Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:18])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1
Reactant: CN1CCN(Cc2ccc(O)cc2F)CC1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2F)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 44.5 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.50 g, 11.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 29B (1.3 g, 5.8 mmol) in DMF (25 mL) was added drop-wise over 10 minutes. The mixture was stirred for 20 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.7 g, 6.9 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. for six days and then cooled to RT. Water and some aqueous NaOH was added and the mixture was extracted three times with EtOAc. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 0.98 g (45%) of 29C as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.28 (s, 3H), 2.28-2.72 (bm, 8H), 3.52 (s, 2H), 3.91-4.03 (m, 2H), 4.22-4.33 (m, 2H), 4.76-4.89 (m, 1H), 6.39-6.52 (m, 2H), 7.19-7.28 (m, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH2:13][CH2:14][CH:15]2[N:20]3[CH2:21][CH2:22][CH:17]([C:18](=[O:23])[CH2:19]3)[CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C.C1COCC1>[C:7]1([CH2:13][CH2:14][CH:15]2[N:20]3[CH2:21][CH2:22][CH:17]([CH:18]([OH:23])[CH2:19]3)[CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CN2CCC1CC2CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1CN2CCC1CC2CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of LAH in diethyl ether was added a solution of 6-(2-phenylethyl)quinuclidin-3-one in THF, followed by heating under reflux for 4 hours. To the reaction mixture was added Na2SO4.10H2O, followed by stirring at room temperature for overnight. The reaction mixture was filtered, and the filtrate was then concentrated under reduced pressure to obtain 6-(2-phenylethyl)quinuclidin-3-ol as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4OCC[O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@:25]2(C3[C:34](=CC4OCCOC=4C=3)[O:33][CH2:32]2)[C:24]1=O.BrCC[CH2:48][O:49][CH3:50].BrCCCCC>>[CH3:34][O:33][CH2:32][CH2:25][CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[CH2:50][O:49][CH2:48][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: COCCCBr
Solvent: CCCCCBr
Product: COCCCN1C(=O)C2(COc3cc4c(cc32)OCOC4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 1-bromo-3-methoxypropane to replace 1-bromopentane, 1′-(3-methoxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (71%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.30-6.93 (m, 4H), 6.46 (s, 1H), 6.18 (s, 1H), 4.72 (ABq, 2H), 4.19-4.04 (m, 4H), 3.94-3.72 (m, 2H), 3.41 (t, J=5.9 Hz, 2H), 3.30 (s, 3H), 2.01-1.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.3, 155.2, 144.5, 142.5, 138.2, 132.4, 128.8, 123.8, 123.1, 121.1, 111.4, 108.5, 99.3, 80.0, 69.7, 64.5, 63.9, 58.7, 57.9, 37.6, 27.8; MS (ES+) m/z 367.9 (M+1).
