Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 70 °C
Yield: 39.6 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (26 mg, 0.19 mmol) and iodoethane (11 μL, 0.14 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 70° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) followed by trituration with diethyl ether afforded 11 mg (39%) of 3-(2-pyridyl)-5-(3-cyano-5-ethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.91 (m, 1H), 7.49 (m, 1H), 7.38 (s, 1H), 4.17 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].[CH2:20]=[C:21]([C:26](OS(F)(=O)=O)([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]>COCCOCCOC>[CH2:20]=[C:21]([C:26]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]
Reactant: OCC(F)(F)F
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Solvent: CCCCN(CCCC)CCCC
Solvent: COCCOCCOC
Product: C=C(C(F)(F)F)C(F)(F)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
A 100 ml flask is charged with tributylamine (15 g), diglyme (20 ml) in a dry box. 2,2,2-Trifluoroethanol (8.05 g) is added to the mixture. CH2═C(CF3)CF2OSO2F (19.5 g) is added dropwise while the mixture is cooled in an ice-water bath. The resulting mixture is stirred at room temperature for 3 hours. The mixture is then distilled to give a liquid, which is redistilled (spinning band column) giving 5.8 g CH2═C(CF3)CF2OCH2CF3, b.pt. 85-86° C., a yield of 30%. Less pure fractions are not included in the yield calculation.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16](=[S:31])(OC1C=CC=CN=1)OC1C=CC=CN=1>C(Cl)Cl>[N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:14][CH:13]=1)=[C:16]=[S:31]
Reactant: Cc1cccnc1Oc1ccc(N)cc1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: Cc1cccnc1Oc1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round bottomed flask were added 4-(3-methylpyridin-2-yloxy)benzenamine (100 mg, 0.5 mmol), O,O-dipyridin-2-yl carbonothioate (122 mg, 0.52 mmol) and DCM (2 mL). The reaction mixture was stirred at RT for 16 h. The reaction was partitioned between DCM and water, brine. The aqueous layer was extracted with DCM and the combined organics was dried (Na2SO4) and concentrated to give 2-(4-isothiocyanatophenoxy)-3-methylpyridine as tan solid. MS (ESI, pos. ion) m/z: 243.1 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].S.[OH:10][CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:17][CH:18]([N:20]1[C:33]2[CH:32]=[C:31]([C:34](=S)N)[CH:30]=[CH:29][C:28]=2[S:27][C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19]>C(OCC)(=O)C>[NH:1]1[CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[N:8]=[C:34]1[C:31]1[CH:30]=[CH:29][C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH:18]([CH3:19])[CH2:17][N:13]3[CH2:14][CH2:15][CH2:16][C@@H:12]3[CH2:11][OH:10])[C:33]=2[CH:32]=1
Reactant: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: NC1CCCCC1N
Agent: S
Solvent: CCOC(C)=O
Product: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 150 °C
Reaction time: 2 h

Procedure:
1,2-Diaminocyclohexane (10.57 g) is added to an ethanolic solution (40 cc), saturated with hydrogen sulphide, of 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, D series (3.65 g). The mixture is heated in an autoclave to 150° C. for 11 hours, then diluted with ethyl acetate (250 cc) and washed with distilled water (4×200 cc). The organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is diluted in boiling absolute ethanol (200 cc) and a small amount of insoluble matter is filtered off. The filtrate is stirred at 25° C. for 2 hours and then cooled to 5° C. for 12 hours. The precipitate formed is filtered off, washed with cold ethanol (3×10 cc) and dried under reduced pressure (5 mm Hg; 0.67 kPa) at 40° C. to give 2-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-10-{1-[(2R)-2-(hydroxymethyl)pyrrolidinyl]-2-propyl}phenothiazine, D series (1.1 g) in the form of a cream-coloured solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>O1CCOCC1>[CH3:26][C:27]1[N:28]([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH:29]=[CH:30][N:31]=1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: Cc1ncc[nH]1
Solvent: C1COCCO1
Product: Cc1nccn1Cc1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (105 mg, 0.236 mmol; see Example 1(e)) in dioxane (2.0 mL) was added 2-methylimidazole (58 mg, 0.71 mmol) and the reaction mixture was stirred for 1.5 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the sub-title compound in 77% yield as a colourless syrup (81 mg, 0.182 mmol).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Cl:1][CH2:2][CH2:3][C:4]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:17])[C:8]2([CH3:18])[CH3:7])=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1(C)C(=O)Nc2ccc(C(=O)CCCl)cc21
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
