Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH3:15][Si:16]([CH3:42])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>COCCOC>[CH3:42][Si:16]([CH3:15])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:37])=[CH:39][CH:40]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 16.9 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is evaporated and the residue is recrystallized to yield the title product.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[NH:4][CH3:5].Br.Br[CH:14]([C:16]1[CH:17]=[C:18]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH:19]=[C:20]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])[CH3:15]>>[CH3:36][N:35]([CH3:37])[C:33]([C:18]1[CH:19]=[C:20]2[C:25](=[C:16]([CH:14]([N:4]([CH3:5])[C:3]3[CH:6]=[C:7]([F:11])[CH:8]=[C:9]([F:10])[C:2]=3[F:1])[CH3:15])[CH:17]=1)[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])=[O:34]
Reactant: CNc1cc(F)cc(F)c1F
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1F
Yield: 7.9 %

Procedure:
2,3,5-trifluoro-N-methylaniline (197 mg, 1.22 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.31 mmol) using an analogous procedure to the one described in Example 3.03 to give N,N-dimethyl-8-(1-(methyl(2,3,5-trifluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (12 mg, 8%) as a white solid. Mass Spectrum: M+H+ 490. NMR Spectrum (DMSOd6): 1.63 (d, 3H), 2.67 (s, 3H), 2.92 (bs, 3H), 3.02 (bs, 3H), 3.18-3.26 (m, 2H), 3.22-3.37 (m partially hidden by H2O, 2H), 3.49-3.56 (m, 2H), 3.56-3.63 (m, 2H), 5.38 (q, 1H), 5.53 (s, 1H), 6.68-6.75 (m, 1H), 6.88-6.96 (m, 1H), 7.78 (d, 1H), 7.86 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C(O)CO>[CH:13]1([NH:19][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]3[NH:10][CH:11]=[CH:12][C:3]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Reactant: NC1CCCCC1
Solvent: OCCO
Solvent: O
Product: O=Cc1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (845 mg, 4.68 mmol) and cyclohexylamine (2.5 mL, 22 mmol) in ethylene glycol (2 mL) were stirred at 170° C. for 1 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with chloroform. The organic layer was stirred with 2 M hydrochloric acid (20 mL) for 1 hour, and the organic layer was separated. The aqueous layer was adjusted to pH 9 or above with 10 M aqueous sodium hydroxide and extracted with chloroform. The organic layers were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1 (v/v)) to give the title compound as a pale yellow oil (804 mg, yield 71%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.Cl>CS(C)=O.C(OCC)C>[Cl:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[CH:3]=1)[C:7]#[N:8]
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CN1CCN(c2cc(Cl)cc(C#N)c2)CC1
Temperature: 80 °C
Yield: 92.8 %