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[CH:10][CH:9]=1.[C:21]1(=O)[CH2:24][CH2:23][CH2:22]1>>[C:5]([C:21]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[CH:12][CH:13]=2)[CH2:24][CH2:23][CH2:22]1)#[N:6]
Reactant: O=C1CCC1
Reactant: CNC(=O)CCCc1ccc(N)cc1
Reactant: C[Si](C)(C)C#N
Product: CNC(=O)CCCc1ccc(NC2(C#N)CCC2)cc1
Yield: 66.6 %

Procedure:
TMSCN (0.09 mL, 0.70 mmol) was added to a mixture of the compound 30 (90 mg, 0.47 mmol), cyclobutanone (0.05 mL, 0.70 mmol) and 12 (6 mg, 0.05 mmol) with stirring. The reaction mixture was stirred at room temperature for 10 min, and concentrated in vacuo. The residue was diluted with aq Na2SO3, and extracted with DCM. The combined organic layers were washed with aq Na2SO3 and brine, dried over Na2SO4 and concentrated. The residue was purified with silica gel column chromatography using Petroleum ether:Ethyl acetate (10:1) affording to compound 39 (85 mg, 67%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ6.98 (d, 2H, J=8.4 Hz), 6.56 (d, 2H, J=8.4 Hz), 5.39 (br s, 1H), 2.66-2.76 (m, 5H), 2.50 (t, 2H, J=8.4 Hz), 2.28-2.40 (m, 2H), 2.10-2.22 (m, 2H), 2.08 (t, 2H, J=8.4 Hz), 1.80-1.90 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[C:18]([NH:32][CH2:33][CH2:34][CH2:35]O)=[N:19][C:20]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)=[N:21][CH:22]=1.O.C(OCC)(=O)C>C(Cl)Cl.COCCN(S(F)(F)F)CCOC>[N:32]1([C:18]2[C:17]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])=[CH:22][N:21]=[C:20]([NH:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[N:19]=2)[CH2:33][CH2:34][CH2:35]1
Reactant: N#Cc1ccc(Nc2ncc(C#CCCCN3C(=O)c4ccccc4C3=O)c(NCCCO)n2)cc1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(Nc2ncc(C#CCCCN3C(=O)c4ccccc4C3=O)c(N3CCC3)n2)cc1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a suspension of 4-((5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)-4-((3-hydroxypropyl)amino)pyrimidin-2-yl)amino)benzonitrile (J15, 51 mg) in methylene chloride (1 mL), bis(2-methoxyethyl)aminosulfur trifluoride (188 μL) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, water and ethyl acetate were added. The solid matter was taken by filtration, washed successively with water and ethyl acetate, and then dried under reduced pressure to obtain 4-((4-(azetidin-1-yl)-5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)pyrimidin-2-yl)amino)benzonitrile (J16, 48 mg) as pale yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:3]1[CH:14]=[CH:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.[BH4-].[Na+].C(O)(=O)C(O)=O>CCO.O.O>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:3]1[CH:14]=[CH:15][CH:16]([OH:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCC(=O)C=CC1=C(CCC(=O)OC)C(=O)CC1O
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCCCCC(O)C=CC1=C(CCC(=O)OC)C(=O)CC1O

Procedure:
Methyl 3-[3-hydroxy-5-oxo-2-(3-oxodec-1-enyl)cyclopent-1-enyl]propanoate (2.1g.) was dissolved in EtOH/H2O 9:1 (30ml.) and chilled in an ice bath. Triethylamine (0.95ml.) was added followed by sodium borohydride (0.24g.) dissolved in water (2ml.). The reaction mixture was stirred for fifteen minutes and then water was added, followed by dilute oxalic acid solution to adjust the pH to 5. Ethyl acetate extraction, washing and drying of the extract followed by evaporation gave an oil. This was chromatographed on silicic acid, using as an eluent: MeOH/CHCl3. The appropriate fractions containing the major component were combined and evaporated to dryness (~800mg.oil). This was rechromatographed using a similar column. In this way, pure Methyl 3-[3-hydroxy-5-oxo-2-(3-hydroxydec-1-enyl)cyclopent-1-enyl]propanoate was obtained. Spectroscopic data was in full accord with the expected structure of the final product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[CH:23]=O)=[C:5]([CH3:25])[O:4][N:3]=1.Cl.[NH2:27][OH:28].N1C=CC=CC=1.Cl>C(O)C.C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[CH:23]=[N:27][OH:28])=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: NO
Reactant: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C=NO
Temperature: 150 °C

Procedure:
The semi-crude 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde from step (d) was mixed with hydroxylamine hydrochloride (200 mg, 2.89 mmol) and pyridine (0.3 mL, 3.71 mmol) in dry ethanol (3 mL) and heated at 150° C. for 10 minutes in the microwave. 1 M HCl and CH2Cl2 were added and the phases were separated. The oxime was purified on preparative IIPLC, to give 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime (13 mg, 0.037 mmol).