Under nitrogen atmosphere, add chloropropionyl chloride (1.54 mL, 16.13 mmol) to a mixture of 3,3-dimethyl-1,3-dihydro-indol-2-one (2.0 g, 12.41 mmol) and aluminium trichloride (10.26 g, 76.92 mmol) in carbon disulphide (70 mL). Heat under reflux for 3 h then allow to cool. Decant off the solvent and replace it carefully with ice/water (200 mL). Allow the resultant suspension to stir for 20 min before filtering off the product and washing with water (80 mL). Dry in vacuo to obtain the desired intermediate as a pale brown solid (3.08 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(OCC)(=O)C.[Ni]>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1
Reactant: CNc1ccc(F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CNc1ccc(F)cc1N
Reaction time: 4.5 h
Yield: 76.4 %

Procedure:
6.2 g (4-fluoro-2-nitrophenyl)-methylamine are suspended in 200 ml of ethyl acetate and hydrogenated with 1 g of Raney nickel at a pressure of 5 bar and ambient temperature. After 4.5 hours the catalyst is suction filtered and the filtrate is evaporated to dryness. 3.9 g product are obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:21]([CH3:20])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Reactant: CNc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(c1ccccn1)S(=O)(=O)c1cc(Br)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
To 5-bromo-4-chloro-2-fluorobenzenesulfonyl chloride (1.5 g, 4.89 mmol) in dry DCM (15 mL), at −20° C. was added pyridine (1.98 mL, 24.5 mmol) followed by methyl-pyridin-2-yl-amine (1.06 g, 9.78 mmol). The mixture was allowed to warm slowly to ambient temperature over 16 hrs. 1N NaOH solution (5 mL) was added and stirred for 15 mins. The mixture was extracted with DCM and the organics were washed with brine, dried over MgSO4 and the filtrate evaporated. The residue was purified by silica gel chromatography [eluent: 10% ethyl acetate in hexane] to give 5-bromo-4-chloro-2-fluoro-N-methyl-N-pyridin-2-yl-benzenesulfonamide as an oil (0.57 g, 31%). MS: 380.9 (M+H)+; tR=2.80 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.CC1(C)C(C)(C)OB([C:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1cncc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2c(F)cncc2Cl)CC1
Temperature: 90 °C
Yield: 77.7 %

Procedure:
3-chloro-5-fluoro-4-iodo-pyridine (750 mg, 2.913 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (990.7 mg, 3.204 mmol) and Pd(PPh3)2Cl2 (102.2 mg, 0.1456 mmol) in DME (15 mL) were degassed using 3×vacuum/nitrogen cycles. Na2CO3 (4.370 mL of 2 M, 8.739 mmol) was added followed by further degassing and the reaction heated at 90° C. for 2 hours. The reaction was cooled to ambient temperature and diluted with EtOAc/water. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 20% EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl 3′-chloro-5′-fluoro-5,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate as an off-white solid (708 mg, 78% Yield). MS (ES+) 313.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:13])(=O)[CH2:8][CH2:9][CH:10]=[CH2:11].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.CN(C=O)C>[C:15]1([NH:14][C:7](=[O:13])[CH2:8][CH2:9][CH:10]=[CH2:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: C=CCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a stirred solution of oxalyl chloride (2.0 M in CH2Cl2, 11.5 mL, 23.1 mmol) in CH2Cl2 (100 mL) and DMF (1 drop) at 0° C. was added 4-pentenoic acid (2.25 mL, 22.0 mmol). This was allowed to warm to ambient temperature. Upon cessation of gas evolution, the mixture was returned to 0° C. and a solution of aniline (2.00 mL, 22.0 mmol) and TEA (6.72 mL, 26.3 mmol) in CH2Cl2 (5 mL) was added dropwise. After warming to ambient temperature, the reaction was allowed to proceed for 3 h. The mixture was concentrated under reduced pressure, and then partitioned between HCl (1 N, 10 mL) and EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×15 mL) and the organic layers combined, washed with brine, dried over MgSO4, and filtered. Concentration under reduced pressure gave a yellowish solid, which was recrystallized with toluene to obtain 42 as white crystals (1.97 g, 11.24 mmol, 51%). TLC Rf 0.68 (50% EtOAc/hexanes); 1H-NMR (300 MHz, CDCl3) δ 7.49 (d, 2H), 7.29 (t, 2H), 7.08 (t, 1H), 5.88 (m, 1H), 5.10 (dd, 2 H), 4.42 (br s, 4 H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]([CH:7]([C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:8])CO.[CH:14]([Cl:17])(Cl)[Cl:15]>C1S(=O)(=O)CCC1.S(Cl)(Cl)=O>[ClH:15].[ClH:1].[NH2:3][CH:4]([CH:7]([C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:8])[CH2:14][Cl:17]
Reactant: CC(c1c[nH]cn1)C(N)CO
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: O=S1(=O)CCCC1
Solvent: O=S(Cl)Cl
Product: CC(c1c[nH]cn1)C(N)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3 g (13.2 mmol) 2-amino-3-(1H-imidazol-4-yl)butanol dihydrochloride are solved in a mixture of 25 ml tetramethylenesulfone and 10 ml thionyl chloride and stirred 12 hours at room temperature. Dropwise addition of 200 ml chloroform affords 2-amino-1-chloro-3-(1H-imidazol-4-yl)butane dihydrochloride. Yield: 2.87 g (88.2%) of a hygroscopic precipitate.
