours. Acetone was distilled off and water (2 L) was added. Crude 39 was filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:6) to get pure 39 (130 g, 45.1%) as a white powder. M.p: 84.5.5-86.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]2[NH:16][CH2:15][CH:14]([OH:17])[CH2:13]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.FC1C([O:46][C:47](=O)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][N:53]2[C:61](=[O:62])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]2=[O:63])=C(F)C(F)=C(F)C=1F.CO.C(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]2[CH2:13][CH:14]([OH:17])[CH2:15][N:16]2[C:47](=[O:46])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][N:53]2[C:54](=[O:63])[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:61]2=[O:62])=[CH:7][CH:8]=1
Reactant: O=C(CCCCCN1C(=O)c2ccccc2C1=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN2C(=O)c3ccccc3C2=O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Amine 38 (9.32 g, 22.2 mmol) and triethyl amine (4.55 g, 6.27 mL, 45 mmol) weres dissolved in anhydrous dichloromethane (20 mL) and cooled to 0° C. under argon. To that solution was added compound 43a (9.5 g, 22.2 mmol) at 0° C. The reaction mixture was brought to ambient temperature and stirred further. After 30 mins, disappearance of starting materials were ascertained by TLC. (10% MeOH/CHCl3). The reaction mixture was diluted with dichloromethane (100 mL) and washed with 5% NaOH solution (3×50 mL) followed by water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Upon purification over silica gel compound 44a was obtained as foamy white solid in good yield. (13.2 g, 89%).
Reaction SMILES: C[O:2][P:3]([CH2:7][N:8]([S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)(=[O:12])=[O:11])[CH3:9])(=[O:6])[O:4]C.Br[Si](C)(C)C>ClCCl>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=[C:13]1[S:10]([N:8]([CH2:7][P:3](=[O:2])([OH:6])[OH:4])[CH3:9])(=[O:11])=[O:12]
Reactant: COP(=O)(CN(C)S(=O)(=O)c1cc2ccccc2s1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN(CP(=O)(O)O)S(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 550 mg (1.58 mmol) of the compound (xiv) in 10 mL of anhydrous dichloromethane at 0° C., 0.49 mL of bromotrimethylsilane was added. The mixture was warmed up to room temperature and left overnight. Dichloromethane was evaporated; the oily residue was dissolved in another 10 mL of dichloromethane, filtered, again evaporated and redissolved in 10 mL of MeOH. The methanolic solution stirred at room temperature 30 min., evaporated and the residue was triturated with a mixture ether/hexane to form a white crystalline product which was separated by filtration (390 mg, 70%): 1H NMR: (300 MHz, DMSO-D6) δH 2.88 (s, CH3), 3.21 (d, J=12.1 Hz, 2 H), 7.49-7.61 (m, 2 H, Ar—H), 8.01-8.17 (m, 3 H, Ar—H).