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[NH:11]([C:15]1[S:19][N:18]=[C:17]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])[N:16]=1)[C:12]([NH2:14])=[NH:13].[NH3:25]>>[NH2:25][C:3]1[C:7]([NH:24][CH2:23][CH2:22][S:21][CH2:20][C:17]2[N:16]=[C:15]([NH:11][C:12]([NH2:14])=[NH:13])[S:19][N:18]=2)=[N:6][S:5](=[O:10])[N:4]=1
Reactant: N=C(N)Nc1nc(CSCCN)ns1
Reactant: COC1=NS(=O)N=C1OC
Reactant: N
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)N=C2N)ns1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide is successively treated with an equimolar amount of 2-[(5-guanidino-1,2,4-thiadiazol-3-yl)methylthio]ethylamine and excess ammonia, the title compound is thereby produced.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[Na+].[C:29]([C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33])#[N:30]>>[C:29]([C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH:33][C:2]1([C:26]#[N:27])[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:6][CH2:7]1)#[N:30]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: N#Cc1ccccc1N
Reactant: [C-]#N
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4ccccc4C#N)CC3)c(F)c2)C(=O)O1
Yield: 47 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 2-cyanoaniline the compound was obtained in 47% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:7]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1nc2ccc(Br)cn2n1
Product: CS(=O)(=O)c1ccc(-c2ccc3nc(N)nn3c2)cc1

Procedure:
6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (200.0 mg, 0.9388 mmol) and (4-methylsulfonylphenyl)boronic acid (210.0 mg, 1.050 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.158 g, 58%). MP=301-303° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.08-9.05 (m, 1H), 8.06-7.97 (m, 4H), 7.86 (dd, J=9.2, 1.7 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 6.15 (s, 2H), 3.26 (s, 3H). MS=289 (MH)+.
Reaction SMILES: Cl[S:2]([O:5][Si](C)(C)C)(=[O:4])=[O:3].[CH3:10][N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[Sn](CCCC)(CCCC)CCCC.C(=O)([O-])O.[Na+:33]>C(Cl)(Cl)(Cl)Cl>[OH2:3].[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([S:2]([O-:5])(=[O:4])=[O:3])=[CH:12]1.[Na+:33]
Reactant: C[Si](C)(C)OS(=O)(=O)Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1ccc(S(=O)(=O)[O-])c1
Product: O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under an argon gas atmosphere, a solution of 9.44 g (50 mmol) of trimethylsilyl chlorosulfonate in 50 ml of carbon tetrachloride was gradually added under stirring to a solution of 18.5 g (50 mmol) of 1-methyl-2-tri-n-butylstannylpyrrole in 150 ml of carbon tetrachloride, followed by stirring at 50° C. for 30 minutes and further at room temperature for 30 minutes. To the reaction mixture, 300 ml of a saturated aqueous solution of sodium hydrogencarbonate were added, followed by stirring at room temperature for 20 minutes. The reaction mixture was allowed to separate into two layers. The water layer was collected and then washed with ethyl ether (100 ml×3 times). From the water layer, water was distilled off under reduced pressure, followed by the addition of ethanol to the residue. The resulting mixture was boiled and then subjected to hot filtration. The solvent in the filtrate was distilled off under reduced pressure, and the thus-obtained solid was washed with n-pentane (200 ml×2 times) and then dried under reduced pressure. Colorless powdery crystals (6.67 g) were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[N:13]=2)=[N:6][CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C1COCC1>[NH2:21][C:14]1[N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:5]2[N:4]=[C:3]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:2]([NH:1][C:30](=[O:32])[CH3:31])=[CH:7][N:6]=2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine and 1 mmol of acetic anhydride were stirred at room temperature for four hours in THF. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 5-10% methanol/methylene chloride.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH:14](=O)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:7][C:3]1[CH:2]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCC=O
Reactant: Nc1cccc(-c2ccccc2)c1
Product: CCCCNc1cccc(-c2ccccc2)c1
Yield: 90.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, biphenyl-3-amine (500 mg, 2.95 mmol) and butyraldehyde (265 μL, 2.95 mmol) were converted to the title compound (600 mg, 83%). 1H NMR (CDCl3) δ 7.65-7.57 (m, 2H), 7.55-7.41 (m, 2H), 7.40-7.32 (m, 1H), 7.31-7.23 (m, 1H), 6.99-6.90 (m, 1H), 6.85 (t, J=2.0 Hz, 1H), 6.64 (ddd, J=8.0, 2.4, 0.9 Hz, 1H), 3.78 (br s, 1H), 3.21 (t, J=7.2 Hz, 2H), 1.75-1.59 (m, 2H), 1.54-1.44 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 226.1 (M+H)+.
