Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH:21]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH:21]=[C:16]([CH:11]3[C:10]([CH3:33])([CH3:32])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=[N:18][CH:19]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(-c3ccc(C(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(-c2cncc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
A mixture of 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (880 mg, 1.99 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was re-crystallized from methanol to afford 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (800 mg, 97%) as a yellow solid: LC/MS m/e calcd for C27H30N2O2 (M+H)+: 415.55, observed: 415.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cccc2nccn12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cccc2ncc([N+](=O)[O-])n12
Temperature: 0 °C

Procedure:
To a solution of 19.02 g (0.10 mol) of 5-ethoxycarbonylimidazo[1,2-a]pyridine in 50 ml of conc. sulfuric acid was added dropwise, while stirring under ice-cooling, 40 ml of conc. nitric acid. The mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into ice-water, which was neutralized with a 10% aqueous solution of NaOH. The resulting precipitates were collected by filtration, washed with water and dried to afford 20.38 g of the desired compound (86.6%, a pale yellow solid).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N+:11]([C:14]1[C:15]([Cl:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18])([O-:13])=[O:12].C(N(CC)CC)C>ClCCl>[N+:11]([C:14]1[C:15]([Cl:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(CO)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cccc([N+](=O)[O-])c1Cl
Temperature: -65 °C
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
A solution of oxalyl chloride in dichloromethane (2.0M, 116 mmol) was chilled to −70° C. (internal temperature) under a nitrogen atmosphere. DMSO (15 mL, 211.3 mmol) was added dropwise maintaining −65° C. and then stirring was continued for 45 min. at −70° C. A solution of the 3-nitro-2-chlorobenzyl alcohol (14.4 g, 76.6 mmol) in dichloromethane (250 mL) was then added and the reaction stirred at −70° C. for 2 h. Triethylamine (54 mL, 387 mmol) was added dropwise and the reaction stirred for 2 h at −70° C. and then 12 h at room temperature. The reaction was quenched by the addition of 500 mL of water. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried with MgSO4, filtered, and evaporated to obtain a light brown solid. Column Chromatography (silica gel, 30% dichloromethane/hexanes to 70% dichloromethane/hexanes) produced 11.1 g (78%) of the desired 3-nitro-2-chlorobenzaldehyde as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:3]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:4]2[N:3]=[C:2]([N:23]3[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: Cc1cc(C)[nH]n1
Product: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(-n3nc(C)cc3C)nc21

Procedure:
Was prepared according to Example 6 from (2-chloro-9-ethyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine and 3,5-dimethylpyrazole.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:30].[OH-].[Na+]>O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:30]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(N)=O
Temperature: 70 °C
Yield: 101.5 %

