Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8].[C:16]([C:20]1[S:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][C:24]=1[OH:25])([O:18][CH3:19])=[O:17]>CC(C)=O>[C:16]([C:20]1[S:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][C:24]=1[O:25][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8])([O:18][CH3:19])=[O:17]
Reactant: CCOP(=S)(Cl)OCC
Reactant: COC(=O)c1cc(O)c(C(=O)OC)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1cc(C(=O)OC)sc1C(=O)OC
Temperature: 20 °C
Reaction time: 15 h
Yield: 48.9 %

Procedure:
7 g of potassium carbonate and 8.9 g of O,O-diethyl chlorothiophosphate were added to a solution of 10.9 g of 2,5-dicarbomethoxy-3-hydroxy-thiophene in 500 ml of acetone and the mixture was stirred for 15 hours at 20° C. and was then filtered. The filtrate was evaporated to dryness and the residue was empasted with a 10-1 petroleum ether-isopropyl ether mixture. The mixture was vacuum filtered and the precipitate was crystallized from ethanol to obtain 8.5 g of 2,5-dicarbomethoxy-3-(diethoxythiophosphoryloxy)-thiophene melting at 50° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:35][CH2:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: COc1ccc(CN)cc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCc3ccc(OC)cc3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and (4-methoxyphenyl)methanamine as a yellow solid (100%). MS 466 (MH+).
Reaction SMILES: [CH:1]([C:4]1([C:13]([O:15]C(C)(C)C)=[O:14])[CH2:8][CH2:7][C:6](OC)([O:9]C)[CH2:5]1)([CH3:3])[CH3:2].O>Cl.O1CCOCC1>[CH:1]([C:4]1([C:13]([OH:15])=[O:14])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)C)C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C1(C(=O)O)CCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 1-isopropyl-3,3-dimethoxycyclopentanecarboxylate (8.32 g, 30.5 mmol) was dissolved in 4N anhydrous HCl in dioxane (50 mL) and water (10 mL) was added. The reaction mixture was stirred at rt overnight, then was concentrated. The residue was dissolved in DCM, dried over anhydrous MgSO4, filtered, and concentrated to give 1-isopropyl-3-oxocyclopentanecarboxylic acid (used without purification). 1H NMR (500 MHz, CDCl3) δ 2.70 (d, J=18.1 Hz, 1H), 2.44-2.39 (m, 1H), 2.30-2.15 (m, 2H), 2.14 (dd, J=18.1, 1.0 Hz, 1H), 2.06 (p, J=6.9 Hz, 1H), 1.98 (m, 1H), 0.98 (dd, J=11.4, 6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH4+].[Cl-]>CCOC(C)=O.[Fe]>[CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([NH2:17])[C:11]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(N)cc(Br)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A 1000 mL RBF equipped with an overhead stirrer was charged with 5-bromo-2-methyl-3-nitro benzoic acid benzyl ester (75.0 g, 0.214 mol) and water (200 mL). While stirring vigorously, Fe powder (−325 mesh, 47.81 g, 0.857 mol) and NH4Cl (13.88 g, 0.257 mol) were added. The mixture was heated to reflux for 4.5 hours. The reaction mixture was then allowed to cool to room temperature, diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with water (2×), saturated NaCl (1×), dried (MgSO4), and concentrated. Upon trituration with hexanes, 63.2 g (92.1%) of an off-white powder was obtained. 1H NMR (CDCl3) δ 7.38 (m, 6H), 6.90 (s, 1H), 5.31 (s, 2H), 3.76 (br s, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[O:9]=[C:10]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]1[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]12[O:3][C:4]([CH3:8])([CH:14]3[C:10](=[O:9])[N:11]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:27])[F:26])[CH:17]=4)[C:12](=[O:15])[CH:13]31)[C:5]([CH3:7])=[N:6]2
Reactant: Cc1nc(C)c(C)o1
Reactant: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1=NC2(C)OC1(C)C1C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C12
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 35.9 %

