Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[C:11](=[O:12])[N:10]2[CH:5]1[CH2:6][CH2:7][O:8]C2(C)C)=[N+:2]=[N-:3].O>FC(F)(F)C(O)=O>[N:1]([CH:4]1[CH:5]([CH2:6][CH2:7][OH:8])[NH:10][C:11]1=[O:12])=[N+:2]=[N-:3]
Reactant: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NC1C(=O)NC1CCO

Procedure:
7-Azido-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]-octane (0.2 mol) is dissolved in 2:1 trifluoroacetic acid --H2O (200 ml) and the solution is kept at room temperature (25° C.) for 10 minutes. The solution is concentration under vacuum to a syrup which is taken up in ethylacetate, washed with 5% sodium bicarbonate and brine, dried with sodium sulfate, and filtered. Evaporation of the solvent provides 3-azido-4-(2-hydroxyethyl)-azetidin-2-one.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:5]1)(=[O:22])=[O:21]
Reactant: O=C(c1coc(N2CC(O)C2)n1)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCOCC3)co2)C1
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
To a solution of 3-hydroxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (370 mg, 1.48 mmol) (obtained as described in Reference Example 72(2)) in methylene chloride (19 ml) were added methanesulfonyl chloride (344 μl, 4.44 mmol) and triethylamine (622 μl, 4.44 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium chloride, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (93:7) as the eluant to afford 3-methanesulfonyloxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (404 mg, yield 100%) as pale yellow crystals.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH2:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:14][CH2:13]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Reaction time: 0.25 h
Yield: 77 %

Procedure:
Triethylamine (17 ml) was added dropwise to a solution of benzyl 4-hydroxy-1-piperidinecarboxylate (28.83 g) in dichloromethane (100 ml) at 0° C. and stirred for 15 minutes. Benzenesulfonyl chloride (14 ml) was added and the reaction allowed to stir at room temperature for 48 h. The mixture was washed with water (50 ml), saturated sodium bicarbonate solution (50 ml), water (50 ml) and brine (50 ml) then dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by chromatography (SiO2, 20% ethyl acetate in hexane to 30% ethyl acetate in hexane) to give the title compound (31.88 g, 77%) as a white crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([N:19]([CH3:30])[CH:20]4[CH2:29][CH2:28][C:23]5([CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[CH:16]=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([N:19]([CH3:30])[CH:20]4[CH2:29][CH2:28][C:23]5([CH2:27][N:26]([C:34](=[O:35])[CH2:33][C:31]#[N:32])[CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[CH:16]=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: N#CCC(=O)O
Reactant: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CCNC5)CC4)n3)cc2nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CC4)CCN(C(=O)CC#N)C5)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of N2-(2,3-dimethyl-2H-indazol-6-yl)-N4-methyl-N4-(2-azaspiro[4.5]decan-8-yl)pyrimidine-2,4-diamine (300 mg, 0.74 mmol), 2-cyanoacetic acid (156 mg, 1.83 mmol) in a mixture of DCM and DMF (4/1 (v/v), 35 mL) were added HATU (925.8 mg, 2.44 mmol) and Et3N (0.49 g, 4.84 mmol). After addition, the reaction mixture was stirred at rt for 0.5 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), and dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as a beige solid (210 mg, 60.0%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([CH3:13])[C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[NH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:31][CH:32]([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([O:6][P:4]([CH:9]([CH3:13])[C:10]([NH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:31][CH:32]([CH3:33])[CH3:34])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: CCOP(=O)(OCC)C(C)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)C(C)P(=O)(OCC)OCC)c1)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
