Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH:20]([C:23]1[C:24]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)=[CH:25][C:26]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:27]([CH:31]=1)[C:28](O)=[O:29])([CH3:22])[CH3:21].C(N=C=NCCCN(C)C)C>ClCCl>[CH:20]([C:23]1[C:24]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=2)=[CH:25][C:26]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:27]([CH:31]=1)[C:28]([N:11]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:29])([CH3:22])[CH3:21]
Reactant: COc1ccc(COc2cc(OCc3ccc(OC)cc3)c(C(C)C)cc2C(=O)O)cc1
Reactant: Cn1ccc2cc(NCC(=O)OC(C)(C)C)ccc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc(COc2cc(OCc3ccc(OC)cc3)c(C(C)C)cc2C(=O)N(CC(=O)OC(C)(C)C)c2ccc3c(ccn3C)c2)cc1
Reaction time: 2 h

Procedure:
tert-butyl 2-(1-methyl-1H-indol-5-ylamino)acetate (1) and 5-isopropyl-2,4-bis(4-methoxybenzyloxy)benzoic acid were dissolved in dichloromethane at room temperature. 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) was added to the reaction solution and stirred for 2 hours. Work-up with water and extracted with dichloromethane followed by drying and concentration produced tert-butyl 2-(5-isopropyl-2,4-bis(4-methoxybenzyloxy)-N-(1-methyl-1H-indol-5-yl)benzamido)acetate (2). Without further purification, compound 2 was treated with Lawesson's reagent in toluene at 100° C. produced tert-butyl 2-(5-isopropyl-2,4-bis(4-methoxybenzyloxy)-N-(1-methyl-1H-indol-5-yl)phenylthioamido)acetate (3) in 82% over 2 steps.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.C(#N)CC.CCN(C(C)C)C(C)C.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:35]([O:34][C:30](=[O:33])/[CH:31]=[CH:32]/[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:5]2)([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)C1Cc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COC(=O)C1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a suspension of methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (300 mg, 1.06 mmol), prepared as in J. Med. Chem. 2003, 46, 9, 1627-1635, in DMF (1 mL) and proprionitrile (3.5 mL) under Argon were added DIPEA (175 μL, 2.271 mmol), tert-butyl acrylate (615 mL, 4.24 mmol), tri(o-tolyl)phosphine (64 mg, 0.21 mmol) and palladium acetate (48 mg, 0.21 mmol). The mixture was stirred at 100° C. overnight. LCMS analysis showed that some unreacted starting material was remaining, so 24 mg of palladium acetate and 64 mg of tri(o-tolyl)phosphine were added. After 5 h at 100° C., the reaction was allowed to come back to room temperature, filtered through Celite pad and rinsed with methanol. The residue obtained after concentration was purified by flash chromatography (eluent: gradient DCM/EtOAc) to give the title compound as an orange solid (115 mg, 32%) contaminated with traces of tri(o-tolyl)phosphine oxide.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].Br[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CCCC)CCCC)CCC.C(O)C>C(O)(=O)C>[C:7]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:3][CH:1]=[O:2])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: C=CC=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCC=O)C(=O)OCC
Reaction time: 2.5 h

Procedure:
First, 100 ml acrolein was added to a solution of 180 g diethyl bromomalonate, 14 g tributylamine, and 600 ml ethanol while cooling in an ice bath. After 2-3 hours, an additional 1.5 g tributylamine and 20 ml acrolein was added. The stirring was continued for an additional 1 to 2 hours without additional cooling. The reaction mixture was neutralized with 7 ml glacial acetic acid and the ethanol and unreacted acrolein were removed on a rotary evaporator. The residue was diluted with 500 ml benzene and washed with 3×100 ml H2O and 2×100 ml saturated NaCl solution. The benzene solution was dried over CaSO4 and rotary evaporated to yield 207 g of yellow oil which was indicated to be 48% product by glc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](O)(=O)C.S(=O)(=O)(O)O.[N:18]([O-:20])=[O:19].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([N+:18]([O-:20])=[O:19])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1F
Reactant: CC(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of 26.6 grams (0.21 mole) of the fluorophenol in 63 ml. of acetic acid and 8.5 ml. of sulfuric acid was stirred at 8°-12° C. While the mixtute was cooled and stirred, a solution of 15 grams of sodium nitrite in 42 ml. of water was added dropwise over a period of about 1 hour. Stirring was continued for an additional 30 minutes. The mixture then was poured into a large volume of ice water. The resulting crude product was collected by filtration, thoroughly washed with water, and air dried while on the filter. The resulting crude nitroso compound then was added in portions to a stirred solution of 20 ml. of 70 percent nitric acid and 60 ml. of water maintained at 40°-50° C. Heating and stirring were continued until the evolution of brown fumes became negligible. The mixture then was poured into ice water, and the crude product was collected. The crude product then was recrystallized from ethanol-water to obtain a first and a second crop. A total of 25.4 grams (70 percent) of 2-fluoro-4-nitro-5-methylphenol was obtained, m.p. 110°-111.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][O:53][CH3:54])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:54][O:53][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1
Reactant: COCc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COCc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (220 mg) was added toluene/ethanol/water (10/1/1, 6 ml) and then were added 4-(methoxymethyl)phenyl borate (86 mg) and potassium carbonate (123 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (19 mg), and the mixture was stirred at 90° C. for 9 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-methoxymethylphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 80) (99 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:27]([F:32])([F:31])C([O-])=O.[Na+]>C(#N)C.O>[Cl:1][C:2]1[C:3]([O:19][CH:27]([F:32])[F:31])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(OC(F)F)cc21
Temperature: 80 °C
Yield: 10.6 %

