Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[N+:12]([O-])([OH:14])=[O:13]>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:3]=12
Reactant: O=[N+]([O-])O
Reactant: Fc1cnc2[nH]ccc2c1F
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncc(F)c(F)c12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79.8 %

Procedure:
4,5-Difluoro-1H-pyrrolo[2,3-b]pyridine (0.63 g, 4.09 mmol) was added slowly to fuming nitric acid (8.18 mL, 164 mmol) at 0° C. and stirred slowly for 5 minutes. Ice (20 g) was added followed by water (40 mL). The solid formed was collected by filtration to give 4,5-difluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.65 g, 80% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]([CH2:20][CH:21]=[CH2:22])[C:6](=[O:19])[CH:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]C=C.CS(C)=O>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[CH2:20][CH:21]=[CH:22][CH2:8][CH:7]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:6]1=[O:19]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)N(CC=C)CC(=O)OC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)CN1CC=CCC(NC(=O)OC(C)(C)C)C1=O
Reaction time: 12 h

Procedure:
Grubbs catalyst (0.3 g) is added to a solution of [allyl-(2-tert-butoxycarbonylamino-pent-4-enoyl)amino]acetic acid methyl ester, 1, (0.815 g, 2.5 mmol) in 50 mL of CH2Cl2. The solution is refluxed for 12 hours after which additional catalyst (0.29 g) is added and the solution is refluxed for another 3 hours. The solution is then cooled, 1 mL of DMSO is added, and stirring continued at room temperature for an additional 12 hours. The solvent is removed in vacuo and the residue purified over silica gel to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20][NH2:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH:8]([C:17]#[N:18])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:30]([O:32][C:33](=[O:35])[CH3:34])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:35])[CH3:34])[CH3:31].[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][N:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:19])[C:7]=1[CH:8]([C:17]#[N:18])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(NN)cc1Cl
Solvent: CCOC(C)=O
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(NN=Cc2ccccc2)cc1Cl
Yield: 68 %

