Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH:9]2[C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[NH:3][CH:2]=1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32]>C1COCC1>[CH2:32]([N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:9]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:10][CH2:11][CH2:12][CH:13]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=[CH:2]1)[CH:31]=[CH2:30]
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cnc[nH]1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1cnc(CCN2C(c3ncccc3C)CCCC2c2ncccc2C)c1
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
To a solution of 1′-[2-(3H-imidazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (202 mg, 0.56 mmol) in THF (5 mL) at 0° C. was added NaH (60%, 8 mg, 0.21 mmol). After 30 min at 0° C., allyl bromide (16 mL, 0.19 mmol) was added. After 4 h, the reaction mixture was concentrated to afford an orange solid. Purification by radial chromatography on silica gel (2 mm plate; using CH2Cl2/CH3OH/NH4OH; 50:1:1→10:1:1) afforded the product as a pale yellow oil (25 mg, 33%). 1H NMR (CDCl3) δ 1.58-1.73 (m, 3H), 1.95-2.08 (m, 3H), 2.38-2.48 (m, 8H), 2.93 (s, 2H), 4.14 (d, 2H, J=9.0 Hz), 4.27 (d, 2H, J=6.0 Hz), 5.02 (d, 1H, J=18.0 Hz), 5.16 (d, 1H, J=9.0 Hz), 5.71-5.84 (m, 1H), 5.96 (s, 1H), 7.06 (dd, 2H, J=6.0, 3.0 Hz), 7.12 (s, 1H), 7.40 (d, 2H, J=9.0 Hz), 8.46 (s, 2H). 13C NMR (CDCl3) δ 19.21, 23.68, 25.45, 30.08, 31.94, 49.56, 62.43, 114.86, 118.69, 122.07, 131.27, 133.15, 136.13, 138.79, 141.84, 147.25, 160.74. ES-MS m/z 402 [M+H]+. Anal. Calcd. for C25H31N5.1.5H2O: C, 70.06; H, 8.00; N, 16.34. Found: C, 70.19; H, 7.98; N, 16.05.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]1[CH2:25][OH:26].C(N(C(C)C)CC)(C)C>CS(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:22]3[CH2:23][CH2:24][NH:19][C@@H:20]([CH2:25][OH:26])[CH2:21]3)=[N:3][N:4]=2)=[CH:13][CH:14]=1
Reactant: OC[C@H]1CNCCN1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: OC[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1
Yield: 83.4 %

Procedure:
Dissolve 1-chloro-4-(4-fluorophenyl)phthalazine (0.1 g, 0.39 mmol), (R)-piperazin-2-ylmethanol (0.07 g, 0.58 mmol) and diisopropylethylamine (0.34 mL, 1.93 mmol) in DMSO (1 mL). Stir the reaction at 120° C. for 64 h. Purify the reaction mixture by flash silica gel chromatography (0-10% 2 M ammonia/MeOH in CH2Cl2) to yield the title compound as a brown solid (0.11 g, 84%). ES/MS m/z 339.0 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br.O>CO>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C)c(S(N)(=O)=O)c1
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)CBr)cc1S(N)(=O)=O
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
21.3 Grams (0.1 M) of 5-acetyl-2-methylbenzenesulfonamide was dissolved in 180 g of methanol, while the resulting solution was kept at 35°-40° C., 16.0 g (0.1 M) of bromine was added dropwise by taking 1.5 hours. The reaction mixture was stirred for 10 minutes after the dropwise addition, 80 g of water was added to the reaction mixture and the whole reaction mixture was stirred for further 30 minutes at room temperature. A part of methanolwater was removed by evaporation, then the crystals formed were collected by filtration, washed with water and dried to obtain 28.0 g of 5-bromoacetyl-2-methylbenzenesulfonamide in the form of white crystals. Melting point: 146.5°-147.5° C Yield: 95.9%.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18]O.[OH-].[Na+]>CO>[C:1]1([CH:7]2[O:18][C:8]2([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: CC(=O)C(=Cc1ccccc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)C1(c2ccncc2)OC1c1ccccc1
Yield: 20 %