Procedure:
To the stirred solution of 8-chloro-9-hydroxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.5 g, 1.456 mmol), prepared as described in Example 89, Part B in acetonitrile (5 mL) was added K2CO3 (0.604 g, 4.37 mmol) followed by sodium 2-chloro-2,2-difluoroacetate (0.444 g, 2.91 mmol). The mixture was heated to 80° C. for 18 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×80 mL). The organic layer was washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 8-chloro-9-(difluoromethoxy)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (50 mg, 0.154 mmol, 11% crude yield) as a semi solid. The material was carried on without further purification. LC/MS (ESI) m/e 325.0 [(M+H)+, calcd for C15H12ClF2N2O2 325.04]; LC/MS retention time (method C): tR=2.39 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:6]=1)=[O:4].[CH3:15][NH:16][C:17]([NH:19][CH3:20])=[S:18]>>[ClH:1].[CH3:20][N:19]1[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:6]=2)([OH:4])[CH2:2][S:18][C:17]1=[N:16][CH3:15]
Reactant: CNC(=S)NC
Reactant: NS(=O)(=O)c1cccc(C(=O)CCl)c1
Product: CN=C1SCC(O)(c2cccc(S(N)(=O)=O)c2)N1C
Product: Cl

Procedure:
3.5 g of 2-chloro-3'-sulfamoylacetophenone and 1.56 g of ground 1,3-dimethylthiourea were reacted as prescribed in Example 12 and the end product was precipitated with a mixture of 1 part of diethyl ether and 2 parts of ethyl acetate. Colorless crystals, melting point: 184° C.
Reaction SMILES: [ClH:1].[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:16])(=[O:4])[CH3:3].[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[F:31]>>[ClH:16].[ClH:1].[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][C:19]2[N:18]([CH3:17])[CH:22]=[CH:21][N:20]=2)=[C:25]([F:31])[CH:26]=1)(=[O:4])[CH3:3]
Reactant: Cn1ccnc1Sc1ccc(N)cc1F
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Agent: Cl
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(Sc4nccn4C)c(F)c3)c2c1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline hydrochloride was reacted with 4-amino-2-fluorophenyl 1-methylimidazol-2-yl sulphide to give 6-acetoxy-4-[3-fluoro-4-(1-methylimidazol-2-ylthio)anilino]quinazoline dihydrochloride salt in 58% yield, m.p. 245-248 (decomposes);
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.CCCCCC.O>[Cl:1][C:2]1[CH:14]=[C:13]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1ccccc1Cl
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(=O)CCC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
To a stirred solution of ethyl 2-chlorophenoxyacetate (32.0 g, 149 mmol) in dichloromethane (75 mL) at ambient temperature under nitrogen was added succinic anhydride (22.4 g, 224 mmol). The reaction mixture was cooled in ice-water and to this was added portion wise aluminum trichloride (59.6 g, 447 mmol), whilst maintaining the temperature below 20° C. The reaction mixture was then allowed to stir at ambient temperature for 20 minutes and was then heated to reflux and stirred at this temperature for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then poured into a mixture of ice, water (200 ml) and HCl (10 N, 100 ml). The two phase system was separated and the aqueous layer was extracted with ethyl acetate (5×100 mL). All organic layers were then combined and washed with water (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure to give an orange oily solid. Hexane (300 mL) was added, and after standing at ambient temperature for 1 hour, the precipitate was filtered off and re-crystallized from ethyl acetate/hexane to give 9 as a light yellow powder (21.5 g, 46% yield, 98% pure by LCMS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.79 (m, 1H); 7.66 (m, 1H); 6.79 (m, 1H); 4.90 (s, 2H); 4.12 (q, 2H); 2.82 (m, 2H); 2.42 (m, 2H); 1.30 (t, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH:10]=[C:11]2[N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:3]1.O.NN.C(O)(=O)C>CCO>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:3]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cncn3)=CC[C@@H]12
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2n1cncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 74.4 %