Procedure:
In 50 ml of acetic acid ethyl ester was dissolved 3.0 g of 3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)phenylhydrazine. To the solution was added equimol. of benzaldehyde, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was dried over anhydrous magnesium sulfate, which was then concentrated to afford the titled compound in a yield of 68%, m.p.75-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28].N>CCO.CO.C(Cl)Cl>[O:20]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[NH:28])[CH:3]=2)[N:8]1[CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCN1CCCCC1
Agent: I
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCN1CCCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (225 mg, 0.82 mmol) in 10 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (470 mg, 1.65 mmol) and stirred overnight at room temperature. A TLC analysis indicated that the starting amine is still present. An additional 235 mg of methyl thiophene-2-carbimidothioate hydroiodide was added and stirring was continued for 1 day. Argon was bubbled through the mixture for 20 minutes then it was concentrated to give a brownish oil. This residue was partitioned between CH2Cl2 (50 mL) with 10% MeOH and saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a brown residue which was subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 to 10% 2M NH3 in MeOH/CH2Cl2 to give a yellow solid which contained a mixture of starting amine and the desired product. This mixture was then subjected to preparative TLC using 10% MeOH:10% Et3N:80% EtOAc as eluant. A small amount of product was obtained in pure form (analyzed by HPLC). This compound was converted to the dihydrochloride salt by dissolving in 10 mL of a 10% MeOH/CH2Cl2 solution, cooled to 0° C. and treated with 0.5 mL of a 1M HCl in Et2O solution. The solution was stirred for 20 minutes then concentrated to give a yellow-brown oil. A yellow solid was obtained after drying under high vacuum overnight. Yield: 12 mg of compound 1. HPLC analysis indicated that the product is >99% pure. 1H-NMR (MeOH-d4) δ: 8.08-8.05 (m, 2H), 7.40-7.38 (m, 4H), 4.42 (t, J=6.7 Hz, 2H), 3.77-3.73 (m, 2H), 3.41 (t, J=6.7 Hz, 2H), 3.32-3.02 (m, 4H), 2.76-2.72 (m, 2H), 2.00-1.53 (m, 6H); MS (ESI): 383.2 (M+1), 30%, 192.1 (M+2), 100%. ESI-HRMS calculated for C21H27N4OS (MH+): 383.1900, Observed: 383.1908.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:24]1([CH2:34][C:35](Cl)=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.O>C(Cl)Cl>[C:24]1([CH2:34][C:35]([N:12]2[CH2:11][CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:14][CH2:13]2)=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: O=C(Cl)Cc1cccc2ccccc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccc2ccccc12)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 7.5 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 4.6 ml of triethylamine in 40 ml of methylene chloride, 6.75 g of 1-naphthylacetyl chloride in 30 ml of methylene chloride area added dropwise at 0° C. The mixture is stirred at 0° C. for 2 hours and water is added. The organic phase is separated, washed with water many times and concentrated under reduce pressure to give 11 g of crude product. Crystallization from 95% ethanol yields 8 g of 1-(1-napthylacetyl)4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; m.p. 137°-140° C.
Reaction SMILES: C([Li])CCC.[CH:6]([NH:9][CH:10](C)C)(C)C.[CH2:13]([N:15]([CH2:24][CH3:25])[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:14].[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:24]([N:15]([CH2:13][CH3:14])[C:16](=[O:23])[C:17]1[C:22]([C:30](=[O:26])[C:29]2[CH:6]=[N:9][CH:10]=[CH:27][CH:28]=2)=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:25]
Reactant: CCN(CC)C(=O)c1ccccn1
Reactant: C1CCOC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Product: CCN(CC)C(=O)c1ncccc1C(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium (1.6M in hexane, 3.65 mL, 5.85 mmol) was added dropwise over a 5-minute period to a solution of diisopropylamine (818 μL, 5.85 mmol) in 20 mL of anhydrous tetrahydrofuran held at −78° C. and under nitrogen. The reaction was warmed to 0° C., held at that temperature for 15 min, and then cooled to −78° C. The resulting solution was added dropwise over a 10 minute period to a solution of N,N-diethylpicolinamide 14 (2.09 g, 11.7 mmol) in 20 mL of anhydrous tetrahydrofuran under nitrogen at −78° C. The reaction was then allowed to warm slowly overnight to ambient temperature and then quenched with 10 mL of water and 10 mL of saturated brine. The reaction mixture was extracted with 3×30 mL of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was crystallized from ethanol/hexanes to give N,N-diethyl-3-picolinoylpicolinamide 12 (750 mg, 2.64 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.69-8.60 (m, 1H), 8.62-8.53 (m, 1H), 8.09-7.95 (m, 3H), 7.66-7.53 (m, 2H), 3.43-3.24 (m, 2H), 3.07 (q, J=7.1 Hz, 2H), 1.22 (t, J=7.0 Hz, 2H), 0.55 (t, J=7.1 Hz, 2H). LCMS: (M+H)+, 284.
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:4]=1[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:28][C:29](=[O:31])[CH3:30])C=CC=CC=1>C1(C)C=CC=CC=1>[O:31]=[C:29]([CH3:30])[CH:28]=[CH:1][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:4]=1[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCc1c(C)c(C)c(C)c(C)c1C=O
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCc1c(C)c(C)c(C)c(C)c1C=CC(C)=O
Yield: 87.3 %

Procedure:
A solution of ethyl 4-(2-formyl-3,4,5,6-tetramethylphenyl)butyrate (5 g) and 1-triphenylphosphoranylidene-2-propanone (6 g) in toluene (100 ml) was boiled under reflux for 24 hours. The toluene was removed by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel (eluant chloroform) to give ethyl 4-[2-(3-oxo-1-butenyl)-3,4,5,6-tetramethylphenyl]butyrate (5 g) as a pale brown oil. Proton nuclear magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.24 (3H,t); 1.6-2.0 (2H,m); 2.1-2.4 (14H,m); 2.40 (3H,s); 2.5-2.8 (2H,m); 4.11 (2H,q); 6.12 (1H,d); 7.71 (1H,d).
Reaction SMILES: [CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>>[CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([CH2:26][CH2:25][CH:27]3[CH2:29][CH2:28]3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Reactant: C#CC1CC1
Product: C[C@](O)(CNC(=O)c1cnc(CCC2CC2)c(-c2ccc(Cl)cc2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 117, using 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide and ethynylcyclopropane as starting materials to yield the product as colorless foam, MS (ISP) 400.1 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:18][B:19](OC(C)C)[O:20]C(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>C1COCC1>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:19]([OH:20])[OH:18])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Ic1ccc(N2CCCCCC2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(N2CCCCCC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
Under an argon atmosphere, 1-(4-iodophenyl)azepane (200 mg) and triisopropylborate (162 mg) were dissolved in THF (2 ml), followed by cooling to −78° C. A 1.59 M butyl lithium/hexane solution (0.5 ml) was added thereto, followed by elevating the temperature to 0° C. over 1 hour, and further stirring at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain (4-azepan-1-ylphenyl)boronic acid (52 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[C@H:13]([CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]([F:19])([F:17])[F:18])[C@H:13]([CH2:20][NH2:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](CN2C(=O)c3ccccc3C2=O)[C@H](C(F)(F)F)C1
Agent: NN
Solvent: O
Solvent: CO
Product: NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.3 %

