Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]([CH3:10])[CH:5]=[C:6]2[CH:9]=[N:11][NH:8][C:7]=12
Reactant: O=N[O-]
Reactant: Cc1cc(C)c(N)c(Br)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2cn[nH]c2c(Br)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-bromo-4,6-dimethylpyridin-3-amine [104829-98-3] (4.00 g, 19.9 mmol) in acetic acid (300 mL) was treated with a solution of sodium nitrite (1.37 g, 19.9 mmol) in water (2.5 mL). The reaction mixture was stirred at RT for 15 min and was then allowed to stand at ambient temperature for 24 h. An additional solution of sodium nitrite (500 mg, 7.25 mmol) in water (1 mL) was added to the mixture which was allowed to stand at RT for 16 h. Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The precipitate was filtered off, washed and discarded. The combined filtrates were washed with water and brine, then dried (Phase separator) and concentrated under vacuum to give 7-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 212 [M+H]+, tR (HPLC conditions k): 2.49 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH2:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19]O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH2:17])[C:13]([O:15][CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 2(S)-benzyloxycarbonylamino-3-aminopropionoic acid (2.4 g) in methanol at 0° C. was saturated with HCl gas. After stirring for 2 h at 20° C. the solution was evaporated to obtain the title compound. 1H NMR (300 MHz, CD3OD) δ7.35 (5H, m), 5.13 (2H, s), 4.50 (1H, m), 3.77 (3H, s), 3.45 (1H, m), 3.22 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].C1COCC1.[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[C:47](F)[CH:48]=1)[C:44]#[N:45]>CS(C)=O.O>[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([CH3:10])[C:6]=2[F:9])[CH:48]=1)[C:44]#[N:45]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Temperature: 125 °C
Yield: 62.8 %