Reaction SMILES: [C:1]([C:8]1[NH:9][CH:10]=CN=1)([C:3]1[NH:4][CH:5]=[CH:6]N=1)=S.NC1C=CN=CC=1.[NH:20]([C:22](=[O:43])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)=[O:24])[NH2:21].CCN=C=NCCCN(C)C>CC(N(C)C)=O.O>[N:4]1[CH:3]=[CH:1][C:8]([NH:9][C:10]2[O:43][C:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C@H:32]4[CH2:37][CH2:36][C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[O:24])=[N:20][N:21]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccncc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccncc4)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thiocarbonyl diimidazole (190 mg, 1.06 mmol) was added in one portion to a solution of 4-aminopyridine (100 mg, 1.06 mmol) in DMA (8 mL) and the solution was stirred at room temperature for 3 h. Methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)cyclohexyl]-acetate (Intermediate 43, 284 mg, 0.85 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 30 minutes and then heated at 80° C. for 10 minutes in the microwave. The solution was cooled to room temperature and EDCI (205 mg, 1.06 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 20 minutes in the microwave. The reaction mixture was cooled to room temperature and poured into water (200 mL). The mixture was filtered and the resulting solid was recrystallised (CH3CN) to give the title compound (93 mg, 20%) as a solid; 1H NMR δ 1.15 (2H, t), 1.42-1.51 (2H, m), 1.74-1.82 (5H, m), 2.24-2.26 (2H, d), 3.61 (3H, s), 7.23 (2H, d), 7.54-7.55 (2H, m), 7.69-7.71 (2H, m), 8.43 (2H, s) MS m/e MH+ 436.
Reaction SMILES: C([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C@@H:16]2[C:26]3([CH2:28][CH2:27]3)[C@H:25]3[C@@H:18]([O:19][Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)[O:23][CH2:24]3)[C@@H:17]2[F:41])[C:10]1=[O:42])(=O)C1C=CC=CC=1>CO.N.C(O)(C(F)(F)F)=O.O>[F:41][C@H:17]1[C@H:18]([OH:19])[C@@H:25]([CH2:24][OH:23])[C:26]2([CH2:27][CH2:28]2)[C@H:16]1[N:11]1[CH:12]=[CH:13][C:14](=[O:15])[NH:9][C:10]1=[O:42]
Reactant: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@H](F)[C@H](n1ccc(=O)n(C(=O)c3ccccc3)c1=O)C21CC1
Agent: N
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccn([C@H]2[C@@H](F)[C@H](O)[C@@H](CO)C23CC3)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 28 (0.2 g, 0.32 mmol) was dissolved in saturated MeOH with NH3 (20 mL) and stirred for 8 h at room temperature. The solvent was evaporated under vacuum and the residue was purified by silica gel vacuum column (35% EtOAc/hexane) to give the debenzolated compound. Debenzoylated compound was dissolved in 10 mL of CF3COOH/H2O (2:1, v/v) and heated to 50° C. for 3 h. The solvent was removed under vacuum and the residue was co-evaporated with ethanol (3×10 mL) under vacuum. The residue was purified by combiflash chromatography (7% MeOH/CH2Cl2) to give 29 in 60 mg (68%) as white foam. [α]24D 5.4° (c 0.67, MeOH); 1H NMR (500 MHz, DMSO-d6) δ 11.17 (bs, 1 H), 7.68 (d, J=15.6, 1 H), 5.80 (d, J=19.7, 1H), 5.67 (d, J=14.5 Hz, 1 H), 4.74-4.78 (bs, 2 H, —OH), 4.70 (m, 1H), 4.10-4.13 (bm, 1 H, —OH), 3.32-3.43 (m, 2 H), 2.1-2.08 (m, 1 H), 0.69-0.74 (m, 1 H), 0.49-0.56 (m, 2 H), 0.43 (m, 1 H); 13C NMR (500 MHz, MeOH-d4) δ 164.9, 161.4, 152.3, 140.2, 109.6, 76.0, 74.0, 60.2, 51.4, 21.1, 14.7, 11.0, 7.3; HR-MS Cald. For (C12H15FN2O4+H)+ 270.16, found 270.1226.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)cc1