Reaction SMILES: [CH3:1][C:2](C)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:8]=1)[C:3](O)=O.C([N:29](CC)CC)C.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH3:1][C:2]([NH2:29])([CH3:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:8]=1
Reactant: CC(C)(Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)C(=O)O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(N)Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.17 g (6.09 mmol) of the Intermediate 86 are dissolved in 200 ml of acetone. 1.95 ml (13.99 mmol) of triethylamine are added and the solution is cooled to 0° C. A solution of 0.89 ml (6.84 mmol) of isobutyl chloroformiate in 15 ml of acetone is dropped into the system. After 30′ at 0° C. a solution of 0.99 g (15.23 mmol) of sodium azide in 10 ml of water is slowly added, and the stirring at 0° C. is prosecuted for an additional period of 30 min. Excess water is added, the system is extracted with ethyl ether which is washed with water, dried and concentrated at room temperature. The residue is dissolved in 15 ml of toluene and this solution added slowly to 150 ml of refluxing toluene. The reflux is prosecuted for an additional hour and the solution is concentrated. The residue is dissolved in 15 ml of dioxane, 35 ml of 5N HCl are added and the system is stirred at 100° C. for 30′. The solution is neutralised with 2N NaOH and is extracted with ethyl ether. The ethereal layer is washed with water, dried and concentrated. The residue is chromatographied on silicagel eluting with ethyl acetate/methanol 10:1 then 6:1 giving 1.46 g (72%) of yellowish oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3=[CH:12][NH:13][N:14]=[C:8]3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C)C=O.CO>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3=[CH:12][N:13]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[N:14]=[C:8]3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1[nH]nc2c1CCN(C1CCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1ccc(Cn2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 70 °C

Procedure:
6-Cyclobutyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 31) (0.03, 0.16 mmol) in dimethylformamide (2 ml) was treated with sodium hydride (60% dispersion in oil) (0.007 g, 0.172 mmol). After 20 minutes 4-(bromomethyl)benzonitrile (0.037 g, 0.172 mmol) was added and the mixture was then heated at 70° C. for 18 hours. The reaction was then cooled to room temperature, diluted with methanol and applied to a SCX ion exchange cartridge and washed with methanol and then 2M solution of ammonia in methanol. The ammonia containing fractions were then combined and reduced and the resulting crude residue was chromatographed on silica gel eluting with a 2:98 mixture of 2M ammonia in methanol and dichloromethane to furnish the title compound (E46); (MS (ES+): [M+H]+ at m/z 307.1
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH3:15][N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:17].C(O)C.OO>O1CCCC1>[CH3:17][N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:15]
Reactant: CN(C)Cc1ccc(C2CCC(=O)CC2)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)Cc1ccc([C@H]2CC[C@@H](O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
50 ml (0.05 mol) of a 1 molar solution of lithium tri-sec.-butyl-borohydride in absolute tetrahydrofuran are diluted with 100 ml of absolute tetrahydrofuran under a nitrogen atmosphere and then, at -65° C. to -70° C., with stirring and within 10 minutes, a solution of 5.8 g (0.025 mol) of 4-(4-dimethylaminomethylphenyl)-cyclohexanone in 50 ml of absolute tetrahydrofuran is added thereto. The reaction mixture is then left to react for 3 hours at -70° C. and then heated to ambient temperature within 1 hour. It is then hydrolysed with 20 ml of 75% aqueous ethanol and the organoborane is oxidised with alkaline hydrogen peroxide (10 ml of 6M NaOH/15 ml 30% H2O2). The organic phase is separated off, the aqueous phase is saturated with potassium carbonate and extracted with 50 ml of ethyl acetate. The combined organic extracts are dried with sodium sulphate and evaporated down in vacuo. The greasy residue remaining, which consists of a mixture of cis/trans-4-(4-dimethylaminomethylphenyl)cyclohexanol (trans fraction <5%) is purified by column chromatography (aluminium oxide neutral, activity stage III, ICN; petroleum ether/methylethyl ketone=5:1). The product is obtained as a colourless oil. Yield: 4.1 g (71% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:16]=1.[I:17][Si](C)(C)C.II>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[CH:9]([I:17])[CH2:8][CH2:7][C:6]=2[CH:16]=1