Procedure:
A mixture of 5-cyano-4-(2-methylphenyl)-2-(4-morpholinyl)pyridine (17.71 g), 18 mL of toluene, and 17.0 mL (33.1 g, 319 mmol) of concentrated sulfuric acid was heated at 70° C. for 12 hours, cooled to room temperature, and quenched by addition of 100 mL of cold H2O. Ethyl acetate (100 mL) was added followed by a solution of 25.5 g (638 mmol) of sodium hydroxide in 50 mL of H2O. The aqueous layer was separated and extracted three times with 50 mL of ethyl acetate. The organic layers were combined and concentrated to afford 19.14 g of 4-(2-methylphenyl)-6-(4-morpholinyl)-3-pyridinecarboxamide as a colorless solid (LC assay 87.7 wt %) (yield 94.9–97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][CH2:21][C:22](=O)[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=O)[N:9]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:39]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:39][C:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[CH:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)Cc1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ncc(Cc3cccc(C(F)(F)F)c3)[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
50 mg (0.10 mmol) of the compound from Example 27A were dissolved in 1 ml of DMF and mixed with 23 mg (0.30 mmol) of ammonium acetate, and the mixture was stirred in a microwave oven at 200° C. for 15 min. After cooling, a further 30 mg (0.39 mmol) of ammonium acetate were added, and the mixture was stirred in a microwave oven at 200° C. for another 30 min. After cooling to RT, the mixture was partitioned between 10 ml of ethyl acetate and 10 ml of water. The organic phase was separated off, washed with in each case 10 ml of water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC [Method 19]. This gave 17 mg (35% of theory) of the target compound as a yellowish resin.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-])[CH2:2][CH3:3].O.C([O-])([O-])=[O:13].[Na+].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH2:2]([C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:13])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCCc1cccc[n+]1[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)c1ccccn1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
19 g of 2-propylpyridine-N-oxide were dissolved in 40 ml of glacial acetic acid/40 ml of acetic anhydride and stirred for 6 hours at 85° C. and 12 hours at ambient temperature. Excess anhydride was decomposed with H2O, the solution was neutralized with Na2CO3 and extracted with diethyl ether. After rotating in the ether phase, 12 g of 2-(1-acetoxypropyl)-pyridine remained. This product was dissolved in 120 ml of methanol (70%), mixed with 4 g of NaOH and refluxed for 6 hours. After rotating out the methanol mixing took place with water, extraction with diethyl ether and the organic phase was rotated in. 5.4 g of 2-(1-hydroxypropyl)-pyridine were left. 0.5 g of this substance was refluxed for 2 hours with 1 g of MnO2 and 30 ml of dichloromethane. After filtering off the MnO2, rotation in took place to dryness. 0.3 g of ethyl-2-pyridylketone was obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)([O-:5])=[O:4].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1>CN(C=O)C>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (NaH) 95% (0.81 g, 34.1 mmol) was added to a solution of 5-nitro-1H-indazole Compound 4a (5.3 g, 32.5 mmol) in DMF (33 mL) at 0° C. under nitrogen. The mixture was stirred for 1 hour at RT, then 1-bromomethyl-3-fluoro-benzene Compound 4b (6.14 g, 32.5 mmol) was added dropwise at 0° C. After stirring at RT for 12 hours, the reaction mixture was partitioned between ethyl acetate and icy water. The organic layer washed with water, brine, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (100% dichloromethane) to yield 1-(3-fluoro-benzyl)-5-nitro-1H-indazole Compound 4c (4.02 g, 46%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.76-8.75 (1H, m), 8.27-8.23 (2H, m), 7.40-7.38 (1H, m), 7.33-2.27 (1H, m), 7.01-6.97 (2H, m), 6.89-6.86 (1H, m), 5.64 (2H, s); MS (ES+) m/z 272.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CN(C)C=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
A solution of 2,5-dichloronicotinic acid (25.0 g, 130 mmol) in methylene chloride (650 mL) was treated with oxalyl chloride (22 mL, 260 mmol) followed by N,N-dimethylformamide (1.0 mL) and stirred at room temperature for 18 hours. The gas evolution ceased and the reaction mixture was concentrated. The acid chloride intermediate was taken up in methylene chloride (300 mL), cooled to 0° C. and treated with methanol (26 mL). The reaction was stirred at 0° C. for 30 minutes, allowed to warm to room temperature and was concentrated in vacuo to give an oil. This oil was taken up in ethyl acetate, washed with water saturated potassium carbonate, brine, dried over magnesium sulfate and concentrated to give methyl 2,5-dichloronicotinate (24.5 g, 92%) as an oil. LCMS calculated for C7H6Cl2NO2(M+H)+: m/z=205.9, 207.9. found: 205.9, 207.9.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]([OH:15])[C@@H:9]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C:8]=2[CH:27]=1)(=[O:3])[CH3:2].O.FC(F)(F)C(O)=[O:32].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>C(#N)C>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[C:17]([NH:16][C@H:9]1[C:8]2[CH:27]=[C:4]([C:1](=[O:3])[CH2:2][OH:32])[CH:5]=[CH:6][C:7]=2[O:12][C:11]([CH3:14])([CH3:13])[C@H:10]1[OH:15])=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccc(F)c(Cl)c1)[C@H](O)C(C)(C)O2
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CC1(C)Oc2ccc(C(=O)CO)cc2[C@H](NC(=O)c2ccc(F)c(Cl)c2)[C@@H]1O
Yield: 23.5 %