Procedure:
6-chloro-2-fluoro-3-methylphenol (8.03 g, 50.0 mmol) and 18-crown-6 (7.7 g, 29.1 mmol) were dissolved in dry DMSO (100 mL) and treated with 20% potassium t-butoxide in THF (28.1 g, 50.0 mmol) for 15 minutes at room temperature. 3-bromo-5-fluorobenzonitrile (10 g, 50.0 mmol) was added in one portion and the reaction mixture heated at 125° C. for 20 h at which time LC-MS indicated >90% conversion. The reaction mixture was cooled to ambient temperature and water was added to afford the crude product as a black precipitate which was filtered off, washed with water and air dried. The crude product was dissolved in DCM, dried over MgSO4, and filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized by addition of IPA (100 mL). The precipitate was cooled in an ice bath and filtered to afford 3-bromo-5-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (10.7 g, 31.4 mmol, 62.8% yield) as a tan solid in >90% purity as determined by LCMS. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.28-7.45 (m, 2H), 2.28 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6](=C=O)[C@@H:7]([C:19](=O)[NH2:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:9]([NH:8][CH:7]([C:19]#[N:20])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CCOC(=O)CC(=C=O)[C@H](NC(=O)OCc1ccccc1)C(N)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)CCC(C#N)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a suspension of 21.45 g of N-carbobenzoxy-carbonyl-L-isoglutamine ethyl ester in 200 mL of dry tetrahydrofuran kept at 0° C. to -5° C. in an ice-bath 11.82 mL of pyridine is added. To the above solution 9.84 mL of trifluoroacetic anhydride in 100 mL of tetrahydrofuran is added dropwise at such a rate that the bath temperature is maintained. The solution is stirred for 2 hours at this temperature. The solution is evaporated to dryness and the oil is dissolved in ethyl acetate. The organic layer is washed with 1.0 N hydrochloric acid and sterile water. The solution is dried and evaporated in vacuo to give an oil to give 14.8 g of ethyl γ-(N-carbobenzoxy)amino-γ-cyanobutanoate, 17.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7]1[C:11]2[CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH:27]=O)[C:17]3=[O:29])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CO>C(O)(=O)C.C(Cl)(Cl)Cl>[S:7]1[C:11]2[CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH2:27][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:17]3=[O:29])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
Morpholine (0.032 mL, 0.3699 mmol) was added to a stirred solution of 3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde (I-177b: 100 mg, 0.3082 mmol) in acetic acid (2 mL) and stirred at room temperature for 4 hours. This was followed by the addition of NaBH(OAc)3 (98 mg, 0.4624 mmol). The resulting reaction mass was stirred at room temperature for 24 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mixture was concentrated under reduced pressure, added ice, basified using saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2% methanol in chloroform) followed by preparative HPLC afforded 25 mg of the product (20.6% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@:4]([C:11]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])([CH2:7][CH:8]([F:10])[F:9])[CH2:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:41][O:42][C@H:43]1[C:48](=O)[CH2:47][CH2:46][O:45][CH2:44]1.[OH-].[Na+]>ClCCl.O>[C:23]([O:22][C:20]([N:16]1[CH2:15][C@@H:14]2[CH2:19][C@H:17]1[CH2:18][N:13]2[C:11]([C@@:4]1([CH2:7][CH:8]([F:9])[F:10])[CH2:5][CH2:6][C@@H:2]([NH:1][C@@H:48]2[C@H:43]([O:42][CH3:41])[CH2:44][O:45][CH2:46][CH2:47]2)[CH2:3]1)=[O:12])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CO[C@@H]1COCCC1=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@]1(CC(F)F)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A 0° C. solution of tert-butyl (1S,4S)-5-{[(1S,3R)-3-amino-1-(2,2-difluoroethyl)cyclopentyl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.45 g, 9.2 mmol) in dichloromethane (50 ml) was treated with sodium triacetoxyborohydride (5.34 g, 25.2 mmol) and (3R)-3-methoxytetrahydro-4H-pyran-4-one (2.31 g, 17.8 mmol). The reaction was stirred under nitrogen at 0° C. for 30 minutes then allowed to warm to room temperature and stirred for 47 hours. The reaction was treated with 2.5N NaOH (35 mL) and stirred for 10 minutes. The reaction was diluted with water and the layers separated. The aqueous layer was extracted twice with ethyl acetate. The dichloromethane layer was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layers were combined, washed with brine, dried over MgSO4, concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1,5-anhydro-3-{[(1R,3S)-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol (2.13 g, 47%) which was used without further purification in the next step.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:17]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccc(N(Cc2ccccc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-iodophenyl)pyrimidin-2-amine (75 mg) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and benzyl bromide (0.039 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=1/15) to obtain N-benzyl-N-(4-iodophenyl)pyrimidin-2-amine (67 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C@H:10]1[O:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:20][C@@H:21]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C@@H:10]([OH:12])[CH2:11][S:20][C@@H:21]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CO1
Reactant: CCOC(=O)[C@@H](S)CC(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@H](CC(C)C)SC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 85.1 %