Reactant: C[Si](C)(C)I
Reactant: CC(C)N1C(=O)CCCc2cc(F)ccc21
Agent: II
Solvent: ClCCl
Product: CC(C)N1C(=O)C(I)CCc2cc(F)ccc21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
An oven-dried round-bottom flask containing the product of Step 4 (1.92 g, 8.68 mmol) was fitted with a stirbar and septa and flushed with nitrogen. Dichloromethane (50 mL) and N,N′,N′-tetramethylethylenediamine (5.80 mL, 38.4 mmol) were added, giving a solution that was cooled to −10° C. Iodotrimethylsilane (4.80 mL, 35.3 mmol) was added, and stirring was continued at −10° C. for 30 minutes. Iodine (4.71 g, 18.6 mmol) was then added, and the reaction was warmed to 0° C. After stirring 2 hours at 0° C., the reaction was diluted with dichloromethane (100 mL) and washed with 10% aqueous sodium sulfite solution (2×50 mL). The organic layer was then dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (0% to 30% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: Cl.[C:2]([C:6]1[N:10]=[CH:9][N:8]([CH2:11]Cl)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:2]([C:6]1[N:10]=[CH:9][N:8]([CH2:11][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ncn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ncn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 33.6 %

Procedure:
1.61 g of 3-t-butyl-1-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 1.24 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 22 ml of N,N-dimethylformamide. 2.13 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.77 g of [(3-t-butyl-1H-1,2,4-triazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (29), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[CH2:13]O.P(Br)(Br)[Br:16].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:16][CH2:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=1[Cl:12]
Reactant: OCc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c(CBr)c(Cl)c1
Temperature: 0 °C
Yield: 162.4 %

Procedure:
Dissolve (2,6-dichloro-4-trifluoromethyl-phenyl)-methanol (7.5 g, 31 mmol) is THF (40 mL) and cool to 0° C. Add PBr3 (5.0 g, 18 mmol) under nitrogen and stir at 0° C. for 30 minutes. Pour into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify over silica gel (hexanes) to obtain 9.0 g (96%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[OH-].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:11])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1n[nH]c2ncc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(O)c3cc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
5-Bromo-1H-pyrazolo[3,4-b]pyridin-3-ol (8.68 g, 40.56 mmol) and 1-(chloromethyl)-4-methoxybenzene (16.50 mL, 121.7 mmol) were dissolved in DMSO (250 mL). Powdered NaOH (2.433 g, 60.84 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc and water and separated. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with water (3×), saturated aqueous NaHCO3 (3×), brine, and dried over Na2SO4 and concentrated giving an oily solid. This solid was triturated with EtOAc and dried to provide 5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ol (7.0 g, 51.7%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:8]([C:10]2[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[OH:9])[CH:7]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1ccc(Cl)nc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol was added an excess (ca. 2 eq.) of PDC in DCM. The suspension was shaken at room temperature overnight. The reaction was monitored by LC-MS, another 1-2 eq. of PDC was added and the reaction was shaken for another 6 hours. The crude product was filtered through Celite and purified by flash chromatography (silica gel, DCM). 1H NMR (CDCl3): δ (ppm): 7.50 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.68 & 7.70 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.09-8.11 (m, 1 H), 8.24 (d, J=8.8 Hz, 1 H), 8.57 (d, J=2.0 Hz, 1 H. MS: (M+H)/z=296.9