Product: O=C(Cl)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
On the other hand, 4-fluorobenzoic acid (0.01 mol) (1.4 g) was reacted with thionyl chloride (10 ml) at 60° C. for 30 minutes and then at 80° C. for 2 hours to obtain a uniform solution, which was then allowed to stand for one hour, followed by distilling off excess thionyl chloride to obtain 4-fluorobenzoyl chloride as residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:18][C@@H:19]([CH3:31])[CH2:20][C@H:21]([CH3:30])[O:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[Cl:18][C@@H:19]([CH3:31])[CH2:20][C@H:21]([CH3:30])[O:22][C:23]1[CH:28]=[CH:27][C:26]([O:14][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(O)cc1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(=O)Oc3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1

Procedure:
0.50 g of 4-(4'-methoxyphenyl)benzoic acid, 0.44 g of (S,S)-4-(3'-chloro-1'-methylbutoxy)phenol, 0.45 g of dicyclohexylcarbodiimide, 0.05 g of 4-pyrrolidino-pyridine and 20 ml of methylene chloride were stirred together at room temperature for five hours. The crude product obtained in the same manner as the one described in Example 8 was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (85:15) as a developing solvent and recrystallized from ethyl slcohol to thereby give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[C:6]1[N:7]=[N:8][NH:9][N:10]=1.[C:35](=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.S(OC)(OC)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([C:31]([F:34])([F:32])[F:33])=[CH:26][C:3]=1[CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([C:22]([F:23])([F:24])[F:25])[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1)[C:6]1[N:7]=[N:8][N:9]([CH3:35])[N:10]=1
Reactant: Cc1cc(Br)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: Cc1cc(Br)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 97.7 %

Procedure:
To a solution of N-(2-bromo-4-methyl-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine (76 mg, 0.135 mmol) in anhydrous THF (5 mL) was added sodium carbonate (28 mg, 0.270 mmol) and N,N-dimethylformamide (1 mL) followed by dimethyl sulfate (34 mg. 0.270 mmol). The solution was heated to 70° C. for 18 hours then the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL) and the combined organics were washed with water (3×20 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (76 mg, 97.5%). 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H) 7.62 (s, 2H) 7.44(s, 1H) 7.40(s, 1H) 4.79(s, 2H) 4.76(s, 2H) 4.20(s, 3H) 2.39(s, 3H). LC-MS calc. 576 found 577 (M+H)
Reaction SMILES: [ClH:1].[Cl-].[CH3:3][N+:4]([CH3:22])([CH2:11][CH2:12][N:13]([CH2:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][NH:8]C=O>>[Cl-:1].[CH3:22][N+:4]([CH3:3])([CH2:11][CH2:12][N:13]([CH2:20][CH3:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: Cl
Reactant: CCN(CC[N+](C)(C)CCCNC=O)c1ccccc1
Agent: [Cl-]
Product: CCN(CC[N+](C)(C)CCCN)c1ccccc1

Procedure:
Dilute hydrochloric acid hydrolysis of N,N-dimethyl-N-2-(N'-ethylanilino)ethyl-N-3-formamidopropylammonium chloride following a procedure similar to that of B-4 above gives N,N-dimethyl-N-2-(N'-ethylanilino)ethyl-N-3-aminopropylammonium chloride.