Procedure:
A solution of 2.85 g (10.6 mmole) of (2R,3S) 3-(t-butoxycarbonylamino)-4-cyclohexyl-1,2-epoxybutane, 1.86 g (10.6 mmole) of ethyl (S)-2-mercapto-4-methylpentanoate, and 1.48 ml (1.07 g. 10.6 mmole) of triethylamine in 40 ml of absolute ethanol was stirred overnight at room temperature under N2. The solution was concentrated in vacuo. The residue was taken up in CH2Cl2 and washed with 0.2N HCl followed by saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered, and rotary evaporated. The residual oil was chromatographed on a column of silica gel (57×4.3 cm) packed in hexane (elution with 7:1 and then 4:1 hexane ethyl acetate). Concentration of clean product fractions yielded 4.02 g (85%) of an oil, [α]20D -63.9°, TLC in 4:1 hexane-ethyl acetate. Mass spectrum and 200 MHz NMR confirmed the structure.
Reaction SMILES: [OH2:1].[N+]([C:5]1C=C([N+]([O-])=O)C=C[C:6]=1[NH:14][C@H:15]([C:22]([OH:24])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O-])=O.C([OH:32])C1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:5]([CH2:6][NH:14][C@H:15]([C:22]([OH:24])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([OH:32])=[O:1]
Reactant: OCc1ccccc1
Reactant: O=C(O)[C@H](Cc1c[nH]cn1)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(O)CN[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.2 g of Nα -t-butoxycarbonyl-Nim -2,4-dinitrophenyl-L-histidine monohydrate, 0.62 ml of benzyl alcohol, 1.03 g of N,N'-dicyclohexylcarbodiimide and 1.53 g of 1-hydroxybenzotriazole in 20 ml of methylene chloride was stirred overnight at ambient temperature. The mixture was then filtered and the solid rinsed with methylene chloride. The filtrates were combined and concentrated under vacuum. Chromatography of the residue over silica gel (gradient 1% to 2% methanol in methylene chloride) provided 1.76 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].C1C2NC3C(=CC=CC=3)C=2C=CC=1>>[OH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: OCCCCCCCCBr
Reactant: Oc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: c1ccc2c(c1)[nH]c1ccccc12
Product: OCCCCCCCCOc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Yield: 84.3 %

Procedure:
Demethylate 3-methoxy-9-phenylcarbazole (E-4) in the same manner as in Synthesis of Carbazole Derivative 1 to obtain 3-hydroxy-9-phenylcarbazole (E-5) having a colorless needle-like form with a yield of 91.8%; etherify the thus obtained 3-hydroxy-9-phenylcarbazole having a colorless needle-like form with 8-bromooctanol in the same manner as in Synthesis of Carbazole Derivative 2 to obtain 3-(8-hydroxyoctyloxy)-9-phenyl carbazole (E-6) having a colorless needle-like form with a yield of 84.3%; tosylate, thioacetylate, and hydlolyze the thus obtained 3-(8-hydroxyoctyloxy)-9-phenyl carbazole in the same manner as in Synthesis of Carbazole Derivative 2 to obtain 3-(8-meracaptooctyloxy)-9-phenyl carbazole (E-9) (hereinafter referred to as carbazole derivative 3) having a colorless needle-like form represented by the chemical structure 9.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:27])[CH:12]([NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:13](=O)[CH3:14])[CH3:9].II.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:8]([O:10][C:11]([C:12]1[N:16]=[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[O:26][C:13]=1[CH3:14])=[O:27])[CH3:9]
Reactant: CCOC(=O)C(NC(=O)c1ccc(OC)cc1)C(C)=O
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
23.2 ml Triethylamine and a solution of 11.3 g 2-(4-methoxy-benzoylamino)-3-oxo-butyric acid ethyl ester in 200 ml dichloromethane were added sequentially to a stirred solution of 20.5 g iodine and 21.2 g triphenylphosphine in 500 ml dry dichloromethane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the resulting residue purified by flash chromatography on silica gel to obtain 6.0 g 2-(4-methoxy-phenyl)-5-methyl-oxazole-4-carboxylic acid ethyl ester as pale yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 3-(4-benzylphenyl)propanoate (S39, 320 mg, 1.19 mmol) in THF/MeOH (1/1, 10 mL) was treated with aqueous 4 N NaOH (1 mL) and stirred for 3 h at 25° C. The reaction mixture was concentrated, diluted with aqueous 1 N HCl and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated to afford S40 (260 mg, 1.08 mmol, 91%) as a white solid: 1H NMR (CDCl3, 500 MHz) 7.27-7.06 (m, 9H), 3.91 (s, 2H), 2.86 (br s, 2H), 2.59 (br s, 2H); 13C NMR (CDCl3, 100 MHz) 179.9, 141.1, 138.8, 138.4, 128.9, 128.8, 128.4, 128.2, 126.0, 41.4, 36.9, 30.7.
Reaction SMILES: C1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13](=[CH2:23])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=O)C=CC=CC=1.C(O)CC.O.[NH2:29][NH2:30]>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=3)[CH2:23][NH:30][N:29]=2)=[CH:17][CH:18]=1
Reactant: C=C(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CCCO
Product: Clc1ccc(C2=NNCC2c2ccccc2)cc1