Procedure:
2,4,5-Trimethyl oxazole (0.48 mL, 4.14 mmol) was dissolved in toluene (2.0 mL) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile (1.00 g, 3.76 mmol) was added. The reaction mixture was stirred at 75° C. under nitrogen for 2.5 hrs. The solution was cooled to room temperature and the resulting precipitate was filtered and rinsed with toluene to give 0.51 g (35%) of compound 211 as a light grey solid. NMR analysis revelaed that compound 211 was one isomer (exo/endo) however the identity of the isomer could not be determined by NMR analysis. HPLC: 100% at 2.85 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 378.42 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].B.CSC.Cl>C1COCC1>[C:11]1([CH2:10][CH2:9][NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCCCCNC(=O)Cc1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCCCCNCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
N-Heptyl-2-phenylacetamide (0.886 g, 3.797 mmol) was dissolved in THF (10 ml) and was cooled to 0° C. under argon atmosphere. (Methylthio)methane compound with borane (1:1) (0.721 g, 9.492 mmol) was added and the mixture was refluxed for 5 hours. After the mixture was cooled to room temperature, 5 ml HCl (10%) was gently added and the mixture was stirred overnight. The solvent was removed by evaporation. EtOAc (20 ml) was added and the organic phase was washed with K2CO3 (2M, 2×20 ml). The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.584 g of N-(2-phenylethyl)heptan-1-amine (yield 70.1%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:12][CH2:13][CH2:14][CH2:15][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccccc1OCCCBr
Yield: 83.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 4.0 grams (0.025 mole) of 2-trifluoromethylphenol, 17.8 mL (0.178 mole) of 1,3-dibromopropane, and 9.0 grams (0.065 mole) of potassium carbonate in 120 mL of acetone was heated at reflux for about 18 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using petroleum ether. The product containing fractions were combined and concentrated under reduced pressure, yielding 5.9 grams of 2-trifluoromethylphenyl 3-bromopropyl ether. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])([CH3:16])[CH3:15].C([N-]C(C)C)(C)C.[Li+]>>[CH3:16][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][C:27]([CH:10]1[CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:13][C:11]1=[O:12])=[O:28])[CH3:15]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCC1CCC(=O)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCC1CC(C(=O)Nc2c(C(C)C)cccc2C(C)C)C(=O)O1

Procedure:
The title compound, mp 95°-98° C., was prepared from undecanoic γ-lactone (5.0 g, 0.027 mol), 2,6-diisopropylphenyl isocyanate (5.50 g, 0.027 mol) and lithium diisopropylamide (0.027 mol) using the procedure described in Example 1.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([CH3:18])[N:8]=1>C(N(CC)CC)C>[Cl:3][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([CH3:18])[N:8]=1
Reactant: CCOC(=O)c1cnc(C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(C)nc1Cl
Temperature: 40 °C
Yield: 53 %

Procedure:
In cold (˜0° C.) phosphorous oxychloride (40 mL) was carefully added triethylamine (1.87 mL) with stirring. To this was added, in parts, ethyl 4-hydroxy-2-methylpyrimidine-5-carboxylate (5.00 g, 27.4 mmol). The mixture then warmed to 40° C. and stirred under Argon for 2 hours. The mixture was evaporated free of phosphorous oxychloride, diluted with chloroform (150 mL) and poured carefully into ice (400 mL) and allowed to warm to RT. The organic phase was separated, washed with saturated sodium bicarbonate (75 mL), then brine (100 mL) and dried over sodium sulfate. The solvents evaporated to give a thick oil which was purified by chromatography (Biotage Si-40 column, 15-40% ethyl acetate/hexane) to give ethyl 4-chloro-2-methylpyrimidine-5-carboxylate as a clear oil (2.96 g, 53% yield). 1H NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3 H), 2.66 (s, 3 H), 4.34 (q, 2 H), 9.06 (s, 1 H); MS (ESI) m/z: 201.0 (M+H+).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[CH:29][CH:28]=2)[O:12][CH2:13][CH2:14][NH:15]C(=O)C2C(=CC=CC=2)C(O)=O)=[CH:7][CH:6]=1>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:37]=[N:36][NH:35][CH:34]=3)=[CH:29][CH:28]=2)[O:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccccc1C(=O)NCCOC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: NCCOC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Hydrazine monohydrate (159 □l, 3.28 mmol) was added to a solution of N-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-phthalamic acid (260 mg, 0.55 mmol) in methanol (6 ml) and the reaction mixture stirred at 80° C. for 16 hours. Upon cooling, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO2), eluting with dichloromethane:methanol:acetic acid:water (90:18:3:2). Further purification by Phenomenex_Strata_SCX column chromatography, eluting with methanol followed by 2N ammonia in methanol, afforded the desired product as the free base (120 mg). LC/MS: (FL-A) Rt 2.07 [M-NH2CH2CH2O+H]+ 267. 1H NMR (Me-d3-OD) δ 2.85 (2H, t), 3.55 (2H, t), 5.45 (1H, s), 7.35-7.40 (6H, m), 7.58 (2H, d), 7.95 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:30])([F:29])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:17]1[CH:18]=[N:19][C:14]([C:13]([F:29])([F:30])[F:12])=[N:15][CH:16]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[CH2:13]([Li])CCC.IC>O1CCCC1>[CH2:1]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1)[CH3:13]
Reactant: [Li]CCCC
Reactant: Cc1cc(=O)[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cc(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-methylquinolin-2(1H)-one (5 g, 31 mmol) in anhydrous tetrahydrofuran (100 mL) under a nitrogen atmosphere cooled in an acetone/dry ice bath was added dropwise by syringe a 1.6N solution of n-butyl lithium in hexanes (49 mL, 78 mol). The resulting solution was warmed to r.t. for 2 h at which time iodomethane (3 mL, 47 mmol) was added by syringe. The reaction mixture was stirred at r.t. for 0.5 h then cooled in an ice bath. The reaction mixture was quenched by the addition of aq. 2N HCl and then extracted with excess chloroform. The combined organic extracts were washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and the solvent removed under vacuum to provide a solid.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]1)[CH3:6]
Reactant: CCOCCn1c(NC2CCNCC2)nc2cccnc21
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(NC2CCN(CC#N)CC2)nc2cccnc21
Temperature: 25 °C
Yield: 21 %