643 mg of 2-diethylphosphonopropionic acid and 973 mg of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropionate were dissolved in 10 ml N,N-dimethylformamide, and 470 μl diethyl cyanophosphonate and 1.07 ml triethylamine were successively added thereto. The mixture was stirred overnight at room temperature, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 1.310 g of ethyl 3-[3-([2-(diethoxyphosphoryl)propanoyl]aminomethyl)-4-methoxyphenyl]-2-isopropoxypropionate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH2:19]([N:26]([CH3:33])[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]([CH:27]1[CH2:28][CH2:29][N:30]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]=3[CH:10]=2)[CH2:31][CH2:32]1)[CH3:33])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(Cc1ccccc1)C1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: CN(Cc1ccccc1)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde was reacted with benzyl-methyl-piperidin-4-yl-amine (hydrochloride salt) using the general reductive amination procedure to yield benzyl-[1-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-methyl-amine, which was reacted with 2-aminopyrimidine-5-boronic acid, pinacol ester in General Procedure A. Purification on silica yielded 396. NMR (CDCl3); 1.65-1.73 (2H, m), 1.79-1.83 (2H, m), 2.05-2.09 (2H, m), 2.20 (3H, s), 2.45-2.47 (1H, m); 3.02 (2H, d), 3.60 (2H, s), 3.78 (2H, s), 3.85-3.89 (4H, m), 3.92-3.96 (4H, m), 5.23 (2H, s, br.), 7.12 (1H, s), 7.23-7.24 (1H, m), 7.31-7.33 (4H, m), 9.30 (2H, s). MS ESI m/z 531 (MH+, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:43]=[CH:42][NH:41][N:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>C1COCC1.CCOC(C)=O>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:43]=[CH:42][N:41]([C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:12][CH3:13])[N:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COc1ccc(-c2cc[nH]n2)cc1OC
Reactant: COC(C(=O)O)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccn(C(=O)C(OC)c3ccc(F)cc3)n2)cc1OC
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-methoxyacetic acid (0.11 g, 0.61 mmol) in anhydrous THF (2 mL) at room temperature was added DCC (0.14 g, 0.67 mmol) in one portion. After stirring for 10 min, 3-(3,4-dimethoxyphenyl)-1H-pyrazole (0.14 g, 0.67 mmol) was added in one portion. After 48 hrs, the reaction mixture was diluted with EtOAc and the solids removed via filtration. The filtrate was concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexanes) gave the product as an oil (0.12 g, 46% yield). MS: m/z 371.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1.O>[OH:2][CH2:1][CH2:3][NH:4][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=1)(=[O:22])=[O:21]
Reactant: NCCO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 3.5 mL (3.54 g, 58 mmol) of ethanolamine in 20 mL of THF and 5 mL of water, was added 10.7 mL of triethylamine. After cooling in an ice bath, 10.53 g (51 mmol) of para-methoxybenzenesulfonyl chloride was slowly added over ten minutes. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure and ethyl acetate and water added. The organic layer was separated, washed with 5% KHSO4 and brine, dried over sodium sulfate, filtered and stripped to afford 10.3 g of the desired N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide, m/e=238 (M+Li).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[CH2:18][CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11]1.CCN(C(C)C)C(C)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>CC#N.C(O)CCC>[C:41]([N:38]1[CH2:37][CH2:36][N:35]([C:32]2[CH:33]=[CH:34][C:29]([NH:28][C:2]3[N:7]=[C:6]([N:10]4[CH2:18][CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11]4)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:39]1)(=[O:43])[CH3:42]
Reactant: NC(=O)C1CCCNC1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCCC(C(N)=O)C4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (167 mg, 1.00 mmol), nipecotamide (128 mg, 1.00 mmol) and DIEA (0.350 mL, 2.01 mmol) in CH3CN (4 mL) was stirred at room temperature for 20 h. It was concentrated in vacuo. The residue was dissolved in nBuOH (4 mL). 2 mL of the nBuOH solution was taken, to which 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (150 mg, 0.68 mmol) was added. The solution was stirred at 116° C. for 6 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (75 mg). MS 442.4 (M+H); UV 208.8, 261.8 nm.
