Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=CC=CN=2)CCCC1.Cl[C:38]([O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:39]>N1C=CC=CC=1>[CH2:41]([O:40][C:38]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])=[O:39])[CH2:42][CH2:43][CH3:44]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reactant: CCCCOC(=O)Cl
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
The crude 3-(4-imidazol- 1 -ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide from step (f) above was dissolved in pyridine (2 mL, dried over 4 Å molecular sieve). Pyrrolidinopyridine (40.52 mg, 0.2618 mmol) and butyl chloroformate (363.5 mg, 0.339 mL) were added to the mixture. The mixture was stirred overnight under a N2 atmosphere at room temperature. Evaporation and co-evaporation with acetonitrile to remove the solvents and purification on column chromatography with 10% MeOH in chloroform as eluent gave the title compound (57.8 mg, 0.1217 mmol) in a 46.5% yield (over the last two steps).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.[C:9](=O)([O:15]C1C=CC=CC=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]>CCO>[C:11]([O:10][C:9](=[O:15])[NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: NC1CCC(N)CC1
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reaction time: 2.5 h

Procedure:
To a 3 L 3-neck RB flask equipped with a mechanical stirrer, condenser with N2 inlet and temperature probe is added 1,4-diaminocylcohexane P1 (152.2 g, 1332.9 mmol), EtOH (1 L) and t-butyl phenyl carbonate (250 mL, 1351.5 mmol). The reaction mixture is wrapped with Al foil and heated using a heating mantle (JKem temperature controller >2 L setting, Tset=100° C.). A brown solution is obtained and an internal temperature of 73.8° C. is recorded after 2.5 h. After heating for 18 h the now heterogeneous reaction mixture is allowed too cool. The mixture is filtered to remove bis-Boc protected amine, which precipitated as a white solid. The filtrate is concentrated in vacuo to a thick peach colored syrup. The mixture is transferred to an Erlenmeyer flask and the transfer is completed with CH2Cl2 (50 mL). To the mixture H2O (100 mL) is added (pH=9) followed by concentrated HCl (180 mL to pH=2) resulting in the precipitation of the (4-aminocyclohexyl)carbamic acid tert-butyl ester as a hydrochloride salt. The mixture is swirled vigorously until a thick slurry is obtained. Additional CH2Cl2 is added to maximize the amount of precipitate and the slurry is filtered (additional product is obtained from this filtrate #1, as described below). The solid is washed with Et2O (1.4 L). To free-base the HCl salt H2O (500 mL) is added followed by NaOH (2.5N, to pH=12). The mixture is extracted with CH2Cl2 (3×). The combined organic extracts are washed with H2O (3×400 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give (4-aminocyclohexyl)carbamic acid tert-butyl ester P2a (92.89 g) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1.Cl[C:21]1[CH:26]=[CH:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])=[C:29]([O:39][CH3:40])[CH:28]=2)[C:23](=[O:41])[CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])=[C:29]([O:39][CH3:40])[CH:28]=3)[C:23](=[O:41])[CH:22]=2)=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-n2ccc(-c3ccc(OC(F)F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 100 °C
Reaction time: 16 h
Yield: 36.7 %

Procedure:
A mixture of 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Part A (62.6 mg, 0.23 mmol), 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part D of Procedure 9 (50 mg, 0.15 mmol), Potassium phosphate tribasic (65.6 mg, 0.31 mmol), Palladium (II) acetate (1.7 mg, 7.7 μmol), and 2-DICYCLOHEXYLPHOSPHINO-2′,6′-DIMETHOXY-1,1′-BIPHENYL (3.1 mg, 7.72 μmol) in Toluene (1.4 mL) and Water (0.15 mL) was stirred at 100° C. for 16 h. The mixture was filtered, diluted with EtOAc, washed with sat. NaHCO3, dired (MgSO4), and concentrated. The crude was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA to afford 4-(4-(difluoromethoxy)phenyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one B-9 (26.26 mg, 0.057 mmol, 36.7% yield) as a white solid. LC/MS 432 (M+H)+, tR 0.87 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63 (2H, d), 7.42 (1H, d, J=7.04 Hz), 7.24 (2H, d, J=8.58 Hz), 6.95-7.03 (2H, m), 6.90-6.93 (1H, m), 6.86 (1H, s), 6.48 (1H, d, J=7.26 Hz), 6.40-6.78 (1H, m), 3.88 (3H, s), 3.87 (2H, s), 1.37 (6H, s)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:19]=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc2c1cc(CO)n2Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cccc2c1cc(C=O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 113.1 %