Procedure:
A mixture of Compound 6 (200 mg, 0.590 mmol), hydrazine hydrate (0.57 ml, 1.77 mmol), and acetic acid (0.35 ml) in EtOH (20 ml) was heated at 80° C. while a stream of air was passed through the solution for 6 h. The reaction mixture was concentrated to about 10 ml and after cooling, it was diluted with EtOAc (30 ml) followed by washing with saturated aqueous NaHCO3 (10 ml×2), and brine (10 ml ×2), dried (Na2SO4) and concentrated to give a crude product (190 mg). This was purified by FCC (silica gel, CH2Cl2 /EtOH, (30:1)) to give the Compound 8 (150 mg, 74.6%), mp 246-248° C. 1H NMR (300 MHz, CDCl3): δ 0.56 (3H, s, 18-Me), 1.01 (3H, s, 19-Me), 3.53 (1H, m, 3α-H), 4.19 (1H, t, J=9.6 Hz, 17α-H), 5.37 (1H, d, J=5.2 Hz, 6-H), 7.93 (1H, s, 3'-H) and 8.10 (1H, s, 5'-H). Analysis calculated for C21H31ON3 : C, 73.85; H, 9.16; N, 12.31. Found: C, 73.75; H, 9.40; N, 12.28.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(O)(=O)C.[O:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=[C:24]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=23)[N:23]=1>O1CCCC1>[N+:28]([C:27]1[C:22]([NH:20][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[N:23][C:24]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=23)=[N:25][CH:26]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cnc(-c2cnn3ccncc23)nc1Cl
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(-c2cnn3ccncc23)nc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
Diisopropylethylamine (2.30 mL, 13.20 mmol) and tetrahydro-2H-pyran-4-amine acetate (526 mg, 3.28 mmol) were added to a stirred suspension of 3-(4-chloro-5-nitropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 24e, 0.91 g, 3.29 mmol) in tetrahydrofuran (15 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated and water was added. The mixture was filtered to give the title compound (0.785 g, 70%) as a yellow solid.
Reaction SMILES: [C:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:49]1[C:54](=[O:55])[CH2:53][CH2:52][C:50]1=[O:51])=[N+](C)C)C>C1COCC1>[C:18]([O:20][N:49]1[C:54](=[O:55])[CH2:53][CH2:52][C:50]1=[O:51])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 18 h
Yield: 29 %

Procedure:
To a solution of mono-tert-butyl octadecanedioate (1.00 g, 2.7 mmol) in dry THF (8 ml), was added DIPEA (0,555 ml, 3.2 mmol) followed by TSTU (1.00 g, 3.2 mmol). The reaction mixture was stirred under nitrogen for 18 h. The solvent had evaporated. AcOEt was added to the residue and the resulting suspension was filtered. The filtrate was washed with cold 0.1 M HCl (2×) and water, dried and concentrated to give succinimidyl tert-butyl octadecandioate as a white solid.
Reaction SMILES: [CH3:1]N1CCCC1=O.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH2:29][C:30]4[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=4[F:38])[C:25]([C:39]([NH2:41])=[O:40])=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.CI.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH2:29][C:30]4[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=4[F:38])[C:25]([C:39]([NH2:41])=[O:40])=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: CN1CCCC1=O
Reactant: NC(=O)c1cnc(Nc2ccc(OC3CCNCC3)cc2)nc1NCc1c(F)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CN1CCC(Oc2ccc(Nc3ncc(C(N)=O)c(NCc4c(F)ccc(F)c4F)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 10 ml portion of 1-methyl-2-pyrrolidone solution containing 800 mg of 2-{[4-(piperidin-4-yloxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]-pyrimidine-5-carboxamide was mixed with 0.12 ml of methyl iodide and 300 mg of potassium carbonate, followed by stirring at room temperature for 1 hour and then at 60° C. for 30 minutes. A 0.1 ml portion of methyl iodide was further added thereto, followed by stirring for 30 minutes. The reaction mixture was cooled down to room temperature, mixed with water and then extracted with an ethyl acetate-THF mixed solvent. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia) and further recrystallized from ethanol to obtain 197 mg of 2-({4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[Cl:1])[CH2:18][CH2:19]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1OC
Reactant: Cl
Product: COc1ccc(CCN2CCC(NC(=O)c3ccccc3Cl)CC2)cc1OC