Procedure:
In 150 ml of methanol, is dissolved 9.33 g (21.6 mmol) of trans-1-benzyloxycarbonyl-3-phthalimidomethyl-4-trifluoromethylpyrrolidine. To the above solution, is added 2.1 ml (43.2 mmol) of hydrazine monohydrate, and the mixture is stirred at room temperature for 12 hours. The resulting precipitate is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is dissolved in dichloromethane and washed with water. The washed solution is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (elusion solvent; chloroform/methanol (100/2→100/5)) to give 5.89 g of the objective substance as a yellow oily matter (yield 90.3%).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:12]([S:14]([C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([C:23]2[N:28]3[CH:29]=[N:30][CH:31]=[C:27]3[C:26](=[O:32])[N:25]([CH3:33])[CH:24]=2)[CH:22]=1)(=[O:16])=[O:15])[CH3:13]>C1COCC1>[F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([O:8][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])=[CH:22][C:21]=2[C:23]2[N:28]3[CH:29]=[N:30][CH:31]=[C:27]3[C:26](=[O:32])[N:25]([CH3:33])[CH:24]=2)[CH2:4][CH2:3]1
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c(=O)c3cncn23)c1
Reactant: OC1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OC2CCC(F)(F)CC2)c(-c2cn(C)c(=O)c3cncn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To a solution of 4,4-difluorocyclohexan-1-ol (162 mg, 1.19 mmol) in THF (10 mL) was added NaH (48 mg, 1.19 mmol, 60% in mineral oil) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 minutes. Then the title compound from Step 2 (200 mg, 0.6 mmol) was added and the mixture was stirred at 25° C. for 18 hours. The reaction contents were poured into ice-water (v/v=1/1) (150 mL) and stirred for 20 minutes. The aqueous phase was extracted with EA (40 mL×3). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound (57.35 mg, 22%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.26 (s, 1H), 8.04 (dd, J1=8.8 Hz, J2=2.4 Hz 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 4.90-4.84 (brs, 1H), 3.44 (s, 3H), 3.32 (q, J=7.2 Hz, 2H), 1.85-1.83 (m, 4H), 1.69-1.61 (m, 4H), 1.15 (t, J=7.2 Hz, 3H). LCMS: 452.2 (M+H)+
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>>[CH3:13][C:12]1[C:7]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:32])([F:33])[F:23])=[CH:30][CH:29]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(C(F)(F)F)cc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [4-(trifluoromethyl)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.10 (s, 3H), 2.37 (s, 3H), 4.72 (d, J=5.4 Hz, 2H), 6.07 (bs, 1H), 6.55 (bs, 1H), 7.18 (t, J=7.0 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.58-7.65 (m 3H), 8.58 (d, J=3.2 Hz, 1H); MS (ESI) m/z 374.7 (M+1)+.
Reaction SMILES: [Br:1]Br.[Br:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].C(N(CC)CC)C.Cl.[C:18]([OH:22])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[Br:1][CH:6]([CH2:5][CH2:4][Br:3])[C:7]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:8]
Reactant: BrBr
Reactant: CC(C)(C)O
Reactant: O=C(Cl)CCCBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(Br)CCBr
Yield: 86 %

Procedure:
Bromine (31.3 ml, 0.54 mol) was added dropwise over 4 h at 100° C. to neat stirring 4-bromobutyryl chloride (100 g, 0.54 mol). The resulting acid chloride was cooled then added dropwise at 0° C. to a stirred solution of tert-butanol (240 ml) and triethylamine (64 ml, 0,461 mol) in anhydrous dichloromethane (600 ml). 2 M Hydrochloric acid was added and the layers separated. The organic portion was then washed sequentially with 10% sodium metabisulphite solution (2×500 ml), water (500 ml) and brine (500 ml), dried (MgSO4) and evaporated in vacuo to provide the title compound (120 g, 86%) as a brown liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=O.C([Li])CCC>C1COCC1.CCCCCC>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:14](=[O:16])[CH2:13][CH2:12]2
Reactant: O=C(O)CCc1cc(C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCc2cc(C(F)(F)F)ccc21
Yield: 37.2 %

