Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[CH2:10][C:11](=O)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:3]2[S:8][CH:10]=[C:11]([CH3:12])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1csc2c(Cl)cccc12
Yield: 63.9 %

Procedure:
A mixture of 2-chlorothiophenol (750 μL, 6.6 mmol), chloroacetone (1.1 mL, 13.8 mmol) and K2CO3 (1.8 g, 13 mmol) in acetone (15 mL) was refluxed for 2 h. The mixture was filtered and the solvent evaporated. The crude product was dissolved in chlorobenzene (30 mL) and polyphosphoric acid (PPA, 0.5 g) was added. The resulting mixture was refluxed over night (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). Additional PPA (0.5 g) was added and the reaction mixture was refluxed for another 7 h. The solvent was decanted from the PPA-residue, the residue was treated with CH2Cl2 and the combined organic extracts were washed with water and dried, and then the solvents were removed by evaporation. The crude product was purified on silica using heptane as eluent, to give the title compound (770 mg, 64% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.44 (d, J=1.20 Hz, 3 H) 7.14 (q, J=1.20 Hz, 1 H) 7.32-7.38 (m, 2 H) 7.60-7.65 (m, 1 H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.S(=O)(=O)(O)O.O.[NH4+].[CH3:22]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH3:22])=[O:13])=[CH:2]1
Reactant: CO
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: COC(=O)CCc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 93 %

Procedure:
2 g (10.57 mmol) of 3-indolepropionic acid were dissolved in 50 ml of methanol. The solution was cooled to 0° C. and 5 ml of sulfuric acid 96% were dropped under stirring. The solution was maintained at room temperature overnight and then poured onto ice-water, basified with 30% ammonium hydrate and finally extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give 2.3 g of an oily product (93% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[N+:1]1([O-:18])[CH:2]=[CH:3][C:4]2[C:9]=1[NH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: [O-][n+]1ccc2ccc[nH]c1-2
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.2 %

Procedure:
7-Azaindole (100 g, 846 mmol) was dissolved in 1 L of ethyl acetate, and an ethyl acetate solution (400 mL) of m-CPBA (65%, 520 g) was dropwise added thereto under ice-cooling over two hours. The resulting mixture was stirred at room temperature for 14 hours. The precipitated solid was collected by filtration under reduced pressure, washed with ethyl acetate, and dried under reduced pressure. Distilled water (600 mL) was added to the obtained solid, and an aqueous solution prepared by dissolving potassium carbonate (125 g, 907 mmol) in water (350 mL) was added thereto while stirring. The resulting solution was cooled at 4° C. for 2 hours to precipitate crystals. The crystals were collected by filtration under reduced pressure, washed with a minimum amount of iced water, and dried under reduced pressure to give 7-azaindole N-oxide (66.0 g) as an off-white solid (yield: 58%).
Reaction SMILES: COC([C:5]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=O.[OH-].[Na+]>Cl.CO>[CH2:12]([N:7]1[CH2:8][CH2:9][C:10](=[O:11])[CH:5]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1
Reaction time: 48 h

Procedure:
1,3-Dibenzyl-4-oxo-piperidine-3-carboxylic acid methyl ester, (2, R1B═H, Z=benzyl) (17.52 g, 51.92 mmol) was suspended in 150 mL of 6N HCl:MeOH (5:1) and the mixture was heated to reflux temperature with stirring for 48 h. After cooling the mixture was basified to pH 10 with 6N NaOH and extracted with 3×200 mL dichloromethane. The combined organics were dried (MgSO4) and concentrated to give 11.60 g of the title compound as a colorless oil, 80%. LC-MS: RT=0.38 min. (M+H)+ 280.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH3:12][C:13]([CH3:15])=O>[Pd].C(O)C>[CH:13]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)([CH3:15])[CH3:12]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCN(C(C)C)CC1
Temperature: 35 °C

Procedure:
An autoclave was charged with ethyl isonipecotate (50 g, 318.0 mmol), 10% Pd/C (5 g, 10 wt %), acetone (450 mL, 6.13 mol) and ethanol (100 mL). The autoclave was pressurized to 4.1 bar with H2, and the slurry was heated to 35° C. After 14 h the mixture was filtered, rinsed with acetone, and was concentrated to remove excess acetone. The crude material was taken on without any purification:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(Cl)cc1
Product: O=C(Cl)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Chlorophenyl)-propionic acid (3.83 g; 20.7 mmol) is dissolved in 50 ml thionyl chloride and stirred at room temperature overnight. The excess thionyl chloride is removed by rotary evaporation to give 3-(4-chlorophenyl)-propionyl chloride as a pale yellow oil, which is used without purification.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[C:3]1=[O:22].[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([N+:23]([O-:25])=[O:24])=[C:17]([OH:19])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[C:3]1=[O:22]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2[N+](=O)[O-])c1=O
Yield: 35.5 %

Procedure:
This compound was prepared in the manner of Step A of Example 1, using 3.8 grams (0.011 mole) of 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 1.0 gram (0.011 mole) of 70% nitric acid, and 50 mL of sulfuric acid, yielding 1.5 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:28].CC(O)=O>C(Cl)(Cl)Cl>[CH3:26][C:25]([O:24][CH2:23][C@H:21]1[O:22][C@H:5]([Br:28])[C@H:6]([O:7][C:8]([CH3:9])=[O:10])[C@@H:11]([O:12][C:13]([CH3:14])=[O:15])[C@@H:16]1[O:17][C:18]([CH3:19])=[O:20])=[O:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Yield: 85 %

Procedure:
β-D-Glucose pentaacetate (2.5 g, 6.41 mmol) was added to HBr-AcOH (30%) with shaking. The reaction mixture was stirred at room temperature for 2 hours. The resultant reaction mixture was diluted with CHCl3 (50 mL), and the mixture was poured into ice water (15 mL). The chloroform layer was separated into an aqueous layer and a chloroform extraction layer (2×20 mL of CHCl3). The chloroform extraction layer was combined with the chloroform layer, and the mixture was then washed with water and dried over MgSO4, to thereby obtain acetobromo-α-D-glucose (4). The solvent was removed under reduced pressure, and the residue was recrystallized from a mixed solution of AcOEt and n-hexane, to thereby obtain a colorless needles 4 (2.23 g, 85%).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:62])(=O)=O)=CC=1>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:62])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 18 h
Yield: 96.8 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) and N-fluorobenzenesulfonimide (2.2 g 6,813 mmole) were dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 18 hours. The reaction was worked-up in the same manner as Example 1 to afford 4.96 g of crude flurithromycin. This material was recrystallized as described in Example 1 to yield 2.25 g (44% yield) of fluorithromycin. This example shows that reasonably good yields of flurithromycin may be obtained in the process of the invention without buffering.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([O:10][CH2:11]Cl)[CH3:9]>CS(C)=O>[CH2:8]([O:10][CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: CCOCCl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOCn1ccnc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a solution of imidazole (10.0 g, 146.9 mmole) in 100 ml dimethyl sulfoxide at room temperature under nitrogen is added sodium hydride (6.46 g, 161.6 mmole). The solution is stirred at 80° C. for 2 hours. Chloromethyl ethyl ether (16.35 ml, 176.3 mmole) is added dropwise. The reaction mixture is stirred for another 2 hour at 80° C., cooled to room temperature, poured into 5% aqueous solution and extracted with dichloromethane (4×200 ml). The combined organic extracts are dried over sodium sulfate, filtered, concentrated in vacuo. The residue is fresh chromatographed in hexane/ethyl acetate from 5:1 to 2:1 to give 1-ethoxymethyl-1H-imidazole as a brown oil 1.68 g (90%) MS(ES+): (M+H)=127.0 To the solution of 1-ethoxymethyl-1H-imidazole (1.24 g, 0.98 mmole) in 3.92 ml anhydrous tetrahydrofuran at −78° C. is added n-butyllithium (1.6 M in hexane) over 5 minutes. Reaction mixture is stirred at −78° C. for 1.5 hour, then (1S,2E)-1-isopropyl-4-[methoxy(methyl)amino]-3-methyl-4-oxobut-2-enyl(methyl)carbamate (427 mg, 1.36 mmole) in 2 ml anhydrous tetrahydrofuran is added over 10 minutes. The reaction mixture is stirred at −78° C. for 1 hour. Then, it is warmed to room temperature, stirred for 1 hour at room temperature. The reaction mixture is diluted with dichloromethane/water. The organic layer is washed with 5% sodium bicarbonate, dried over sodium sulfate, filtered, concentrated in vacuo. The residue is fresh chromatographed in hexane/ethyl acetate from 3:1 to 1:1 to give light yellow oil: [4-(1-Ethoxymethyl-1H-imidazol-2-yl)-1-isopropyl-3-methyl-4-oxo-but-2-enyl]-methyl-carbamic acid tert-butyl ester (120 mg, 23%) MS(ES+): (M+H)=380.2
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.C([BH3-])#N.[Na+]>CO>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH2:12][N:24]3[CH2:25][CH2:26][CH:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=Cc1ccn(-c2ccccc2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CC2CCN(Cc3ccn(-c4ccccc4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 171 mg of 1-phenyl pyrrole-3-carboxaldehyde in 1 mL of methanol was added 525 mg of 4-benzylpiperidine, 175 mg of 4-benzylpiperidine.HCl and 63 mg of sodium cyanoborohydride. The reaction mixture was stirred overnight at room temperature under an atmosphere of nitrogen. The methanol was removed by evaporation under reduced pressure and the residue was extracted into 50 mL of ethyl acetate, then washed successively with 50 mL aliquots of 10% sodium hydroxide and water. The ethyl acetate extract was dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield 1-phenyl-3[(4-benzylpiperidin-1-yl)methyl]pyrrole, which was purified by chromatography on silica gel using 5% methanol in dichloromethane as elvent. On evaporation of the solvent, the free base was dissolved in ethanol and treated with 1 equivalent of maleic acid. The 1-phenyl-3[(4-benzyl-piperidin-1-yl)methyl]pyrrole maleate salt (compound 7) had a melting point of 159°-161° C.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].C(O)(=O)C=O.[CH2:12]1[O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13]1>C1(C)C=CC=CC=1>[CH2:12]1[O:20][C:15]2[CH:16]=[CH:17][C:18]([CH:3]([OH:4])[C:2]([OH:6])=[O:5])=[CH:19][C:14]=2[O:13]1
Reactant: c1ccc2c(c1)OCO2
Reactant: O=CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C(O)c1ccc2c(c1)OCO2
Reaction time: 3.5 h
Yield: 76.3 %

Procedure:
If, instead of glyoxylic acid monohydrate, an equivalent amount of 50% strength aqueous glyoxylic acid is employed and the mixture is stirred for 6 hours instead of 3.5 hours, 8.58 g of bis-3,4-methylenedioxyphenylacetic acid are obtained from the toluene phase and 73.4 g of 3,4-methylenedioxymandelic acid, corresponding to a yield of 76.3% of theory, relative to 1,2-methylenedioxybenzene employed, are obtained from the aqueous phase.
Reaction SMILES: [P:1]([OH:5])([OH:4])([O-:3])=[O:2].[K+].[O-2].[Mg+2:8]>O>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Mg+2:8].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Mg+2:8].[Mg+2:8]
Reactant: O=P([O-])(O)O
Agent: [K+]
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 0.02 h

Procedure:
This example illustrates that the coating can be applied to organic substrates. A magnesium phosphate coating composition was prepared by combining 60 grams of mono-potassium phosphate crystals (maximum size 300 microns), 20 grams of magnesium oxide powder (maximum size 100 microns), and 50 grams fine sand (maximum size 500 microns). The components were blended in high shear mixer for 1 minute and allowed to cool for 10 minutes. Water in the amount of 35 grams was added to this mixture. The components were then mixed by hand in a container to obtain a slurry. This slurry was applied to an asphalt surface using a brush and allowed to cure for about an hour. Once the slurry coating dried, the coating of Example 3 was applied.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH3:13][N:14]=[C:15]=S.C(Cl)CCl>N1C=CC=CC=1>[CH3:13][NH:14][C:15]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1
Reactant: CN=C=S
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CNc1nc2cc([N+](=O)[O-])ccc2n1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A solution of diamine 248 (1.88 g, 11.2 mmol) in pyridine (20 mL) was treated with methyl isothiocyanate (970 mg, 12.9 mmol) and the mixture was stirred at 80° C. for 30 minutes, cooled down to 15° C., treated with solid EDC (3.03 g, 15.8 mmol, 1.40 eq) and the heating continued at 80° C. for 16 h. After removal of pyridine in vacuo, the residue was purified by flash chromatography (eluent 5% MeOH in CH2Cl2) to afford the title compound 268 (1.44 g, 62% yield). 1H NMR: (CD3OD) δ (ppm): 8.12 (d, J=2.2 Hz, 1H), 7.94 (dd, J=2.2, 8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.44 (bs, 2H), 3.51 (s, 3H), 3.04 (s, 3H). LRMS: (calc.) 206.2; (obt.) 207.1 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C:13](OC)=[O:14])[C@@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)(C)C.ClCCCl>[CH2:20]([N:10]1[C@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(C)O
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 146°-150° C., [α]36525 =-27.6° at c=1 in DMF, 3.68 g) in isopropanol (10 ml) and 1,2-dichloroethane (60 ml) was added dropwise to a mixture of sodium borohydride (760 mg) and isopropanol (20 ml) at 5°-10° C. over a period of 15 minutes. The obtained mixture was allowed to warm up to room temperature and to react at the same temperature for 20 hours. Then, 1N hydrochloric acid (50 ml) was added to the reaction mixture. The mixture was stirred at 55°-60° C. for 30 minutes. Aqueous layer was separated from organic layer and extracted once with 1,2-dichloroethane (50 ml). The organic layers were combined, washed successively with water, 5% aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (3.12 g). M.P., 116°-117° C. [α]D25 =+61.0° (c=1, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(Cl)s1
Temperature: 77.5 °C
Reaction time: 0.5 h