Procedure:
5-Fluoro-3-chloro-benzonitrile (1 g, 6.4 mmol) was dissolved in DMSO (20 ml) followed by addition of K2CO3 (1.3 g, 9.6 mmol) and 1-methyl piperazine (1.4 ml, 12.8 mmol). The reaction mixture was heated at 80° C. for 20 hours. Diethyl ether was added to the crude material (10 ml) then acidified with 1N HCl. A precipitate was filtered off from the crude reaction mixture to give 3-chloro-5-(4-methyl-piperazin-1-yl)-benzonitrile (1.4 g, 93% yield) as a white solid (LC/MS: Rt 1.83 [M+H]+ 236, acidic method).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH:12]1[C:27]([OH:29])=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13][CH:12]1[C:27]([O:29][CH3:32])=[O:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a flask containing N,N'-dibenzyloxycarbonylpiperazine-2-carboxylic acid (Step 1, 12.83 g, 32.20 mmol) dissolved in dry DMF (50 mL) is added methyl iodide (5.6 mL, 90.00 mmol) and potassium carbonate (4.60 g, 32.20 mmol). The mixture is stirred for 4 hours at ambient temperature under an inert atmosphere. The reaction is concentrated in vacuo, diluted with ethyl acetate (150 mL), washed with water (3×50 mL) and saline, dried over MgSO4, concentrated in vacuo, and chromatographed on silica gel (70-230 mesh), eluting with hexane/ethyl acetate (50/50). The appropriate fractions are combined (Rf =0.55, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.31, 5.15, 5.12, 4.70, 4.1-2.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[O:30][CH3:31])=[CH:7][CH:8]=[C:9]([NH:14][C:15]([C:18](OC)=[O:19])([CH3:17])[CH3:16])[C:10]=1[N+:11]([O-])=O)=[O:4].[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]2[NH:11][C:18](=[O:19])[C:15]([CH3:16])([CH3:17])[NH:14][C:9]=2[CH:8]=[CH:7][C:6]=1[C:22]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:30][CH3:31])=[O:4]
Reactant: COC(=O)c1c(-c2c(OC)cccc2OC)ccc(NC(C)(C)C(=O)OC)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2c(OC)cccc2OC)ccc2c1NC(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of biphenyl vi (800 mg, 1.85 mmol) in EtOH (20 mL) was added tin(II) chloride (1.76 g, 9.26 mmol). The mixture was heated at reflux for 16 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (50 mL) and basified with saturated aqueous NaHCO3. The resulting white suspension was stirred at room temperature for 30 min, then filtered through celite and the precipitate was washed by EtOAc (3×20 mL). The two layers were separated and the organic layer was collected. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine and dried over MgSO4. After the solvent was removed under reduced pressure, the residue was purified by flash chromatography (EtOAc/hexane, 40% to 70%) to yield vii as a light yellow solid (500 mg, 73%). 1H NMR (CDCl3): δ 7.93 (br s, 1H), 7.14 (t, J=8.4 Hz, 1H), 6.73 (m, 2H), 6.51 (d, J=8.4 Hz, 1H), 3.62 (s, 6H), 3.37 (s, 3H), 1.34 (s, 6H). Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C, 65.00; H, 5.73; N, 7.31.
Reaction SMILES: C(O[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[N:21]=[C:20]1[CH2:28][CH2:29][CH2:30][CH3:31])C1C=CC=CC=1.CC[OH:34]>[Pd]>[CH2:28]([C:20]1[N:19]([C:10]2[CH:9]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([OH:34])=[CH:15]3)[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[N:21]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCc1nc2cccnc2n1-c1c(OCc2ccccc2)ccc2ccccc12
Reactant: CCO
Agent: [Pd]
Product: CCCCc1nc2cccnc2n1-c1cccc2cc(O)ccc12
Reaction time: 72 h