Procedure:
The title compound as its hydrochloride (m.p. 250°-2° C.) was prepared in the same way as for the compound of Example 5 but using o-chlorobenzoyl chloride in place of benzoyl chloride. (Found: C, 60.2; H, 6.1; N, 6.3. C22H26Cl N2O3.HCl requires C, 60.3; H, 6.2; N, 6.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=O)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:22])=O.N1C=CC=CC=1.C(#N)C>O>[Cl:22][C:10]1[O:11][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1
Reactant: COC(=O)CCc1oc(=O)[nH]c1-c1cccc(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)CCc1oc(Cl)nc1-c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of methyl 3-[4-(3-chlorophenyl)-2-oxo-2,3-dihydro-5-oxazolyl]propionate (3.0 g), phosphorus oxychloride (4 mL) was gradually added pyridine (0.86 mL) at room temperature and the mixture was stirred at 90° C. for 3 hrs. The reaction mixture was cooled and acetonitrile was added. The mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-chloro-4-(3-chlorophenyl)-5-oxazolyl]propionate (2.3 g, 72%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Cc1ccnc(N)c1
Solvent: CCO
Product: Cc1ccn2cc(-c3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A mixture of 2,4′-dibromoacetophenone (22.4 g) and 2-amino-4-picoline (8.68 g) in ethanol (80 mL) was heated at reflux temperature for 3 hours. The reaction mixture was cooled to ambient temperature and the crystalline solid isolated by filtration, washed with ethanol and dried in vacuo to give the title compound (13.1 g). Step B Preparation of 2-[4-[4-Hydroxybut-1-ynyl]phenyl]-7-methylimidazo[1,2-a]pyridine The product of Step A (1.8 g) in dry acetonitrile (40 mL) was treated sequentially with tetrakis(triphenylphosphine)palladium(O) (0.1 g), triethylamine (1.27 g), and Cul (10 mg) then heated at 60° C. for 30 minutes. The mixture was cooled to ambient temperature, treated with 3-butyn-1-ol (0.361 g) and heated at reflux temperature for 18 hours. The mixture was cooled to ambient temperature and evaporated to dryness. The residue was crystallized, twice, from acetone to afford the title compound (1.02 g). Step C Preparation of 2-[4-[4-Methanesulfonyloxybut-1-ynyl]phenyl]-7-methylimidazo[1,2-a]pyridine The product of Step B (0.135 g) in dichloromethane (3 mL) was treated with pyridine (0.37 g) and cooled to 10° C. The cold solution was treated with methanesulfonyl chloride (0.112 g) and allowed to stir and warm to ambient temperature over 18 hours. The reaction mixture was washed with 1% H2SO4 solution, saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give the title compound (0.115 g). Step D Preparation of 2-[4-[4-Piperidinobut-1-ynyl]phenyl]-7-methylimidazo[1,2-a]pyridine The product of Step C (1.00 g) in acetonitrile (15 mL) was treated with piperidine (0.269 g) and potassium carbonate (1.17 g) and heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature, washed with water (20 mL), dried over magnesium sulfate, filtered and evaporated to give crude product. Silica gel chromatography (methanol/dichloromethane) afforded the title compound (1.0 g). MS (ESI) m/z 344.1 (M+H+). 1H NMR (DMSO) δ 8.23 (d, J=6.95 Hz, 1 H), 8.15 (s, 1 H), 7.73 (d, J=8.37 Hz, 2 H), 7.25 (d, J=8.34 Hz, 2 H), 7.17 (s, 1 H), 6.58 (dd, J=6.9,1.45 Hz, 1 H), 2.33 (m, 6 H), 2.23 (b, 2 H), 2.18 (s, 3 H). 1.33 (pent, 4 H), 1.21 (pent, 2 H). HRMS: MH+ calcd for C23H26N3, 344.2127; found, 344.2134. Analysis: Calc'd for C23H25N3; C, 80.43; H, 7.34; N, 12.23. Found: C, 80.27; H, 7.15; N, 11.81.