Procedure:
A mixture of 3.2 g of N-benzyl-2-hydroxymethyl-4-methoxyindole (12 mmol) and 15 g of manganese dioxide (172 mmol) in 50 cc of dry dichloromethane was heated at reflux for 6 hours, cooled down to r.t. and filtered through celite. Concentration to dryness afford 3.6 g of a yellow solid. mp.130-31° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1.O[CH2:12][C@@H:13]([N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[S:6][C:5]([N:7]([CH2:12][C@@H:13]([N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CO)Cc1ccccc1
Reactant: CC(=O)Nc1ncc(Br)s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ncc(Br)s1
Reaction time: 0.25 h
Yield: 17 %

Procedure:
N-(5-Bromo-thiazol-2-yl)-acetamide) (442.0 mg, 2.0 mmol), (S)-2-(1-hydroxy-3-phenylpropan-2-yl)isoindoline-1,3-dione (281.0 mg, 1.0 mmol), triphenylphosphine (303.0 mg, 1.5 mmol) and THF (15.0 mL) were charged into a 100 mL round bottom flask. The resulting reaction mixture was a suspension. The flask was immersed in an ice-water bath. After stirring for 15 minutes under nitrogen, a solution of DIAD (421.5 mg, 1.5 mmol) in 3.0 mL THF was slowly added to the flask through a syringe. The reaction mixture became a clear solution after the addition was complete. After 10 minutes, the reaction mixture was brought to room temperature by removing the ice water bath and the stirring was continued for 16 hours. THF was evaporated off, and the residue was diluted with 40 mL saturated sodium bicarbonate and extracted with DCM (75 mL×2). The residue was subjected to a silica gel column chromatography purification with hexane-EtOAc (7:3) as the eluant to afford a compound as a white solid (S)-N-(5-bromothiazol-2-yl)-N-(2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropyl)acetamide (20 mg, yield 17%). LCMS (API-ES) m/z (%): 484.0 (100%, M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][OH:23].C([O-])([O-])=O.[Cs+].[Cs+].CCCCCC.C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:23][CH2:22][CH2:21][O:20][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccc(F)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COCCOc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 25 mL 3-neck RBF equipped with reflux condenser and thermo pocket were charged 2-(benzyloxy)-1-fluoro-4-nitrobenzene (3.3 g), 2-methoxy ethanol (16.0 mL) and Cs2CO3 (8.67 g). The reaction mixture was heated at 80° C. for 2 hr. The reaction was monitored on TLC using hexane:ethyl acetate (5:5) as mobile phase. The reaction was complete after 2 hr. After completion, the reaction mixture was cooled to room temperature and poured into cold water. Solid precipitate was filtered and washed with water. Solid was dried under reduced pressure. The obtained 3.90 g of solid 2-(benzyloxy)-1-(2-methoxyethoxy)-4-nitrobenzene was taken onto the next step without further purification. 1H NMR: DMSO-d6 (400 MHz): 3.34 (s, 3H), 3.722-3.700 (t, 2H, J=4.4), 4.269-4.291 (t, 2H, J=4.4), 5.256 (s, 2H), 7.216-7.239 (d, 1H, J=9.2), 7.328-7.364 (m, 1H), 7.393-7.430 (m, 2H), 7.471 (s, 1H), 7.489 (s, 1H), 7.849-7.855 (d, 1H, J=2.4), 7.889-7.971 (dd, 1H, J=2.4, 6.4).
Reaction SMILES: C([O:5][C@H:6]1[CH2:18][N:9]2[C@@H:10](C(Cl)(Cl)Cl)[O:11][C:12](=[O:13])[C@:8]2([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)[CH2:7]1)(C)(C)C.Cl>CO.C(OCC)C>[Br:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@@:8]2([C:12]([O:11][CH3:10])=[O:13])[CH2:7][C@@H:6]([OH:5])[CH2:18][NH:9]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)O[C@H]1CN2[C@@H](C(Cl)(Cl)Cl)OC(=O)[C@]2(Cc2ccc(Br)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@]1(Cc2ccc(Br)cc2)C[C@@H](O)CN1
Yield: 65.7 %