Procedure:
A solution of 3-(benzyloxy-naphthalen-1-yl)-2-butyl-3H-imidazo[4,5-b]-pyridine (1500 g) in EtOH (75 mL) was added to a mixture of Pd/C (3.56 g) in EtOH (50 mL). The mixture was hydrogenated on a paar shaker at 50 psi for 72 hours. The reaction mixture was filtered through celite and concentrated in vacuo to give 1.13 grams of an amorphous solid. 1H NMR (250 MHz, CDCl3): d 8.48 (d, 1 H), 8.24 (d, 1 H), 7.52 (m), 7.37 (dd, 1 H), 7.26 (d, 2 H), 6.68 (dd, 2 H), 6.60 (s, 1 H), 2.67 (t, 2 H), 170 (m, 2 H), 1.23 (m, 2 H), 0.78 (t, 3 H).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:13].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[CH:6]([C:5]1[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]([O:1][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27])=[C:3]([CH3:13])[CH:4]=1)=[O:7]
Reactant: Cc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1c(C)cc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-3-methyl-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a tan solid: 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.97 (s, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.09 (d, J=1.5 Hz, 1 H), 4.82 (q, J=6.8 Hz, 1H), 3.62 (s, 3H), 2.42 (s, 3H), 1.52 (d, J=6.8 Hz, 3H). ESI-MS: m/z 268.1 (M+H)+.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].[H-].[Na+]>C1(C)C=CC=CC=1>[O:16]=[C:3]1[CH2:4][N:5]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:19][CH:18]1[C:17]([O:21][CH3:22])=[O:20]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A solution of carbobenzyloxyglycine methyl ester (10 g, 44.8 mmol) and methyl acrylate (4.03 mL, 44.8 mmol) in toluene (100 mL) at 0° C. was added 60% NaH in mineral oil (1.971 g, 49.3 mmol) which was stirred for 10 minutes, and then it was warmed up to RT and stirred for 20 minutes. The reaction mixture was heated to 50° C. for 3 hrs. The reaction mixture was quenched with 10% citric acid solution until pH about 3, and then it was extracted with 100 mL×3 of EtOAc. The combined organic phases were washed with 100 mL of brine and dried over Na2SO4. Filtration and concentration to yield the product (12 g, 96% yield). MS(ES+) m/z: 278.2 (M+H); HPLC retention time: 2.44 min (analytical HPLC Method B).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[C:23](Cl)(=[O:25])[CH3:24]>CN(C=O)C.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine (190 mg; 0.58 mmol; 1.0 eq.) and TEA (242 μl; 1.74 mmol; 3.0 eq.) in DMF (3.8 mL) was added acetyl chloride (46 μl; 0.70 mmol; 1.2 eq.) and the reaction mixture was stirred overnight at RT. Reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a white solid. 1H NMR (300 Mz, DMSO) δ: 13.36 (brs, 1H), 8.29 (s, 1H), 8.47 (t, J=5.9 Hz, 1H), 8.36 (dt, J=8.0 Hz, J=1.0 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.60 (dt, J=8.4 Hz, J=1.0 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 1H), 4.34 (d, J=5.9 Hz, 2H), 1.90 (s, 3H). HPLC (Condition A): Rt 2.81 min (purity 97.7%). MS (ESI+): 333.2, MS (ESI−): 331.2.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][C:16](=[O:18])[C:15]([C:19](=O)[CH2:20][CH3:21])=[C:14]([OH:23])[CH2:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:24]([O:27][NH2:28])[CH:25]=[CH2:26]>O1CCCC1>[CH2:24]([O:27][N:28]=[C:19]([C:15]1[C:16](=[O:18])[CH2:17][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=2)[CH2:13][C:14]=1[OH:23])[CH2:20][CH3:21])[CH:25]=[CH2:26]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Reactant: C=CCON
Solvent: C1CCOC1
Product: C=CCON=C(CC)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Reaction time: 15 h
Yield: 68.8 %

Procedure:
Into 10 ml of tetrahydrofuran was dissolved 1.0 g of 5-(4-methanesulfonamidophenyl)-3-hydroxy-2-propionyl-2-cyclohexen-1-one and to the solution was added 0.5 g of allyloxyamine. The mixture was kept at room temperature for 15 hours and then it was treated with similar process in Example 1. Thus, 0.8 g of the objective compound was obtained. It was colorless crystals having a melting point of 134°-135° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc2c1CCNC2CN1CCCC1
Reactant: O=C(Cl)c1cccs1
Solvent: ClC(Cl)Cl
Product: O=C(c1cccs1)N1CCc2c(O)cccc2C1CN1CCCC1

Procedure:
Prepared as Ex. N° 55, from 0.88 g (3.78 mmoles) of 1-(pyrrolidin-1-yl) methyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline and 0.83 g (5.66 mmoles) of 2-thiophene carbonyl chloride in 60 ml of dry chloroform, at -10° C.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][C:16]=2[O:18][CH3:19])[C:11](=O)[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][C:16]=2[O:18][CH3:19])[C:11]([Cl:25])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c2c(Cc3ccccc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)c2c(Cc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-benzyl-5,7-dimethoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:27].[I-]>N.CCO>[NH2:27][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: CSC1=NC2(CC(c3cccc(F)c3)Oc3ccc(Br)cc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3cccc(F)c3)Oc3ccc(Br)cc32)N=C1N
Yield: 49.5 %