Procedure:
To a solution of 3-[2-bromo-5-(trifluoromethyl)phenyl]propanoic acid (2.8 g, 9.4 mmol) in THF (100 mL) and hexane (20 mL) at −78° C. was dropwise added a 2.5 M solution of n-butyllithium in hexane (8.3 mL). After the addition had been completed, the reaction was quenched with saturated NH4Cl. The resulting solution was extracted with ethyl acetate twice. The extracts were washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. The crude material was purified by flash chromatography on silica eluting with 10-20% EtOAc/hexane to afford the desired product as a white solid (0.7 g, 37%). LC/MS calculated for C10H7F3O: (M+H)+ 201. found 201.1.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:7]=[N:8][C:9](=[O:12])[NH:10][CH:11]=1>CN(C)C=O.C(N(CC)CC)C>[CH3:1][NH:2][C:3]([N:10]1[CH:11]=[C:6]([Cl:5])[CH:7]=[N:8][C:9]1=[O:12])=[O:4]
Reactant: CN=C=O
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Methyl isocyanate (56.5 ml) was added dropwise over 15 minutes, with cooling, to a stirred solution of 5-chloropyrimidin-2-one (25 g) in N,N-dimethylformamide (290 ml) and triethylamine (30.4 ml). The temperature of the reaction mixture was kept at approximately 22° C. The mixture was stirred at room temperature for a further 40 minutes and then cooled in an ice bath. The solid was collected, washed with cold dichloromethane (4×215 ml), briefly air dried and then dried in vacuo at room temperature to give the title compound as white crystals (33.36 g), m.p. 241°-243° C. decomp. U.V. data: λmaxEtOH 230 nm (ε10,370), 322.5 mm (ε1,700).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([OH:11])[CH:10]=1)[CH:6]=[O:7])#[CH:2].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:10]=1)[CH:6]=[O:7])#[CH:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C#Cc1cc(O)cc(C=O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.0 g of 3-ethynyl-5-hydroxybenzaldehyde [CAS No. 871345-34-5] in 20 ml of DMF there were added 1.87 g of imidazole and 4.4 ml of chlorotriisopropylsilane. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled 1N hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.92 g) as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10](OCC)=[O:11])[C:3]1=[O:15].[NH2:16][C:17]1[N:21]=[CH:20][NH:19][N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[N:21]=[CH:20][NH:19][N:18]=2)=[O:11])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Nc1nc[nH]n1
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2nc[nH]n2)c(=O)n1C
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 81.3 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 78 mg of 3-amino-1,2,4-triazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 7.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 188 mg of 1,6-dimethyl-4-hydroxy-2-oxo-N-(1,2,4-triazol-3-yl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 23) represented by the formula:
Reaction SMILES: [C:1]1([C@H:7]([CH3:12])[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:32]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]3)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=3)[C:15]=12>ClCCl.N1C=CC=CC=1>[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:32]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]3)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:9](=[O:10])[CH2:8][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:12])=[C:25]([O:30][CH3:31])[CH:24]=3)[C:15]=12
Reactant: C[C@H](CC(=O)Cl)c1ccccc1
Reactant: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)C[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
(3R)-3-Phenylbutanoyl chloride (2.22 g, 12.18 mmol) in dichloromethane (10 mL) was added to a solution of 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (2.86 g, 8.12 mmol) in pyridine (50 mL) at −10° C. After 15 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature overnight. Sodium hydroxide (1.0N, 15 mL) was added and the organic solvent was evaporated. The aqueous residue was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichlromethane/methanol (95:5) as mobile phase to give N1-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-(3R)-3-phenylbutanamide (3.11 g, 77%). 1H NMR (CDCl3) δ 1.40 (d, J=6.97 Hz, 3H), 2.04 (m, 1H), 2.59-2.78 (m, 9H), 3.40 (m, 1H), 3.98 (s, 3H), 5.28 (m, 1H), 5.70 (bs, 2H), 7.15-7.35 (m, 7H), 7.66 (s, 1H), 8.38 (s, 1H), 8.51 (d, J=8.18, 1H). HPLC (Waters Alliance-Column: Waters SymmetryShield, RP8, 3.5 um, 2.1×50 mm. Eluents: 5% B/A to 95% B/A in 9.0 min.(B: acetonitrile, A: 100 mM ammonia acetate buffer, pH 4.5), 0.5 mL/min.): Rt=6.273 min.