Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B(F)(F)F.CCOCC.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>CCOCC.C([O-])([O-])=O.[Na+].[Na+].O>[CH2:30]([O:29][C:27]([CH:26]1[C:11](=[O:14])[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:13][CH2:12]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a 0° C. solution of 1-BOC-4-piperidone (20 g, 0.10 mol) in Et2O (200 mL) was added BF3.Et2O (14 mL, 0.11 mol) followed by drop-wise addition of ethyl diazoacetate (13.7 mL, 0.11 mol) over 1 h. After addition was complete, the mixture was stirred at 0° C. for 1 h. The mixture was diluted with 30% aq. Na2CO3 and water at 0° C. and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. Purification of the residue (FCC) afforded the title compound (25.6 g, 98%). 1H NMR (CDCl3): 4.25-2.03 (m, 11H), 1.47-1.45 (d, J=7.8 Hz, 9H), 1.31-1.24 (m, 3H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[C:8]1([C:14]#[C:15][C:16](OCC)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C>CCCCCC.O1CCCC1>[O:17]=[C:16]([C:15]#[C:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: COP(C)(=O)OC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C#Cc1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
N-Butyl-lithium (13.5 ml. of a 2.29 M solution in hexane) was added dropwise to a stirred solution of dimethyl methylphosphonate (3.84 g.) in anhydrous tetrahydrofuran (25 ml.) at -78° under argon. After 15 minutes, a solution of ethyl phenylpropiolate (2.5 g.) in anhydrous tetrahydrofuran (20 ml.) was added. The reaction mixture was stirred for 2 hours at -78° C., allowed to warm to ambient temperature and stirred for 18 hours, and adjusted to pH 5 by addition of glacial acetic acid. The tetrahydrofuran was evaporated at room temperature under reduced pressure and the residue was partitioned between water and diethyl ether. The diethyl ether layer was separated, washed with water and dried, and the solvent was evaporated. Chromatography of the crude product on silica gel MFC (75 g.)., eluting with diethyl ether/ethyl acetate (9:1), gave unreacted ethyl phenylpropiolate, and subsequent elution with diethyl ether/ethyl acetate (1:1), gave dimethyl 2-oxo-4-phenylbut-3-ynylphosphonate as an oil, RF = 0.28 (ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following absorptions (δ values):
Reaction SMILES: O=O.[CH2:3]([N:10]1[CH2:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:12]([C:22]([OH:24])=[O:23])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C(C2C(OC)=CC=CC=2P(C2OC=CC=2)C2OC=CC=2)=C(P(C2OC=CC=2)C2OC=CC=2)C=CC=1.[H][H]>CO>[CH2:3]([N:10]1[CH2:14][C@@H:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C@@H:12]([C:22]([OH:24])=[O:23])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Agent: COc1cccc(P(c2ccco2)c2ccco2)c1-c1c(OC)cccc1P(c1ccco1)c1ccco1
Agent: O=O
Solvent: CO
Product: O=C(O)[C@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
An autoclave was charged under argon in a glove box (O2 content<2 ppm) with 1-benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1.00 g, 3.19 mmol), [Ru(OAc)2((S)-2-furyl-MeOBIPHEP)] (9.72 mg, 0.01 mmol) (2-furyl-MeOBIPHEP=(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(di-2-furylphosphine) and methanol (30 ml). The asymmetric hydrogenation was run for 20 h at 30° C. under 40 bar of hydrogen (>95% conversion, determined by NMR). After the pressure was released, the grey suspension was evaporated to dryness to yield 1.01 g of the crude title compound. The crude product was dissolved in methanol (15 mL) and heated to reflux for 1 h. After cooling to ambient temperature it was stirred for 2 h at 0° C. The resulting suspension was filtered and dried (40° C., 15 mbar) for 2 h. affording the title compound (0.984 g, 95%, e.e. 99.8% R,R (chiral HPLC)) as white solid. MS m/e: 316.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:9])=[O:10]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
Sulfur trioxide pyridine complex (847 mg, 5.36 mmol) was added to a solution of 619 mg (1.74 mmol) 3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared according to step c of Example 1, 411 μL (3.23 mmol) of N,N-diisopropylethylamine, and 230 μL (3.0 mmol) of dimethylsulfoxide in dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 h and then quenched with 10% citric acid (20 mL). The reaction mixture was extracted with diethyl ether (3×30 mL), dried (MgSO4), and purified by flash chromatography (diethyl ether/petroleum ether (2:1 to 4:1)) to afford 289 mg (47% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ9.83 (t, 1H, J=1.4 Hz), 7.97 (dd, 1H), 7.56-7.65 (m, 2H), 7.35-7.42 (m, 1H), 6.60 (br s, 1H), 6.57 (br s, 1H), 6.49 (br s, 1H), 4.19 (t, 2H, J=6.1 Hz), 2.86 (dt, 2H, J=6, 1.4 Hz), and 2.25 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:22][N:14]4[CH2:15][CH2:16][N:17]([C:19](Cl)=[O:20])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:22][N:14]4[CH2:15][CH2:16][N:17]([C:19]([O:32][C:28]5[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:33])[F:34])[CH:27]=5)=[O:20])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Oc1cccc(OC(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 114A (26 mg, 0.081 mmol) and 3-(trifluoromethoxy)phenol (14 mg, 0.081 mmol) in anhydrous N,N-dimethylformamide (0.8 mL) was added potassium carbonate (17 mg, 0.12 mmol), and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-60% ethyl acetate in hexanes to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.89-1.01 (m, 4 H), 1.83-2.09 (m, 3 H), 2.30-2.59 (m, 3 H), 2.60-2.93 (m, 1 H), 2.97-3.38 (m, 2 H), 3.76 (dd, J=9.9, 6.7 Hz, 1 H), 4.15-4.29 (m, 1 H), 4.30-4.45 (m, 1 H), 5.38 (q, J=5.8 Hz, 1 H), 7.00-7.13 (m, 3 H), 7.37 (t, J=8.1 Hz, 1 H), 7.95 (d, J=1.2 Hz, 1 H), 8.04 (d, J=1.2 Hz, 1 H); MS (ESI) m/z 465.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([CH:35]3[CH2:38][CH2:37][CH2:36]3)[N:28]3[C:33]=2C(=O)NC=N3)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([CH:35]3[CH2:36][CH2:37][CH2:38]3)[N:28]3[C:33]=2[C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1nc[nH]n1
Reactant: O=c1[nH]cnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Nc1ncnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,4-triazole (167 mg, 2.417 mmol) in anhydrous pyridine (1.5 mL) was added phosphorous oxychloride (POCl3) (75 μL, 0.806 mmol) and stirred at rt for 15 min. To this mixture was added dropwise a solution of 5-(3-benzyloxy-phenyl)-7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (100 mg, 0.269 mmol) in anhydrous pyridine (2.5 mL) over a 3.5 min period and stirred at rt for an additional 3 h. The reaction was cooled to 0° C. and quenched with 2M NH3 in i-PrOH (10 mL ) and stirred for an additional 30 min at rt. The mixture was filtered through a fritted funnel and the filtrate was concentrated in vacuo, partitioned between CHCl3 and H2O and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined CHCl3 fractions were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 2% MEOH in CHCl3] resulting in a dark brown oil which was crystallized from EtOAc/hexanes to obtain the title compound as a light tan solid. 1H NMR (CDCl3, 400 MHz) δ 1.95-2.08 (m, 1H), 2.09-2.22 (m, 1H), 2.39-2.50 (m, 2H), 2.59-2.72 (m, 2H), 4.14 (quint, J=8.4 Hz, 1H), 5.16 (s, 2H), 5.57 (brs, 2H), 7.02-7.09 (m, 1H), 7.22-7.28 (m, 3H), 7.31-7.50 (m, 5H), 7.85 (s, 1H); MS (ES+): m/z 372.1 (100) [MH+]; HPLC: tR=3.05 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].Br[CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.C(OCC)(=O)C>CN(C)C=O>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: BrCC1OCCO1
Reactant: O=c1ccc2ccncc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2ccncc2n1CC1OCCO1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a suspension of 6.0 g of 1,7-naphthyridin-2(1H)-one in 60 mL of N,N-dimethylformamide, 2.5 g of 60% sodium hydride was added at room temperature, and the mixture was stirred at 50 to 60° C. for 1 hour. Thereto was added 6.4 mL of 2-bromomethyl-1,3-dioxolan, the temperature was increased to 90 to 95° C., and the reaction mixture was stirred for 2 hours 30 minutes. The temperature was further increased to 95 to 100° C., and the mixture was stirred for 4 hours. Thereto were added 0.82 g of 60% sodium hydride and 2.1 mL of 2-bromomethyl-1,3-dioxolan and the mixture was further stirred at the same temperature for 2 hours. Thereto were added 0.49 g of 60% sodium hydride and 1.3 mL of 2-bromomethyl-1,3-dioxolan and the mixture was stirred at 90 to 100° C. for 2 hours. Thereto were further added 0.49 g of 60% sodium hydride and 1.3 mL of 2-bromomethyl-1,3-dioxolan and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was cooled to 5° C., and ethyl acetate and ice water were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 0:100 and then, using gradient elution with chloroform:methanol=100:0 to 90:10 to obtain 3.1 g of 1-(1,3-dioxolan-2-ylmethyl)-1,7-naphthyridin-2(1H)-one as a brown solid.
Reaction SMILES: C(OC(=O)C[C:6]([CH2:8][CH2:9][CH:10]=[CH2:11])=[O:7])C.[CH3:13][CH:14]([NH:23][NH2:24])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.[CH2:25](O)[CH3:26]>>[CH3:25][C:26]1[NH:24][N:23]([CH:14]([CH3:13])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:6](=[O:7])[C:8]=1[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCC(=O)CC(=O)OCC
Reactant: CC(NN)c1ccc(Cl)c(Cl)c1
Reactant: CCO
Product: C=CCc1c(C)[nH]n(C(C)c2ccc(Cl)c(Cl)c2)c1=O

Procedure:
17 g (0.1 mol) of allylacetoacetic acid ethyl ester were added to a mixture of 20.5 g of α-methyl-3,4-dichorobenzylhydrazine and 30 ml of absolute ethanol under nitrogen, whereupon the temperature rose to 55° C. The reaction mixture was heated to the reflux temperature for 2 hours. After cooling, the reaction product crystallized out
Reaction SMILES: C([N:5]1[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:14])[C:8]=2[C:7]([C:15]2[CH:16]=[C:17]([C:20]([NH2:22])=[O:21])[S:18][CH:19]=2)=[N:6]1)(C)(C)C>FC(F)(F)C(O)=O.O>[O:14]=[C:9]1[C:8]2[C:7]([C:15]3[CH:16]=[C:17]([C:20]([NH2:22])=[O:21])[S:18][CH:19]=3)=[N:6][NH:5][C:13]=2[CH:12]=[CH:11][NH:10]1
Reactant: CC(C)(C)n1nc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)c1cc(-c2n[nH]c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
4-(1-tert-Butyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (475 mg) obtained in Example 129 was dissolved in a mixed solvent of trifluoroacetic acid (60 mL)/water (6 mL), and the mixture was heated with reflux at 24 hr. The reaction mixture was allowed to be cooled to room temperature, and concentrated under reduced pressure. The residue was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was crystallized from DMF-ethyl acetate, and dried in vacuum to give the title compound (240 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CC(O)(C)C.C(OCC)C>[CH:2]([C@@H:3]1[CH2:5][C@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:1]
Reactant: CN(C[C@]1(c2ccccc2)C[C@H]1CO)S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CN(C[C@]1(c2ccccc2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Yield: 68.1 %

Procedure:
N-{[(1R,2R)-2-(hydroxymethyl)-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide (600 mg, 1.82 mmol), accessed via the method of preparation 7B, was dissolved in 18 mL DCM with 270 uL 2-methylpropan-2-ol and treated with Dess-Martin Periodinane (1.23 g, 2.90 mmol, 1.6 eq) at ambient temperature for 16 h. The reaction mixture was diluted with 42 mL diethyl ether and treated with 22 mL 1N NaOH at ambient temperature for 15 min. The organic phase was separated, the aqueous phase extracted twice with diethyl ether, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted successively with DCM, EtOAc/hexanes (1:4)) to the title product (410 mg, 1.24 mmol, 69%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J=6.7 Hz, 1H), 7.65 (m, 2H), 7.55 (m, 1H), 7.47 (m, 2H), 7.31-7.23 (m, 5H), 3.50 (d, J=14.3 Hz, 1H), 3.09 (d, J=14.3 Hz, 1H), 2.52 (s, 3H), 2.15-2.08 (m, 1H), 1.93 (m, 1H), 1.76-1.73 (m, 1H).
Reaction SMILES: ClC1C=C(C=C(F)C=1)N[C:6]1[C:15]2[C:10](=CC(F)=C([N+]([O-])=O)[CH:14]=2)N=CN=1.N1(CCCO)CCOCC1.[C:34]([OH:38])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:15]([CH3:14])([CH3:6])[CH3:10])([CH3:37])([CH3:36])[CH3:35]
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(F)cc(Cl)c3)ncnc2cc1F
Reactant: CC(C)(C)O
Agent: OCCCN1CCOCC1
Product: CC(C)(C)OC(C)(C)C

Procedure:
This reaction was all the more surprising since the tert.-butyl alcohol present in the reaction mixture does not react with (V) in an analogous manner to the 3-morpholin-4-yl-propan-1 -ol (VI) to give the corresponding tert.-butyl ether.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[C:11]=2[C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:25]=[CH:24][C:23]=2[CH3:36])=[CH:6][CH:5]=1.B(Cl)(Cl)Cl.CO>ClCCCl>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[C:11]=2[C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[CH:25]=[CH:24][C:23]=2[CH3:36])=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2-c2cc(OCCN3CCCC3)ccc2C)cc1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: Cc1ccc(OCCN2CCCC2)cc1-c1c(-c2ccc(O)cc2)ccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a solution of the product of Example 18 (1.61 g, 2.60 mmol) in 1,2-dichloroethane (30 mL) stirring at 0° C. was added boron trichloride (10 ml, 117 mmol). The resulting dark purple solution was stirred overnight at ambient temperature in a sealed tube. After cooling the solution to 0° C., methanol (25 mL) was carefully added over a period of 30 minutes (caution, gas evolution). The solution was subsequently concentrated and the resulting material dissolved in 30% isopropanol/chloroform then washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by radial chromatography (methanol/chloroform gradient) to give 0.34 g (27%) of the desired product as a white foam: 1H-NMR (300 MHz, DMSO-d6) δ9.45 (s, 1H), 9.36 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.00-7.10 (m, 2H), 6.80-6.90 (m, 2H), 6.70-6.80 (m, 4H), 5.45 (s, 1H), 4.84 (s, 1H), 4.25 (s, 2H), 3.90-4.05 (m, 2H), 2.75-2.90 (m, 2H), 2.50-2.65 (m, 4H), 1.60-1.80 (m, 4H); 13C-NMR (75 MHz, DMSO-d6) δ203.32, 191.97, 188.16, 186.14, 185.95, 177.43, 173.46, 169.60, 167.74, 163.48, 162.30, 159.87, 158.14, 154.98, 152.43, 60.50, 56.25, 54.00, 45.05, 41.00, 37.50, 35.00, 30.05, 27.50, 26.00, 22.50, 20.00; Anal. Calc'd. for: C, 79.24; H, 6.65; N, 3.19. Found: C, 78.99; H, 6.51; N, 2.92; MS (FD) m/e 440 (M+); IR (KBr) 3382.61, 2964.00, 1610.77, 1509.49 cm−1.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH2:15]([N:7]1[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]1[CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CNCCN1Cc1ccccc1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
tert-Butyl (3S)-3-methylpiperazine-1-carboxylate (380.0 g, 1.897 mol) and benzyl bromide (248 mL, 2.09 mol) were mixed in acetonitrile (440 mL). Triethylamine (300.0 mL, 2.152 mol) was carefully added and the mixture was refluxed overnight. After the mixture was cooled down to room temperature, the solid was filtered out. The filtrate was concentrated. The residue was combined with the solid and dissolved in methylene chloride. The methylene chloride solution was washed with 1N NaOH and dried over magnesium sulfate. After the solvent was removed, the residue was directly treated with 6 N HCl at 0° C., and 3 hours later, the solution was basified by slowly adding solid sodium hydroxide. The resulting mixture was extracted with methylene chloride and the extracts were dried over magnesium sulfate. After removal of the solvent, 330 g (91.4%) of product was obtained. The product was used directly for next step. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.30 (m, 5H), 4.05 (d, 1H), 3.15 (d, 1H), 2.92 (m, 1H), 2.83 (m, 2H), 2.67 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.36 (bs, 2H), 2.06 (m, 1H), 1.14 (d, 3H). MS (EI) 191.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[S:8].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:8][N:11]2[C:10](=[N:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=32)[N:9]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)c1cnccn1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)nc1nc(-c3cnccn3)sn12
Reaction time: 15 h

Procedure:
To 0.51 g. of 2-(2-pyrazinylthiocarbonylamino)-benzimidazole [(IV), R = 2-pyrazinyl] in 200 ml. of chloroform at 20°-30° C. (room temperature) is added 0.5 g. of m-chloroperbenzoic acid. The reaction mixture is allowed to stand for 15 hours (overnight) and washed with 20 ml. of potassium bicarbonate solution, 20 ml. of water and dried over magnesium sulfate. The chloroform is evaporated and the residue is recrystallized from methanolchloroform to yield 2-(2-pyrazinyl)-1,2,4-thiadiazolo-[2,3-a]-benzimidazole [(I), R = 2-pyrazinyl].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N=[N+]=[N-])C.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20]>CC#N>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CCN=[N+]=[N-]
Solvent: CC#N
Product: CN(C)CCNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-5-nitropyridine 106-A and EtN3 (4.7 g, 46.5 mmol) in CH3CN (150 ml) was added N,N-dimethylethlenediamine 106-B (4.1 g, 46.5 mmol). The solution was stirred at room temperature for 3 hours, extracted with EtOAc, washed (brine), dried(MgSO4) and concentrated to give N,N-dimethyl-N′-(5-nitropyridin-2-yl)ethane-1,2-diamine 106-C (5.2 g) as a yellow solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[CH2:36][OH:37])[CH2:27][CH2:26]1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH2:35][CH2:34][CH2:33][C@@H:32]4[CH2:36][OH:37])[CH2:29][CH2:30]3)=[O:21])=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OC[C@H]1CCCN1C1CCNCC1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Agent: Cl
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 2, 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazole-4-carboxylic acid (intermediate 1) and ((R)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol di-hydrochloride (intermediate 2) gave the title compound as light red amorphous solid. MS: 579.3 (MH+).