Procedure:
Using the procedure of Example A-1, step 2, a solution of 4-phenyl-3-(4-pyridyl)-3-butene-2-one (step 2) (1.25 g, 5.6 mmol) in methanol (20 ml) was treated with 30% aqueous hydrogen peroxide (1 ml) in the presence of sodium hydroxide (230 mg, 5.7 mmol). The crude product was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) to give 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (270 mg, 20%).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][OH:18])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: OCc1ccccc1B(O)O
Product: Nc1ncc(-c2ccccc2CO)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-(hydroxymethyl)-benzeneboronic acid gives “A63”; method 1: HPLC/MS: 1.07 min, [M+H]=321;
Reaction SMILES: C(O[CH:4]([O:8][CH2:9][CH3:10])[O:5]CC)C.C(OC(=O)C)(=O)C.[F:18][C:19]([F:32])([C:28]([F:31])([F:30])[F:29])[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=O>>[CH2:9]([O:8][C:4](=[O:5])[C:21](=[CH:22][O:24][CH2:25][CH3:26])[C:20](=[O:27])[C:19]([F:18])([F:32])[C:28]([F:29])([F:30])[F:31])[CH3:10]
Reactant: CCOC(=O)CC(=O)C(F)(F)C(F)(F)F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(F)(F)C(F)(F)F
Temperature: 135 °C
Reaction time: 2 h

Procedure:
A sealable vial was charged with triethylorthoformate (1.07 mL, 6.41 mmol), acetic anhydride (3.22 mL, 34.2 mmol) and ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (0.747 mL, 4.27 mmol), and the resulting mixture was capped and stirred at 135° C. After 2 h, the reaction mixture was allowed to cool to room temperature, and the volatiles were removed in vacuo to provide the title compound as a mixture of olefin isomers, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][NH2:19])=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].C(O)(=O)C>CO>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][N:19]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[CH3:10])=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: NOCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(CO)cc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NOCc1ccc(Cl)c(C(F)(F)F)c1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(4-hydroxymethyl-phenyl)-ethanone (1 eq) in methanol is added O-(4-chloro-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 5 hours. After concentrated, the residue is purified by column chromatography (30% EtOAc in hexane) to give 1-(4-hydroxymethyl-phenyl)-ethanone O-(4-chloro-3-trifluoromethyl-benzyl)-oxime as an oil [MS: (ES+) 358.1 (M+1)+].
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[S:16]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OCCOS(C)(=O)=O
Reaction time: 2 h

Procedure:
Alternately, combine 2-isopropoxyethanol (5.0 g, 48 mmol) and dichloromethane (50 mL). Cool in an ice bath. Add triethylamine (10.7 g, 105 mmol). Add dropwise methanesulfonyl chloride (1.43 g, 9.6 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with 1 M hydrochloric acid solution, a saturated aqueous solution of sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Distill the residue at reduced pressure to give 2-(isopropoxy)ethyl mesylate.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN.[C:17]([BH3-])#[N:18].[Na+]>CO.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][CH3:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Amine preparation: To a solution of 1-BOC-4-piperidone (1.0 g) in MeOH (10 mL) was added a solution of freshly prepared methylamine in MeOH (1.0 mL). The reaction mixture was stirred for 1 h and then sodium cyanoborohydride (0.315 g) was added. After stirring for 24 h the reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (0.85 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7].[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[N+:17]([C:10]1[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-:19])=[O:18]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC)c(OC)c(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Methyl 3,4,5-trimethoxybenzoate (13.0 g) was dissolved in acetic anhydride (60 mL), a 1:20 mixed liquid (9 mL) of fuming nitric acid and concentrated nitric acid was slowly added dropwise at −10° C. to the solution, and the resultant mixture was stirred for 3 hours under ice cooling. Acetic anhydride was distilled off, water and an aqueous solution of potassium carbonate were added to the residue, and the mixture was stirred at room temperature for 40 minutes and then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([CH:20]=[N:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1C(=O)N([Br:40])C(=O)C1>CN(C=O)C.O>[Br:40][C:20]1[N:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:2])=[O:3])[C:15]=3[N:16]=[CH:17][C:18]2=[C:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=2)[N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)ncn23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc(Br)n23)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
2-(4-(6-Tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.285 g, 0.638 mmol, prepared using J.3 from Example #2, Step B with ethyl formate, L.2 with POCl3, AB and D with Preparation #H.1) was dissolved in DMF (3 mL) then treated with NBS (0.114 g, 0.638 mmol). The mixture was stirred for about 15 min then diluted with water (20 mL). The solid was collected by filtration then washed with water (5 mL). The material was dried under vacuum at about 70° C. to a constant weight to give 2-(4-(1-bromo-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.285 g, 85%): LC/MS (Table 2, Method b) Rt=2.58 min; MS m/z 527 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:13]2[C:8]([C:9]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[CH:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:13]2[C:8]([C:9]([CH2:31][C:32]([OH:34])=[O:33])=[CH:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of biphenyl indolizinyl tert-butyl ester (0.039 mmol, the title compound of Example 1949) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 1950.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(F)cc3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(F)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-fluoro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.O(C)[Na].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.C1COCC1>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH2:2][CH2:1][OH:12])[CH:11]=[CH:10][C:8]=1[O:9][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(CCO)ccc1O
Reactant: BrCCCCc1ccccc1
Agent: CO[Na]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CCO)ccc1OCCCCc1ccccc1