Procedure:
To a suspension of (3R,6R,7aS)-6-tert-butoxy-7a-(4-Bromo-benzyl)-3-(trichloromethyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one (0.4 g) (Prep. 2) in 10 mL of MeOH was added 1 mL of dry HCl in ethyl ether, and the resulting solution was refluxed for 13 hrs. The MeOH was evaporated, and the residue dissolved in DCM and washed with aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure to afford the above-titled compound (0.170 g). 1H NMR (CDCl3): 7.40 (2H,d), 7.05 (2H,d), 4.25 (1H, m), 3.65 (3H,s), 3.15 (1H,d), 2.85–3.0 (2H,m), 2.45–2.6 (2H,m), 1.85 (1H,dd).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]4[C:28]=3[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C-]#N.[Na+].[C:37](O)(=[O:39])[CH3:38]>C(O)C.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]4[C:28]=3[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:18][CH:19]=2)[C:7]([C:11]([O:39][CH2:37][CH3:38])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2nc3ccccn3c2C(=O)OCC)cc1
Reactant: CC(=O)O
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1ccc(-c2nc3ccccn3c2C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
0.28 g (0.6 mmol) of compound A from Example 1d) is dissolved in 5 ml of ethanol. 0.15 g of sodium cyanide is added followed by 53 μl of glacial acetic acid and 1.25 g of manganese dioxide. Stirring at RT for 32 h is followed by filtration with suction, washing with ethanol and concentration of the filtrate. After taking up in H2O, the pH is adjusted to 3-4 with 2% HCl, and extraction with CH2Cl2 is carried out. The organic phase is dried with Na2SO4 and then concentrated. The crude product is reacted without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>CO>[Br:17][C:18]1[CH:19]=[C:20]([CH2:21][NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=Cc1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC1(C)OB(c2ccc(NCc3cccc(Br)c3)cc2)OC1(C)C
Yield: 37.8 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g) and 3-bromobenzaldehyde (0.93 g) were dissolved in methanol (15 mL) and to the resultant solution, sodium triacetoxyborohydride (1.2 g) was added, followed by stirring the resultant reaction mixture at room temperature for 2 hours. To the reaction mixture, 3-bromobenzaldehyde (0.17 g) and sodium triacetoxyborohydride (0.6 g) were further added, and the reaction mixture was stirred further for 1.5 hours. To the resultant reaction mixture, a saturated ammonium chloride aqueous solution was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate 30:1 to 10:1) to obtain the subject compound (0.67 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)C.C(O)(=O)C>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 19 h
Yield: 50 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (3.43 g, 0.0171 mol, 1.15 eq) and 4-hydroxypiperidine (1.51 g, 0.0149 mol, 1 eq) were stirred at room temperature in THF (20 ml), ethanol (3 ml) and acetic acid (0.4 ml) for 4 hours. To the solution was added 0.4 g of 5% palladium on carbon type 87L Johnson Matthey catalyst The reaction was then hydrogenated under a pressure of 2.5 bar at room temperature for 19 hours. The catalyst was filtered off through CELITE™ and washed with ethanol (20 ml). The 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (50% purity by HPLC area %) was not isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH:20]([O:22][C:23](=[O:25])[NH2:24])[CH3:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCC1C=CC=C[N:29]=1>>[N:29]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:1][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH:20]([O:22][C:23](=[O:25])[NH2:24])[CH3:21])[O:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: BrCc1ccccn1
Reactant: CC(OC(N)=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1
Product: CC(OC(N)=O)c1cc(-c2ccc(OCc3ccccn3)cc2)no1

Procedure:
The compound was synthesized using carbamic acid 1-[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-ethyl ester of example 117 in the same manner as in Example 10 by debenzylation following reaction with 2-bromomethylpyridine.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:32])([CH3:31])[CH2:6][S:7][CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][N+:10]=1[C:18]1[NH:19][C:20]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:21]=2[N:22]=1)(=[O:3])[CH3:2].[CH3:33][S:34]([OH:37])(=[O:36])=[O:35]>CO>[CH3:33][S:34]([O-:37])(=[O:36])=[O:35].[C:1]([O:4][C:5]([CH3:32])([CH3:31])[CH2:6][S:7][CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][N+:10]=1[C:18]1[NH:19][C:20]2[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:21]=2[N:22]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)O
Agent: COc1cc[n+](-c2nc3ccc(C(F)(F)F)cc3[nH]2)c(CSCC(C)(C)OC(C)=O)c1C
Solvent: CO
Product: CS(=O)(=O)[O-]

Procedure:
467.5 mg of intramolecularly deprotonized 2-[[(2-acetoxy-2-methylpropyl)thio]methyl]-4-methoxy-3 methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation were dissolved in 5 ml of methanol, whereupon 96 mg of methanesulfonic acid were added thereto, the solution was concentrated, the residue was dissolved several times in ethyl acetate and the solution was again concentrated each time. The resinous residue was dried in a high vacuum, whereby 2-[[(2-acetoxy-2-methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium methanesulfonate (1:1) was obtained as a foam. The microanalysis showed the following values:
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>CC(C)=O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([O:17][CH2:24][CH:26]2[CH2:27][O:28]2)[CH:3]=1
Reactant: ClCC1CO1
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2ccccc2oc2cc(OCC3CO3)cc(O)c12
Temperature: 57.5 °C
Yield: 22.4 %