Procedure:
(3S,4S)-6-Acetyl-4-(3-chloro-4-fluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran D4 (1.97 g, 5.0 mmol) (Example 17 of WO95/34545) was dissolved in acetonitrile (25 ml), water (5 ml) and trifluoroacetic acid (0.77 ml, 10.0 mmol). [Bis(trifluoroacetoxy)iodo]benzene (4.30 g, 10.0 mmol) was added and the reaction stirred under reflux for three hours. The reaction mixture was allowed to cool and the acetonitrile was removed in vacuo giving a yellow solid which was isolated by filtration and recrystallised from ethyl acetate/hexane to give the title compound as a white solid (0.48 g, 24%), m.p. 200° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[H][H].Br[CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1>CN(C)C=O.C(OCC)(=O)C>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([CH2:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH:2]=1
Reactant: c1cc2[nH]cnc2cn1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2cnc3ccncc32)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A stirred solution of imidazo[4,5-c]pyridine (10.0 g. 0.084 mol) in dry dimethylformamide (100 ml) at 18° C. under a nitrogen atmosphere, was treated with sodium hydride (5.04 g of 60% dispersion in mineral oil, 0.126 mol) in portions over a period of 5 minutes. The mixture was stirred for an additional 2.5 hours until hydrogen evolution had ceased. The mixture was cooled to 0° C., treated with ethyl 4-bromomethylbenzoate (22.6 g, 0.093 mol), allowed to warm up to room temperature and then stirred for an additional 18 hours. The mixture was diluted with ethyl acetate (600 ml), washed with water (3×200 ml) and dried over anhydrous sodium sulphate. The solvent was evaporated off under reduced pressure to yield an impure mixture of isomers which was purified by chromatography (silica gel, chloroform) to yield a less polar isomer which was recrystallized from ethyl acetate-hexane to yield ethyl 4-(3H-imidazo[4,5-c]pyridin-3-ylmethyl)benzoate as a colorless crystalline solid, having a melting point of 110°-111.5° C. and the following physical characteristics:
Reaction SMILES: [N:1]([C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O)=[N:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=O.[NH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23].[CH3:24][O:25][Na].[Cl-].[Na+]>CO>[N:2]([C:3]([CH3:8])([CH3:9])[C:4]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:24][OH:25])=[O:6])=[N:1][C:10]([CH3:16])([CH3:15])[C:11]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])=[O:13]
Reactant: NCCNCCO
Reactant: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Reactant: CO[Na]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(N=NC(C)(C)C(=O)NCCNCCO)C(=O)NCCNCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a constantly stirred mixture comprising 23.0 g of V-601, 22.9 g of 2-(2-aminoethylamino)ethanol and 5 ml of methanol, 4.7 g of 28% CH3ONa was added dropwise. The reaction was carried out with stirring at room temperature for 8 hours. After standing overnight, the reaction mixture was mixed with 50 ml of saturated sodium chloride solution, and extracted with 100 ml of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and solvent was distilled off, and there was obtained 29.8 g (yield 80%) of 2,2'-azobis [N-(2-hydroxyethylamino)ethyl-2-methylpropionamide ] of yellow viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][N:18]([CH3:28])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)cc2c1ncn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1cc(Cl)cc2c1ncn2C1CCCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of tert-butyl (6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methylcarbamate (300 mg, 0.82 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in mineral oil, 98.4 mg, 2.46 mmol). After stirring at RT for 30 min, CH3I (349 mg, 2.46 mmol) was added and the reaction mixture was stirred at RT overnight and then quenched with H2O at 0° C. The mixture was extracted with EtOAc (100 mL) and the extract washed with H2O (50 mL×3), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (1:1) to afford tert-butyl (6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methyl(methyl)carbamate as yellow oil (310 mg, 99%). MS (ESI): m/z=380.3 [M+1]+.
Reaction SMILES: C1([C@@H](N2CC[C@H](OC3CCCCO3)C2)CO)C=CC=CC=1.[C:22]1([C@H:28](O)[CH2:29][N:30]2[CH2:34][CH2:33][C@H:32]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH2:31]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl:43][C:44]1[CH:53]=[C:52]([NH:54][CH3:55])[CH:51]=[CH:50][C:45]=1[C:46]([O:48][CH3:49])=[O:47]>>[Cl:43][C:44]1[CH:53]=[C:52]([N:54]([C@@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][N:30]2[CH2:34][CH2:33][C@H:32]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH2:31]2)[CH3:55])[CH:51]=[CH:50][C:45]=1[C:46]([O:48][CH3:49])=[O:47]
Reactant: O[C@H](CN1CC[C@H](OC2CCCCO2)C1)c1ccccc1
Reactant: CNc1ccc(C(=O)OC)c(Cl)c1
Agent: OC[C@@H](c1ccccc1)N1CC[C@H](OC2CCCCO2)C1
Product: COC(=O)c1ccc(N(C)[C@H](CN2CC[C@H](OC3CCCCO3)C2)c2ccccc2)cc1Cl
Yield: 40 %