Procedure:
To a solution of homovanillyl alcohol (10 g, 59.3 mmol) in dry methanol (140 ml), there is added 12 ml of 1N NaOCH3 in methanol. After addition of a solution of 1-bromo-4-phenylbutane (12.6 g, 59.3 mmol) in THF (10 ml) the reaction mixture is kept at reflux for 3 hours. After cooling the reaction is quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate (2 times, 500 ml each). The organic layer is dried over MgSO4 and the solvent is removed by evaporation. The crude residue is then purified on silica gel using ethyl acetate/n-hexane (1/1) as mobile phase.
Reaction SMILES: [CH2:1]([C@@:8]1([O:41][C@H:40]([CH2:42][OH:43])[C@@H:38]([OH:39])[C@H:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@@H:22]([C:35](=[O:37])[NH2:36])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:20])[CH3:18])=[O:15])[C@H:10]1[NH:44][C:45](=[O:47])[CH3:46])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](OC(=O)C)(=[O:50])[CH3:49].CO>N1C=CC=CC=1>[CH2:1]([C@@:8]1([O:41][C@H:40]([CH2:42][O:43][C:48](=[O:50])[CH3:49])[C@@H:38]([OH:39])[C@H:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@@H:22]([C:35](=[O:37])[NH2:36])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:20])[CH3:18])=[O:15])[C@H:10]1[NH:44][C:45](=[O:47])[CH3:46])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N[C@@H]1[C@@H](OCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)[C@H](O)[C@@H](CO)O[C@@]1(O)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1[C@@H](OCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)[C@H](O)[C@@H](COC(C)=O)O[C@@]1(O)Cc1ccccc1

Procedure:
A solution of 0.33 g of benzyl (benzyl 2-acetamido-2-deoxy-α-D-glucopyranosid-3-O-yl)acetyl-L-alanyl-D-isoglutaminate (12A, n = 2, X1 = L-alanyl, R2 = CH3) in 5 ml of pyridine is stirred at 0° whilst a solution of 0.095 ml of acetic anhydride in 1 ml of pyridine is added dropwise over 30 minutes. The resultant solution is stored at 0° C for 16 hours at which time 1 ml of methanol is added and the mixture is evaporated to dryness. The residue thus obtained is partitioned between 100 ml of chloroform and 100 ml of water, the chloroform phase is dried over magnesium sulfate and concentrated in vacuo, giving 0.36 g of crude product which is purified by preparative thick-layer chromatography giving benzyl (benzyl 2-acetamido-6-O-acetyl-2-deoxy-α-D-glucopyranosid-3-O-yl)acetyl-L-alanyl-D-isoglutamine (12F, n = 2, X1 =L-alanyl, R2 = CH3, R3 = --COCH3).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:10][CH2:11][N:12]([CH2:38][CH2:39][NH2:40])[CH2:13][CH2:14][N:15]([CH2:35][CH2:36][NH2:37])[CH2:16][CH2:17][N:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:50]([OH:52])[CH3:51]>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[C:45]([O:44][C:42]([CH2:41][N:9]([CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:11][N:12]([CH2:38][CH2:39][N:40]([CH2:19][CH2:20][OH:21])[CH2:8][CH2:6][OH:7])[CH2:13][CH2:14][N:15]([CH2:35][CH2:36][N:37]([CH2:2][CH2:1][OH:5])[CH2:51][CH2:50][OH:52])[CH2:16][CH2:17][N:18]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)CN(CCN(CCN)CCN(CCN)CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CC(O)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CCN(CCN(CCO)CCO)CCN(CCN(CCO)CCO)CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C