Procedure:
1,3-dihydroxy-9H-xanthen-9-one (1 g, 4.39 mmol) prepared in Step 1 of Example 2 and K2CO3 (1.52 g, 10.98 mmol) were added to a dry round-bottom flask, and anhydrous acetone (25 ml) was added thereto. Epichlorohydrin (1.73 mL, 21.95 mmol) was added dropwise to the reaction mixture, and the reaction liquid was stirred under reflux at a temperature of 55 to 60° C. for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1 (v/v)) to give the title compound (0.28 g, 22%) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>>[Br:15][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH3:14])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ncc(C)cn2)cc1
Reactant: O=C1CCC(=O)N1Br
Product: Cc1cnc(-c2ccc(CBr)cc2)nc1

Procedure:
Reaction of the above 2-(4-methylphenyl)-5-methylpyrimidine with N-bromosuccinimide, as described in Example 15, affords 2-(4-bromomethylphenyl)-5-methylpyrimidine with a melting point of 129°-131° C. (recrystallisation from ligroin). With stirring, a mixture of 184 g of 2-(4-bromomethylphenyl)-5-methylpyrimidine and 465 g of triethylphosphite is slowly heated to 150° C., while simultaneously distilling off ethyl bromide, and then stirred for 5 hours at this temperature. Excess triethylphosphite is distilled off, affording 220 g of the phosphonate in the form of a light brown viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.C([O-])(=[O:20])C.[K+]>C(O)(=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:20])=[CH:4][CH:5]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A solution of 4-bromomethyl-2'-nitro-1,1'-biphenyl (7.27 g, 24.8 mmol) in acetic acid (50 mL) was treated with potassium acetate (4.88 g, 49.1 mmol). The reaction mixture was heated at reflux for 2 hours. After cooling, the reaction mixture was filtered and the precipitate was washed with acetic acid (2×). The filtrate was evaporated under vacuum and the residue was triturated with ethyl ether. The ether layer was washed consecutively with water, saturated aqueous sodium bicarbonate (3×) and water. The organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was dissolved in methanol (50 mL) and treated with a 6N methanolic potassium hydroxide solution (5 mL). After stirring for 1 hour at room temperature, thin layer chromatography indicated the absence of starting material. The reaction mixture was acidified with acetic acid and evaporated under vacuum. The residue was washed free of acetic acid by washing an etheral solution with aqueous sodium bicarbonate and water. After drying over magnesium sulfate, the ethereal solution was evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (3:1) to give 2'-nitro-1,1'biphenyl-4-carboxaldehyde (620 mg) followed by 4-hydroxymethyl-2'-nitro-1,1'-biphenyl (3.06 g, 13.4 mmol, 54%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:15][S:16]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.03 g, 0.0250 mol, Aldrich Cat. No. 495484) in methylene chloride (50 mL) were added methanesulfonyl chloride (2.03 mL, 0.0262 mol, Aldrich, Cat. No. 471259) and triethylamine (3.66 mL, 0.0262 mol) at 0° C. The solution was stirred at r.t. overnight, then diluted with ethyl acetate, and washed with NaHCO3 aqueous solution and brine successively. The organic layers were dried over MgSO4 and then concentrated under reduced pressure to afford the desired product which was directly used in next step. LCMS (M+Na)+: m/z=302.3.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([S:11]([OH:14])(=[O:13])=[O:12])[C:7]([O:9]C)=[O:8])=[N+:2]=[N-:3]>Cl>[N:1]([CH2:4][CH2:5][CH:6]([S:11]([OH:14])(=[O:12])=[O:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3]
Reactant: COC(=O)C(CCN=[N+]=[N-])S(=O)(=O)O
Agent: Cl
Product: [N-]=[N+]=NCCC(C(=O)O)S(=O)(=O)O
Temperature: 100 °C
Yield: 117.2 %

Procedure:
Methyl 4-azido-2-sulfo-butyrate (1.00 g, 4.08 mmol) in the mixture of HCl (50 ml, 1.0 M) and HAC (5 ml) was heated at 100° C. for 8 hrs. The mixture was evaporated and co-evaporated 3×50 ml of water, and crystallized with water/acetone to afford 1.0 g (99%) of the title compound. 1H NMR (DMF-d7): 3.60 (m, 2H), 3.52 (m, 1H), 2.24 (m, 2H). 13C NMR 170.96, 63.04, 50.66, 29.12. ESI MS m/z−207.7 (MW−H); HRMS m/z−(C4H7N3O5S−H) calcd 208.0028, found 208.0021.