Procedure:
A mixture of 9.4 parts of 2-chloroacetonitrile, 30 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 11 parts of sodium carbonate and 658 parts of N,N-dimethylformamide was stirred over weekend at room temperature. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried in vacuo, yielding 7.2 parts (21.0%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetonitrile; mp. 141.4° C. (compound 92).
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3](=[NH:5])[NH2:4].C(O[CH:14]=[C:15]([C:21](=O)[CH:22]([F:24])[F:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.CC[O-].[Na+]>C(O)C>[F:23][CH:22]([F:24])[C:21]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:4]=[C:3]([C:2]([F:10])([F:1])[C:6]([F:9])([F:8])[F:7])[N:5]=1
Reactant: N=C(N)C(F)(F)C(F)(F)F
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Yield: 39.4 %

Procedure:
A mixture of 1.62 g (10 mmol) of 2,2,3,3,3-pentafluoropropanimidamide and 2.22 g (10 mmol) of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate (for preparation see WO 2005/123690) in 10 ml of ethanol is stirred under reflux for 4 days after adding 0.68 g (10 mmol) of sodium ethylate. Concentration by evaporation in vacuo is then carried out and the residue is taken up in 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic phases are washed successively with 5 ml of water and 5 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. Chromatographic purification with a mixture of cyclohexane and ethyl acetate gives 1.26 g of ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate (40%) as a white solid.
Reaction SMILES: CN1C(=O)N(C)CCC1.[F:10][C:11]([F:24])([F:23])[C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:16][CH:17]=1.Br[CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].Cl>C1COCC1>[O:37]=[C:28]1[C:29]2[C:30](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:32])[N:27]1[CH2:26][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:23])([F:24])[F:10])[CH:13]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Over about 5 min, a solution of n-butyllithium (1.6 M in hexane, 18.75 ml, 30 mmol) was added dropwise to a solution, pre-cooled to −20° C., of 4.91 ml (35 mmol) of diisopropylamine in 50 ml of THF. The LDA solution obtained in this manner was cooled to −78° C., and 15.1 ml of DMPU (1,3-dimethyltetrahydro-2(1H)-pyrimidinone, 125 mmol) were added. After 20 min at −78° C., a solution of 5.45 g (25 mmol) of methyl [3-(trifluoromethyl)phenyl]acetate in 35 ml of THF was slowly added dropwise. After a further 20 min at −78° C., a solution of 7.20 g (30 mmol) of N-bromomethylphthalimide in 50 ml of THF was added dropwise. Stirring of the reaction mixture was continued initially at −78° C. for 1 h, then without cooling bath at RT overnight. After addition of 100 ml of 1 N hydrochloric acid, the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was dissolved in 50 ml of DMSO and purified in several portions by preparative HPLC [Method 8]. This gave 2.20 g (22% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[C:5]([O:15][CH3:16])[N:4]=1.[F:17][C:18]([F:28])([C:24]([F:27])([F:26])[F:25])/[CH:19]=[CH:20]/[C:21](O)=[O:22].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:21](=[O:22])/[CH:20]=[CH:19]/[C:18]([F:17])([F:28])[C:24]([F:25])([F:26])[F:27])[CH2:13][CH2:14]2)[CH:6]=[C:5]([O:15][CH3:16])[N:4]=1
Reactant: COc1cc(N2CCNCC2)cc(OC)n1
Reactant: O=C(O)/C=C/C(F)(F)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N2CCN(C(=O)/C=C/C(F)(F)C(F)(F)F)CC2)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
1-(2,6-Dimethoxy-4-pyridyl)piperazine (30 mg, 0.13 mmol) was dissolved in anhydrous dichloromethane (2 ml) together with (E)-4,4,5,5,5-pentafluoropent-2-enoic acid (35 mg, 0.18 mmol), triethylamine (31 mg, 44 μl, 0.32 mmol), HBTU (74 mg, 0.15 mmol) and stirred at room temperature for two hours. The mixture was evaporated to dryness under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 9 mg of a solid (0.023 mmol, 15%).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[CH:21]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30]>O>[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[CH:21]=[N:29][OH:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NO
Reactant: O=Cc1c(OCc2ccccc2)ccc2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=Cc1c(OCc2ccccc2)ccc2ccccc12
Yield: 97.8 %