Procedure:
N,N,N"',N"'-tetra(t-butyloxycarbonylmethyl)-N',N"-di(2-aminoethyl)-triethylenetetramine is dissolved in acetonitrile with an excess of potassium carbonate, and a solution of bromoethanol (3 equivalents) in acetonitrile is added dropwise with stirring; the solution is then heated to reflux for 18 hours. The reaction mixture is then filtered and the filtrate evaporated to dryness to give N,N,N"',N"'-tetra(t-butyloxycarbonylmethyl)-N',N"-di(N,N-bis(2-hydroxyethyl)-2-aminoethyl)-triethylenetetramine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-])[CH:7]=1.CS([Cl:16])(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([Cl:16])=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: [O-][n+]1cc(Br)cc2nc[nH]c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c(Br)cnc2[nH]cnc12
Temperature: 73 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
6-Bromo-3H-imidazo[4,5-b]pyridine 4-oxide (1.88 g, 8.82 mmol) in N,N-dimethylformamide (12 mL) was heated to 50° C., mixed with methansulfonyl chloride (8.00 mL, 103 mmol) and stirred at 73° C. for 3 hours. The reaction mixture was cooled with ice and gradually poured into saturated aqueous sodium hydrogen carbonate (75 mL), and the precipitated solid was collected by filtration, washed with water and chloroform and dried under reduced pressure to give the title compound as a dark brown solid (1.07 g, yield 52%).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:13]=[C:12]([NH2:14])[C:10](=[O:11])[NH:9][CH:8]=2)=[CH:5][CH:4]=[N:3][CH:2]=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[O:11]=[C:10]1[NH:9][CH:8]=[C:7]([C:6]2[CH:1]=[CH:2][N:3]=[CH:4][CH:5]=2)[CH:13]=[C:12]1[NH:14][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(-c2ccncc2)c[nH]c1=O
Solvent: c1ccncc1
Product: O=c1[nH]cc(-c2ccncc2)cc1NS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 57.6 %

Procedure:
Amrinone (100 mg, 0.53 mmol) was suspended in pyridine (2 mL) and benzenesulfonyl chloride (75 μL, 0.59 mmol) was added dropwise at 0° C. The reaction mixture was stirred for 2 hours. The pyridine was removed in vacuo. MeOH was added to the crude mixture and the solid was filtered and rinsed with more MeOH to give the title compound as a light yellow solid (100 mg, 57% yield). MS (ES+) m/e=328. 1H NMR (DMSO-d6) δH 7.51 (2H, dd), 7.54-7.58 (2H, m), 7.61-7.65 (1H, m), 7.75 (2H, dd), 7.90 (2H, dd), 8.56 (2H, dd), 9.78 (1H, br s), 12.33 (1H, br s).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCOCC.CCCCC>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)cn1
Reactant: C1CC2=[N+](C1)CCC2
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1ccc(C23CCCN2CCC3)cn1
Temperature: -95 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
5-Iodo-2-methylpyridine (345 mg, 1.39 mmol) was dissolved in Et2O and cooled to -95° C. A solution of 2.5M t-BuLi (1.7M in pentane, 1.8 mL, 3.06 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (435 mg, 2.1 mmol) was added, and the reaction mixture was allowed to warm to -10° C. with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 95:5) to afford the title compound as an oil (126 mg, 45%): 1H NMR (CDCl3, 300 MHz) δ1.57-1.71 (m, 2H), 1.77-2.05 (m, 6H), 2.52 (s, 3H), 2.64-2.72 (m, 2H), 3.12-3.19 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 7.71 (dd, J=8.1, 2.6 Hz, 1H), 8.56 (d, J=2.6 Hz, 1H); MS (CI/NH3) m/z: 203 (M+H)+.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH2:13](Cl)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].[OH-].[Na+]>CN(C)C=O>[CH3:16]/[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:13][S:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 110 %

Procedure:
To a suspension of sodium hydride (NaH) (0.69 g, 30 mmol) in dimethylformamide (DMF) (100 mL) was added 2-mercaptobenzimidazole (4.5 g, 10 mmol) in DMF (20 mL) at 0° C. under N2. To the resultant solution was added geranyl chloride (5.16 g, 10 mmol) over 30 minutes. The reaction was stirred for five hours at ambient temperature under N2 then treated with 2N NaOH and extracted with diethyl ether (Et2O). The Et2O extract was washed with saturated NaCl, concentrated in vacuo, dissolved in methylene chloride, and dried over Na2SO4. Recrystallization from Et2O gave white crystalline 2-[(3,7-dimethyl-2,6(E)-octadienyl)-thio]-1H-1,3-benzimidazole (3.15 g, 36.6%). m.p. 98°-100° C. NMR (CDCl3):δ7.4(m, 2H), 7.1(m, 2H) 5.3(t,J=8 Hz, 1H) 5.0(m 1H) , 3.90(d, J= 10 Hz, 2H , 2.00(m, 4H), 1.65(m, 9H).