Procedure:
3.00 kg of 5-chlorothiophene-2-carboxylic acid (commercially available) are suspended in 8.48 kg of toluene and heated to 75 to 80° C. At this temperature, 2.63 kg of thionyl chloride are added dropwise over a period of 85 minutes, followed by stirring at 75 to 80° C. for 30 minutes and then at the reflux temperature until gas evolution ceases. After cooling, the reaction mixture is distilled under reduced pressure with gradually increasing internal temperature (up to a maximum of 60° C.) to remove excess thionyl chloride and toluene until an approximately 30% strength solution of the acid chloride in toluene is produced.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(NN)[CH:15]=CC=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:15]=[CH:10][C:11]([CH3:12])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: NNc1cccc(Br)c1
Product: Cc1ccn(-c2cccc(Br)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3-bromophenyl hydrazine · HCl substituted for phenyl hydrazine. There was obtained 1-(3-bromophenyl)-3-methyl-1H-pyrazole-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carboxyamide; HRMS(M+H)+ calc. 511.043949; found: 511.043295.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CS(O[CH2:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)=O.[Na+].[I-]>C(#N)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:22][CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ccc(CN2CCC(CNCCC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 54 %

Procedure:
4-(Aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) was reacted with 3,3-diphenylpropyl methanesulfonate (1.0 equivalent) in the presence of NaI (2.6 equivalents) in acetonitrile at 70° C. for 16 hours. After treatment by a conventional method, the obtained crude product was purified by column chromatography (SiO2) to afford 1-(4-chlorobenzyl)-4-[N-(3,3-diphenylpropyl)aminomethyl]piperidine (118 mg, 54%). The purity was determined by RPLC/MS (98%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:16])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5,7-dichloropyrido[4,3-d]pyrimidin-4(3H)-one (2.16 g, 10 mmol) in dry DMF (50 mL) was added NaH (440 mg, 60% in mineral oil, 11 mmol) at 0° C. under N2. After the reaction mixture was allowed to warm to room temperature and stirred for 20 minutes, CH3I (0.75 mL, 1.7 g, 12 mmol) was added via syringe. The reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL), washed with saturated NH4Cl solution (2×100 mL), water (50 mL) and brine (40 mL), and concentrated to result in a residue that was subjected to chromatography with gradient mixed solvents from hexanes/EtOAc (1:1) to (1:9) to afford the title compound. 1H NMR (DMSO-d6) 3.45 (s, 3H), 7.71 (s, 1H), 8.63 (s, 1H); ESI-MS m/z 230.0 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:18]([CH2:17][CH2:16][CH2:15][Cl:14])(=[O:20])=[O:19])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Yield: 95.8 %

Procedure:
Amine preparation: A mixture of 1-BOC-piperazine (3.26 g), 3-chloropropanesulfonyl chloride (2.63 g) and triethylamine (2.68 mL) was stirred at room temperature in DCM (25 mL). After 2 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g). A mixture of 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g), potassium iodide (1.1 g), potassium carbonate and morpholine (1.6 mL) was heated to reflux in MeCN (100 ml). After 16 h, the reaction mixture was cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-morpholin-4-yl-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.8 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.