Procedure:
To 460 ml of methanol and 150 ml of water were added 120 g (0.46 mole) of 2-benzyloxy-1-naphthaldehyde, 75 g (0.92 mole) of sodium acetate and 48 g (0.69 mole) of hydroxylamine hydrochloride, and the mixture was refluxed by heating for 2 hours. After the reaction, the reaction mixture was added to 1.5 liters of water. The precipitated crystals were collected by filtration to obtain 125 g (0.45 mole) of 2-benzyloxy-1-naphthaldoxime.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[C:4]([NH:9][S:10]([C:13]2[N:14]=[CH:15][N:16]([CH3:18])[CH:17]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].F[C:21]1[C:26]([C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[CH:25][CH:24]=[CH:23][N:22]=1>O>[F:19][C:3]1[C:2]([NH:1][C:21]2[C:26]([C:27]3[N:35]=[CH:34][N:33]=[C:32]4[C:28]=3[N:29]=[CH:30][N:31]4[CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[N:14]=[CH:15][N:16]([CH3:18])[CH:17]=1)(=[O:12])=[O:11]
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Reactant: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(N)c2F)c1
Solvent: O
Product: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
The N-(3-amino-2,4-difluorophenyl)-1-methyl-1H-imidazole-4-sulfonamide (45 mg, 0.16 mmol) prepared at Step 5 and the 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (43 mg, 0.14 mmol) prepared at Step 7 were added and dissolved, and lithium (bistrimethylsilyl) amide (1.0M solution in THF) was applied slowly at 0° C. After stirring the reactant at room temperature for 1 hour, completing the reaction, pouring water, and extracting with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 65 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-methyl-1H-imidazole-4-sulfonamide (percentage yield: 82%), was obtained.
Reaction SMILES: Cl.[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:6].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9]([N:10]1[CH2:15][CH2:14][N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1)=[O:16])=[O:6]
Reactant: BrCc1ccccc1
Reactant: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
Methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate hydrochloride (14) (0.50 g, 1.71 mmol) was reacted at ca. 0° C. with benzyl bromide (BnBr) (0.243 mL, 0.35 g, 2.05 mmol) and diisopropylethylamine (DIEA) (1.00 mL, 0.74 g, 5.76 mmol) in dichloromethane (DCM) followed by warming to room temperature. After aqueous work-up, the crude product was purified by mass-guided preparative HPLC to afford 0.18 g (27% yield) of the title compound (15) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.08-7.01 (m, 5H), 6.72-6.71 (m, 2H), 4.60 (s, 2H), 3.58-3.57 (s, 3H), 3.23-3.19 (br S, 2H), 3.30 (s, 2H), 3.1.19-3.11 (br S, 2H), 2.23 (br S, 4H); MS (ESI) m/z 347.13 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>O1CCCC1>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([CH2:1][NH:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:22])=[O:21]
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCNCS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
A solution of 1.0 g (6.28 mmol) of tert.-butyl N-methyl-β-alaninate, 1.54 g (6.28 mmol) of 2,3-dichlorobenzenesulphonyl chloride and 0.70 g (6.92 mmol) of triethylamine in 30 ml of tetrahydrofuran was stirred at room temperature overnight and then evaporated to dryness. About 50 ml of water were added to the residue, and the mixture was extracted three times with in each case 20 ml of ethyl acetate. The organic extracts were washed with about 20 ml of saturated sodium chloride solution and then evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane).