Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:28])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>N1C=CC=CC=1>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([C:1]([O:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[CH:11][N:10]=3)[CH2:7][CH2:8]2)=[O:28])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: CC(C)N1CCNCC1
Reactant: NC(=O)c1ccc(N2CCC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)OC2CCN(c3ccc(C(N)=O)cn3)CC2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To the solution of 1-(5-carbamoylpyridin-2-yl)-piperidin-4-yl 4-nitrophenyl carbonate (3.0 g, 7.77 mmol) in pyridine (50 ml) was added 1-isopropylpiperazine (1.05 g, 8.16 mmol) and DIPEA (2.01 g, 15.5 mmol). The resulting mixture was stirred at 30° C. for 2 h before it was concentrated to dryness. The residue was further purified by silica gel chromatography (DCM: MeOH=50:1 to 5:1) to afford the title compound as a white solid (1.46 g, 50%). MP: 200.1-203.6° C. [1H NMR (DMSO, 500 MHz): δ 8.61 (d, J=2 Hz, 1H), 7.95 (dd, J=2.5 Hz, 9 Hz, 1H), 7.53 (s, 1H), 7.12 (s, 1H), 6.87 (d, J=9.5 Hz, 1H), 4.83 (m, 1H), 3.90-3.85 (m, 2H), 3.54-3.49 (m, 2H), 3.34 (s, 4H), 2.67-2.64 (m, 1H), 2.38 (m, 4H), 1.89-1.85 (m, 2H), 1.58-1.54 (m, 2H), 0.95 (d, J=6.5 Hz, 6H); LCMS RtA=1.61 min, [M+H]+=376.3].
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[CH:42][CH2:43][CH2:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[H][H]>[Pt]=O.C(O)C>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CCCC=Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: O=[Pt]
Solvent: CCO
Product: CCCCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 62.1 %

Procedure:
To 26 ml of ethanol solution containing 1.08 g (1.60 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(1-pentenyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 68-(a) was added 43.8 mg of platinum oxide, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 3 hours. After completion of the reaction, the insoluble material was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.66 g of the title compound as a colorless oil. (Yield: 626).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.N1C=C[CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:24]([O:5][C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH2:9][CH:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:23]#[CH:22]
Reactant: c1ccncc1
Reactant: CCCCCC(C)CC=CC(C)=CC(=O)O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: C#CCOC(=O)C=C(C)C=CCC(C)CCCCC
Temperature: 22 °C
Reaction time: 1 h

Procedure:
1.6 g of 3,7-dimethyl-2,4-dodecadienoic acid is dissolved in 20 ml of absolute diethyl ether and 0.55 ml of pyridine. The resulting mixture is added dropwise over a period of about 10 minutes to 0.57 ml of thionyl chloride at a temperature between 0°C. and +10°C. Subsequently the mixture is stirred for 1 hour at room temperature (22°C.), then decanted off, and the residue is washed with absolute diethyl ether. The solution is evaporated to dryness under anhydrous conditions. The residue is dissolved in 10 ml of absolute diethyl ether. The ethereal solution is added dropwise at a temperature between 0°C. and +10°C., over a period of about 20 minutes, to a solution consisting of 0.56 ml of propargyl alcohol and 0.55 ml of pyridine in 10 ml of absolute ether. After stirring overnight (16 hours) at room temperature (22°C.) the mixture is diluted with diethyl ether, washed with 1-N hydrochloric acid, saturated aqueous sodium bicarbonate solution and finally with aqueous sodium chloride solution. After drying, the ethereal phase is evaporated. The crude product is chromatographed on a 30-fold amount of Kieselgel, using hexane/diethyl ether (19:1 parts by volume) as the eluant. There is obtained 3,7-dimethyl-2,4-dodecadienoic acid propargyl ester as a colorless oil; boiling point 105°C/0.05 mmHg (bulb tube); n25 25= 1.4951.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:14])([F:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([F:13])([F:14])[CH2:11][O:12][S:16]([CH3:15])(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
A solution of 3-benzyloxy-2,2-difluoropropan-1-ol (Compound 59H, 202 mg, 1 mmol) and methanesulfonyl chloride in DCM (3 mL) was cooled to 0° C. and treated with Et3N (0.28 mL, 2 mmol). The reaction mixture was allowed to warm at RT. After 12 h, the reaction mixture was diluted with DCM (5 mL) and washed with aq. K2CO3 (4×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give 220 mg (82%) of the title compound as yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.33 (m, 5H), 4.62 (s, 2H), 4.47 (t, J=12.4 Hz, 2H), 3.74 (t, J=12.4 Hz, 2H), 3.05 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[OH-].[Na+]>O.CO>[CH3:6][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]([OH:13])=[O:2]
Reactant: COC(=O)CN(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CC(=O)O)c1ccccc1