Procedure:
In a 500 ml round bottomed flask equipped with a reflux condensor was mixed 98 g of 2-phenyl 4'-chlorophenyl acrylophenone (0.40 mole), 200 ml n-propanol, and 50 ml hydrazine monohydrate (1.0 mole). The mixture was refluxed for 1 hour, cooled slightly and 100 ml of methanol added. The resulting solution was cooled in an ice bath and the resulting solid filtered and washed twice with cold ethyl ether yielding 55 g of a white solid. mp 156°-162° C. NMR data was consistent with the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]2[N:32]=[N:33][N:34]([CH3:36])[N:35]=2)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: COc1ccc(NCc2nnn(C)n2)cc1
Product: COc1ccc(N(Cc2nnn(C)n2)[C@H]2c3cc([N+](=O)[O-])ccc3O[C@](C)(C(OC)OC)[C@@H]2O)cc1
Yield: 78 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.07 mmol) obtained in step 1 of example 2 and N-(4-methoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (417 mg, yield: 78%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1C=CC(C([O-])=O)=C[CH:9]=1.ClCCOCCO.[OH:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C([O-])c1ccc(OCCOCCO)cc1
Agent: O=C([O-])[O-]
Agent: OCCOCCCl
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCOCCOCCO)cc1

Procedure:
These compounds were synthesized by a similar method. The representative synthesis of 4-(2-(2-hydroxyethoxy)ethoxy)benzoate (3) is presented. A solution of 2-(2-chloro ethoxy)ethanol 5.338 grams (0.04 mole) in 50 ml of acetonitrile was added dropwise to a solution of methyl 4-hydroxybenzoate 5.1 grams (0.036 mole) and 23.2 grams (0.168 mole) of powdered anhydrous potassium carbonate in 300 ml of acetonitrile at 80° C. After stirring the reaction mixture under reflux for 12 hours, 250 ml of the acetonitrile was then distilled and 250 ml dichloromethane was added. The reaction mixture was filtered through CELITE® and the solid was washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 40% diethyl ether in dichloromethane yielded 7.1 g (87%). 1H-NMR (CDCl3, TMS): d=2.62 (s, 1H, --OH), 3.81-4.25 (m, 8H, --(OCH2CH2)2 --), 3.85 (s, 3H, --COOCH3), 6.9 and 7.9 (2d, 4 aromatic protons).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: COC(=O)CCCCCCBr
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 8 mg of sodium hydride, and stirred for 30 minutes at 20° C. 70 mg of 7-bromoheptanoic acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li]CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccccc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Product: Fc1ccc(N2CCN(CCc3ccccc3)CC2)cc1

Procedure:
According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and 2.22 mmol (=0.23 g=0.25 ml) of styrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (3:1) gives the product 1-(4-fluorophenyl)-4-(2-phenyl-1-ethyl)piperazine as a light-brown solid.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=2)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[N:28]3[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)NNc2ccc(F)cn2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnc3ccc(F)cn23)CC1
Reaction time: 4 h

Procedure:
Hexachloroethane (893 mg, 3.77 mmol) was added portionwise to a solution of Intermediate 7a (667 mg, 1.89 mmol), triphenylphosphine (990 mg, 3.77 mmol) and triethylamine (1.05 mL, 7.55 mmol) in dry THF (20 mL) at RT and stirred for 4 h. The resulting precipitate was filtered off and the filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give an off-white solid. This was triturated (diethyl ether) to give the title compound as a colourless solid LCMS (Method 1): Rt 2.33 min, in/z 336 [MH+].