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]3=[O:14].O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]>CN(C)C=O>[CH3:30][CH:29]([CH3:31])[CH2:28][CH2:27][N:9]1[C:10]2[C:6](=[C:5]3[S:1][CH:2]=[N:3][C:4]3=[CH:12][CH:11]=2)[C:7](=[O:14])[C:8]1=[O:13]
Reactant: CC(C)CCBr
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCN1C(=O)C(=O)c2c1ccc1ncsc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a stirred solution of 6H-thiazolo[5,4-e]indole-7,8-dione (2.83 g, 13.9 mmol) in a mixture of anhydrous tetrahydrofuran (120 mL) and N,N-dimethylformamide (80 mL) was added cesium carbonate (23.0 g, 70 mmol) at ambient temperature. The deep purple mixture was stirred for 0.5 h followed by the addition of 1-bromo-3-methylbutane (4.15 mL, 35.0 mmol) in one portion. The mixture was stirred at ambient temperature for 16 h and poured into 800 mL of ice-water and extracted with ethyl acetate. The orange solution was filtered through Celite, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was triturated with diethyl ether to afford 6-(3-methylbutyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione (2.2 g, 57%): 1H NMR (300 MHz, CDCl3) δ9.36 (s, 1H), 8.38 (d, J=8.6 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 3.77-3.69 (m, 2H), 1.74-1.58 (m, 1H), 1.57-1.47 (m, 2H), 0.94 (d, J=6.5 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[C:14]1([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:1])([F:12])[F:13])=[C:4]2[C:8]([O:10][CH3:11])=[O:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(C(F)(F)F)ccn1-c1ccccc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (810 mg, 4.19 mmol, 1.00 equiv), phenylboronic acid (1.54 g, 12.63 mmol, 3.01 equiv), Cu(OAc)2 (1.52 g, 8.37 mmol, 2.00 equiv), pyridine (1.327 g, 16.78 mmol, 4.00 equiv), 4 {acute over (Å)} Molecular Sieves (1.2 g) and dichloromethane (20.0 mL). The resulting solution was stirred for 2 days at 20° C. The reaction progress was monitored by LCMS. The solids were filtered out and the resulting mixture was concentrated under vacuum. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield methyl 1-phenyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate as a pink solid (0.67 g, 59%)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][CH2:22][CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][CH2:22][CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCO)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-aminoethanol (CAS 141-43-5) (36 mg, 0.6 mmol), HATU (141 mg, 0.36 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide 16. LC/MS (ESI+): m/z 309 (M+H). 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.64 (t, J=5.5 Hz, 1H), 8.60 (d, J=7.9 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.17 (t, J=12.9 Hz, 1H), 8.07 (d, J=24.4 Hz, 2H), 7.98 (d, J=7.7 Hz, 1H), 7.68-7.56 (m, 1H), 4.76 (t, J=5.6 Hz, 1H), 3.57 (q, J=6.0 Hz, 2H), 3.41 (q, J=6.0 Hz, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:7]1[C:24]([OH:26])=O)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[OH:36][NH2:37].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[OH:36][NH:37][C:24]([CH:7]1[CH:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:26]
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)O)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
To a solution of 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid (107 mg, 0.28 mmoL) in 5.6 mL dichloromethane was added N,N-Diisopropyl ethyamine (0.195 mL, 1.12 mmoL). This solution was cooled to 0° C. and Hydroxyl amine (58.4 mg, 0.84 mmoL) was added followed by PyBroP (155 mg, 0333 mmoL). The reaction was warmed to ambient temperature after 15 minutes and was stopped after 5.5 hours. The residue was diluted with ethyl acetate and washed sequentially with 0.5N HCl, and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica: 0.5% to 1.5% methanol in dichloromethane) to yield Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzene sulfonyl)-azepan-3-ylmethyl ester; MS: (M-H)- =399.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:28]=3[Cl:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(Cl)cc1Cl

Procedure:
The title compound, light yellow solid (88 mg, 70%), MS (ISP) m/z=499.3 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2,4-dichloro-benzoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]2[N:18]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:16]=3[N:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:27]1[C:16]2[N:15]=[C:14]([C@@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[N:18]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:17]=2[CH:24]=[CH:25][CH:26]=1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2c(Cl)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c([C@@H]2CCCNC2)nc2c(Cl)cccc21

Procedure:
(R)-tert-Butyl3-(4-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (0.245 mmol, 0.100 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hr. The reaction was then concentrated and dried in-vacuo affording (R)-4-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (48A) as a light brown oil that was used without further purification. ESI-MS: m/z 308.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23](C)[N:22]=3)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].[C:29](Cl)(=[O:31])[CH3:30].CCN(C(C)C)C(C)C.C(Cl)[Cl:43]>>[CH2:1]([O:3][C:4]([N:6]1[CH:7]2[CH2:13][CH2:12][CH:11]1[CH2:10][CH:9]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]([C:29](=[O:31])[CH3:30])[C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([Cl:43])[N:22]=3)[CH2:18][CH2:19]1)[CH2:8]2)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(Nc3cc(C)nc(C)n3)CC1)C2
Reactant: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1C2CCC1CC(N1CCC(N(C(C)=O)c3cc(C)nc(Cl)n3)CC1)C2
Temperature: 80 °C
Reaction time: 14 h

Procedure:
3-[4-(2,6-Dimethyl-pyrimidin-4-ylamino)piperidin-1-yl]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (20 mg; 0.05 mmol; 1 eq.) was dissolved in DCM (3 mL) and acetyl chloride (9.5 mg; 2.5 eq.) and DIEA (9.5 mg; 1.5 eq.) was added and the reaction was stirred overnight (approx. 14 hours) at 80° C. under N2. The solution was diluted with DCM (10 mL) and washed with saturated NaHCO3 (2×20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under high vacuum to provide the product as an oil (18 mg). The crude residue was purified by reversed-phase HPLC (2-99% CH3CN/water gradient with 0.05% TFA). M+1=450.2, Retention time=1.81 minutes; 10-99% CH3CN/H2O gradient with 0.05% TFA.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:2].[Cl:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12]>CO>[Cl-:8].[OH:13][CH:10]([CH2:11][OH:12])[CH2:9][N+:5]1[CH:6]=[CH:7][N:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCn1ccnc1
Reactant: OCC(O)CCl
Solvent: CO
Product: CCn1cc[n+](CC(O)CO)c1
Product: [Cl-]
Reaction time: 48 h
Yield: 94.5 %

Procedure:
1-Ethylimidazole (2.40 g, 25.0 mmol) and 3-chloro-1,2-propanediol (2.76 g, 25.0 mmol) were stirred in a 130° C. oil bath for 48 h, after which the flask was placed under vacuum and stirring continued at 130° C. for another 48 h. The residue was then dissolved in CH3OH, transferred to a tared flask and concentrated to afford the product as a viscous brown oil (4.88 g, 94%). 1H NMR: δH ppm (400 MHz; DMSO-d6) 1.41 (t, J=7.24 Hz, 3H) 3.23 (dd, J=11.17, 6.96 Hz, 1H) 3.37-3.47 (m, 1H) 3.70-3.86 (m, 1H) 4.11 (dd, J=13.74, 7.69 Hz, 1H) 4.22 (q, J=7.33 Hz, 2H) 4.33 (dd, J=13.74, 3.11 Hz, 1H) 5.19 (br. s., 1H) 5.59 (br. s., 1H) 7.78 (t, J=1.74 Hz, 1H) 7.85 (t, J=1.74 Hz, 1H) 9.33 (t, J=1.56 Hz, 1H).
Reaction SMILES: Cl[C:2](=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[N:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.[CH3:15]CN(CC)CC>C(Cl)Cl>[O:7]=[C:2]([NH:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1)[CH2:3][C:4]([O:6][CH3:15])=[O:5]
Reactant: Nc1ccncc1
Reactant: O=C([O-])CC(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
A mixture of 3-chloro-3-oxopropanoate (1 mL, 9.32 mmol), pyridin-4-amine (0.88 g, 9.32 mmol), and Et3N (1.3 mL, 9.32 mmol) in DCM (18.6 mL) was stirred for 2 h at room temperature. The mixture was concentrated and the residue was purified by flash chromatography (eluent EtOAc/MeOH, 19/1) to produce methyl 3-oxo-3-(pyridin-4-ylamino)propanoate (507.7 mg). Part of this material (207 mg) was re dissolved in THF (1 mL); treated with LiOH×H2O (90 mg, 2.14 mmol) in H2O (1 mL) for 1 h at room temperature. The THF was removed under reduced pressure and the residue was lyophilized to afford the title compound 33 (containing 1 equivalent LiCl) (243.1 mg, 100% yield) as a white solid, which was used in the next step without further purification. MS (m/z): 181.0 (M+H).