Procedure:
To 500 ml of water/methanol (1/4 weight ratio), 30 g of N-phenyl-N-methylglycine methyl ester and 12.3 g (1.1 equivalent weight) of NaOH were added and refluxed for 2 hours. The methanol was evaporated from the reaction mixture under reduced pressure. Then, water was added thereto and unreacted starting materials were extracted with methylene chloride. Subsequently, 10% hydrochloric acid was added to the aqueous layer to adjust the pH at about 5, followed by extraction with ether. The ether layer wad dried, and solvent distilled to yield N-methyl-N-phenylglycine in 27.1 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:23]5[O:24][CH2:25][CH2:26][O:27][C:22]=5[CH:21]=4)[CH2:16][CH2:15]3)[C:6]=2[CH:30]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:23]5[O:24][CH2:25][CH2:26][O:27][C:22]=5[CH:21]=4)[CH2:16][CH2:15]3)[C:6]=2[CH:30]=1)(=[O:33])[CH3:32]
Reactant: Nc1ccc2ncn(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc2ncn(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1

Procedure:
Analogously to Example 6, reaction of 6-[4-(4-(6-aminobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane ("D") with acetyl chloride gives 6-[4-(4-(6-acetamidobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C=O)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][CH:17]=C2>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][CH:17]=[C:2]2[CH:1]=[O:5]
Reactant: Fc1cc2cc[nH]c2cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1c[nH]c2cc(F)c(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of oxalyl chloride (1.21 mL, 13.8 mmol) in CH2Cl2 (40 mL) was added a solution of DMF (2.02 mL) in CH2Cl2 (40.0 mL). The reaction was stirred for 30 min, then 5,6-difluoro-1H-indole [169674-01-5] (2.00 g, 13.1 mmol) was added in one portion. The reaction mixture was allowed to warm to RT overnight. Volatiles were evaporated, and the residue was taken up in THF (20 mL) and 20% aqueous ammonium acetate solution (20 mL). The resulting mixture was heated to reflux for 30 min. After cooling, the mixture was treated with saturated aqueous NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were dried (phase separator) and evaporated in vacuo to afford the title compound as a beige solid: MS (LC/MS): 182.0 [M+H]+; tR (HPLC conditions c): 3.94 min. The material thus obtained was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.Cl.O1CCOC[CH2:22]1>>[F:1][C:2]1[C:3]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)=[N:4][CH:5]=[C:6]([CH3:22])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: C1COCCO1
Agent: Cl
Product: Cc1cnc(-c2nn(C)c(OC(F)F)c2Cl)c(F)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
2.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example P15) are introduced into 6 ml of absolute dioxane. In order to remove the oxygen, gentle evacuation is carried out three times (water-jet pump) and the mixture is gassed with argon. 6.4 ml of a 2M solution of trimethylaiuminium in toluene and 0.10 g of tetrakistriphenylphosphinepalladium (Pd(PPh3)4) are added thereto. The mixture is heated to 90° C., with stirring, in an argon atmosphere. The next day the mixture is cooled to 22° C., a further 0.10 g of Pd(PPh3)4 and 6.4 ml of a 2M solution of trimethylaluminium in toluene are added and the mixture is stirred at 110° C. After 4 hours, TLC analysis of a worked-up sample shows that all the starting material has reacted. The reaction mixture is introduced carefully into cold, dilute hydrochloric acid and is then extracted with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The crude product obtained is purified over a flash chromatography column (silica gel; eluant: n-hexane/ethyl acetate 1/1 (v/v)). 1.36 g of the desired compound are obtained in the form of a yellow oil, which slowly crystallises; melting point 41-42° C.
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.[N+:9]([C:12]1[CH:22]=[CH:21][C:15]([CH2:16][O:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10].[OH-].[Na+].Cl>O.O1CCCC1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]([N:3]2[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]2)=[O:19])=[CH:21][CH:22]=1)([O-:11])=[O:10]
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 116.2 %

Procedure:
To a solution of (R)-thiazolidine-4-carboxylic acid (20.0 g) in a mixture of water (100 ml) and tetrahydrofuran (100 ml) was added a solution of 4-nitrobenzyloxycarbonyl chloride (32.4 g) in tetrahydrofuran (60 ml) under ice-cooling with stirring, keeping the pH between 8.5 and 9.0 with 4N aqueous sodium hydroxide. After stirring for 30 minutes, the mixture was adjusted to pH 1 with concentrated hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, and evaporated under reduced pressure to give (R)-3-(4-nitrobenzyloxycarbonyl)thiazolidine-4-carboxylic acid (54.5 g) as a crude syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.C[Si]([C:14]#[CH:15])(C)C.C(N(CC)C(C)C)(C)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN1CCCC1=O>[C:14]([C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)#[CH:15]
Reactant: Nc1ncc(F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1cc(F)cnc1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of 5-fluoro-3-iodo-pyridin-2-ylamine (751 mg, 3.16 mmol) described in Manufacturing Example 173-1-1, trimethylsilylacetylene (874 μL, 6.32 mmol), copper (I) iodide (60.2 mg, 0.32 mmol), N,N-diisopropylethylamine (1.07 mL, 6.32 mmol), and N-methylpyrrolidinone (15 mL) was added tetrakis(triphenylphosphine)palladium (0) (183 mg, 0.16 mmol), which was stirred for 3 hours under nitrogen atmosphere at 70° C. This reaction solution was cooled to room temperature, and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography and then silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (129 mg, 30%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>>[CH3:30][S:31]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:33])=[O:32]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCN(S(C)(=O)=O)C3)cnc21

Procedure:
((R)-1-Methanesulfonyl-pyrrolidin-3-yl)-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methanesulfonyl chloride using DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].[CH:20]1([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][C:24]=2I)[CH2:22][CH2:21]1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:20]1([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][C:24]=2[C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[CH:11]=[C:10]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=23)[CH2:22][CH2:21]1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Reactant: Ic1cnn(-c2ccccc2)c1C1CC1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccc4)c3C3CC3)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (40 mg, 0.160 mmol), 5-cyclopropyl-4-iodo-1-phenyl-1H-pyrazole (62 mg, 0.20 mmol), copper (I) iodide (9.1 mg, 0.048 mmol), and tetrakis(triphenylphosphine)palladium (0) (18.3 mg, 0.016 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.044 ml, 0.32 mmol). The mixture was sparged with argon for 3 minutes and heated to 70° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 3-[(5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: Cl.[CH:2]([C:5]1[N:9]=[CH:8][N:7]([CH2:10]Cl)[N:6]=1)([CH3:4])[CH3:3].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:2]([C:5]1[N:9]=[CH:8][N:7]([CH2:10][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:6]=1)([CH3:4])[CH3:3]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)c1ncn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ncn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 27.3 %

Procedure:
0.78 g of 3-i-propyl-1-(chloromethyl) -1H-1,2,4-triazole hydrochloride and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 12 ml of N,N-dimethylformamide. 1.10 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. 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 0.31 g of [(3-i-propyl-1H-1,2,4-triazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (28), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=O)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.C[N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([NH2:19])=[O:17])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: O=C(O)CCNc1nc(Cl)cc2nccnc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of 3-(7-chloropyrido[4,3-b]pyrazin-5-ylamino)propanoic acid (2.22 mmol), HATU (2.66 mmol), DIPEA (6.65 mmol) and NH4Cl (4.43 mmol) in THF (10 mL) was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was treated with water. The precipitates were collected by filtration and dried to give the title compound. MS (m/z): 252 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>COCCOC>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1cccc(Cl)c1
Yield: 71.3 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-chloro-phenylboronic acid (30 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (39 mg, 72%). LC-MS m/e 421.26 (M+H+)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].F[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc(F)cc2[N+](=O)[O-])CC1
Yield: 104.8 %

Procedure:
To a solution of 1-acetylpiperazine (48 g) in acetonitrile (100 ml) were added 2,5-difluoronitrobenzene (50 g) and potassium carbonate (44 g) and the mixture was refluxed under heating for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated to give the title compound (88 g) as a red solid.
Reaction SMILES: [S-2:1].[Na+].[Na+].CO.[C:6]([N:10]=[N:11][C:12]1(Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7]>O>[C:6]([N:10]=[N:11][C:12]1([S:1][C:12]2([N:11]=[N:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: [S-2]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC1(SC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Temperature: 15 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
A solution of 1.56 grams (.02 moles) of sodium sulfide in 50 ml. of 75% aqueous methanol was prepared in a 200 ml. beaker and cooled to 15°C. To this solution was added 8.2 grams (.0404 moles) of 1-t-butylazo-1-chlorocyclohexane dropwise over a 15 minute period. After the addition was complete, the reaction was stirred for 45 minutes at room temperature and poured into 100 ml. of cold water. A solid formed and was filtered off and dried. The dried material weighed 2.2 grams (30% yield). The infrared spectrum of the product was in agreement with the structure of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)ncc1[N+](=O)[O-]
Yield: 102.3 %

Procedure:
To a mixture of 2-chloro-4-methyl-5-nitropyridine (5.44 g, 26.3 mmol) and dibenzylamine (5.04 mL, 26.3 mmol) in toluene (13.1 mL) was added sodium carbonate (5.58 g, 52.6 mmol). After stirring under a nitrogen atmosphere under reflux for 36 h, the reaction mixture was filtered to remove the sodium carbonate. The filtrate was concentrated to provide the crude material as a light orange oil. The crude oil was dissolved in methylene chloride and treated with 2 N HCl. The resulting precipitate was filtered off and discarded. The filtrate was washed with 2 N HCl and the acidic layers were back-extracted with methylene chloride. The combined extracts were washed with saturated NaHCO3, dried over Na2SO4, filtered and concentrated to provide 2-(dibenzylamino)-5-nitro-4-methylpyridine (8.97 g, 102% theoretical) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ2.53 (3H, s), 4.85 (4H, s), 6.27 (1H, s), 7.19-7.37 (10H, m), 9.05 (1H, s).