Procedure:
A solution of 6-bromo-2-(3-fluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 0.18 mmol) and NH4I (52 mg, 0.36 mmol) in NH3/EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC and then by preparative HPLC to afford 2′-amino-6-bromo-2-(3-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (36 mg, 50%). 1H-NMR (MeOD): 2.16 (m, 2H), 3.12 (s, 3H), 5.87 (d, 1H), 6.90 (d, 1H), 7.08 (m, 2H), 7.25 (m, 2H), 7.33 (d, 1H), 7.41 (m, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([N:13](C)[CH2:14]C2C=CC=CC=2)[CH:10]=[C:9]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:8]=1)=[O:6])([CH3:3])[CH3:2].CO.[H][H]>[Pd].C(O)(=O)C>[CH:1]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([NH:13][CH3:14])[CH:10]=[C:9]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[N:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cc(N(C)Cc2ccccc2)cc(Oc2cccc(C(F)(F)F)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(C)C)c1

Procedure:
1.12 g (0.0012 mol) of N-(i-propyl)-4-(methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide were mixed with methanol and then with a small amount of 10% palladium/carbon and acetic acid. The obtained mixture was stirred at room temperature for about 16 hours in a hydrogen atmosphere. The obtained reaction solution was filtered using Hyflo Super Cell and then concentrated. The concentrate was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[N:18][O:19][CH3:20])[C:15]([NH2:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.Cl>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[N:18][O:19][CH3:20])[C:15]#[N:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
2-(2-Phenoxyphenyl)-2-methoxyiminoacetamide (3.77 g) was dissolved in pyridine (5.53 g). The solution was cooled to 0° C. Trifluoroacetic anhydride (4.40 g) was added dropwise. The mixture was stirred for 2 hours at 0° C., and then diluted with dil. hydrochloric acid and extracted with ethyl acetate. The extract was dried and concentrated to leave a residue, which was purified by column chromatography on silica gel to obtain 2-(2-phenoxyphenyl)-2-methoxyiminoacetonitrile (3.41 g).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([CH2:63][CH2:64][CH2:65][CH2:66][C@H:67]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:68](OCC#N)=[O:69])=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([CH2:63][CH2:64][CH2:65][CH2:66][C@@H:67]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:68]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:69])=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN=[N+]=[N-])C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCCN=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (78 mg, 0.122 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-azido-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk49) (152 mg, 0.488 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 0.75 hour. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-azido-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk50) (30.2 mg, 28%).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[CH2:21][CH2:20][CH2:19]2>CCOCC.Cl>[F:8][CH:2]([F:1])[C:3](=[C:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=2)[C:22]1=[O:26])[OH:5]
Reactant: CCOC(=O)C(F)F
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COc1ccc2c(c1)CCC(=C(O)C(F)F)C2=O
Temperature: 25 °C

Procedure:
A 500 mL one neck round bottomed flask equipped with a nitrogen inlet and provisions for magnetic stirring was charged with ethyl difluoroacetate (6.2 g, 50 mmol) and 75 mL of ether. To this solution was added 12 mL of 25% sodium methoxide in methanol (52.5 mmol). A solution of 6-methoxy-1-tetralone (8.81 g, 50 mmol) in 125 mL of ether was added over about 1 minute. The reaction mixture was stirred at room temperature for 14 hours and was diluted with 150 mL of 1N HCl. The phases were separated and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was taken up in 70 mL of boiling ethanol/water and cooled to room temperature, whereupon crystals of 2-[2,2-difluoro-1-hydroxyethylidene]-3,4-dihydro-6-methoxy-1(2H)-naphthalenone (also known as 6-methoxy-2-difluoroacetyl-1-tetralone) formed which were isolated by filtration and air dried (10.8 g, 85%): mp 52°-54° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[N:22][C:17]2=[N:16][CH:15]=1)CCC>>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[N:22][C:17]3=[N:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Yield: 39.8 %

Procedure:
2,4-Dichloropyrimidine (317 mg, 2.13 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-(2-chloropyrimidin-4-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (167 mg) as a white solid: δH (400 MHz, DMSO) 7.91 (1H, d, J 7), 8.25 (1H, d, J 5), 8.83 (1H, d, J 5), 9.17 (1H, s), 10.22 (1H, d, J 7); m/z (ES+) 300, 302 (M++H).