Procedure:
This was prepared from 2-(R)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and methyl 2-chloro-4-methylaminobenzoate in 40% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC(c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-(2,3-dichlorophenyl)piperidine (20 mg, 0.064 mmol), 1,2-dichloroethane (1 ml), glacial acetic acid (4 mg, 0.064 mmol), paraformaldehyde (2 mg, 0.066 mmol) and sodium triacetoxyborohydride (20 mg, 0.092 mmol) was stirred 15 h at ambient temperature. MS m/z (rel. intensity, 70 eV) 244 (M+, 68), 243 (54), 242 (bp), 208 (61), 115 (29).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11][CH2:12][CH3:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)=[CH:3][C:4]=1[CH2:11][CH2:12][CH3:13])([O-:10])=[O:9]
Reactant: CCCc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 86.7 %

Procedure:
4-Chloro-1-nitro-2-propylbenzene (J. Organometallic Chem. 2001, 624(1-2), 167-171) (0.299 g, 1.50 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (0.553 g, 1.79 mmol), Na2CO3 (0.509 g, 4.80 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.0620 g, 0.0900 mmol) in dioxane (6 mL) and H2O (3 mL) was degassed for 10 min. The mixture was heated at 80° C. overnight. The reaction was filtered through Celite®, washed with EtOAc and H2O, dried (MgSO4), concentrated and purified by flash chromatography to provide the title compound of step A (0.451 g, 1.30 mmol, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.3 Hz, 3H), 1.46 (s, 9H), 1.65 (sextet, J=7.5 Hz, 2H), 2.50 (br. s., 2H), 2.83-2.88 (m, 2H), 3.62 (t, J=5.7 Hz, 2H), 4.08 (q, J=2.7 Hz, 2H), 6.14 (br. s., 1H), 7.25-7.29 (m, 2H), 7.87 (d, J=7.9 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1.[CH3:27][NH2:28]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:4]2[N:3]=[C:2]([NH:28][CH3:27])[C:7]([C:8]#[N:9])=[CH:6][C:5]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)cc1
Reactant: CN
Product: CNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Temperature: 70 °C
Reaction time: 24 h

Procedure:
2-Chloro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example 7) (200 mg, 0.52 mMol) was charged with methylamine. The solution was shaken for 24 hours at 70° C. and 74 psi by a Parr Shaker. The vessel was cooled to room temperature and vented to allow excess methylamine to evaporate leaving a yellow solid. The solid was washed with methyl alcohol and recrystallized from chloroform: m.p. (DSC): 295.63° C. Anal. Calc'd. for C20H16N3O2SF (381.43): C, 62.98; H, 4.23; N, 11.02. Found: C, 62.59; H, 4.15; N. 10.77.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11]([O:13]CC)=[O:12].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:16])([F:17])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 68 %

Procedure:
In 2 ml of ethanol was dissolved 160 mg of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate. To the resulting solution was added 2 ml of a 1N aqueous sodium hydroxide solution at 0°-5° C. The mixture was subjected to reaction at the same temperature for 10 minutes. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained, and the resulting crystals were collected by filtration to obtain 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyric acid.