Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:20][C:21]([F:24])([CH3:23])[CH3:22])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:18])[C:9]=2[N:19]=1)(=O)C.N.C(Cl)Cl>CO>[NH2:18][C:10]1[C:9]2[N:19]=[C:6]([CH2:5][OH:4])[N:7]([CH2:20][C:21]([F:24])([CH3:23])[CH3:22])[C:8]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(=O)OCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(F)Cn1c(CO)nc2c(N)nc3cccnc3c21
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A solution of [4-amino-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate (1.13 g, 3.41 mmol) dissolved in 10 mL of methanol was treated with 10 mL of a 7% solution of ammonia in methanol. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The resulting solid was treated with H2O and the mixture was heated to reflux for 15 minutes. The mixture was cooled and the resulting light-yellow solid was isolated by filtration. The light-yellow solid was then treated with 20 mL of CH2Cl2 and the mixture was stirred rapidly for several minutes. The mixture was filtered and the resulting white solid was washed with several portions of cold CH2Cl2 and dried with suction. Crystallization from ethanol/H2O gave 477 mg of [4-amino-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol as fluffy cream colored crystals, mp 240-241° C. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (dd, J=1.5, 4.3 Hz, 1H), 7.93 (dd, J=1.5, 8.4 Hz, 1H), 7.46 (dd, J=4.3, 8.4 Hz, 1H), 6.92 (s, 2H), 5.62 (t, J=5.8 Hz, 1H), 5.33 (br s, 2H), 4.83 (d, J=4.7 Hz, 2H), 1.33 (d, J=20.3 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 154.3, 152.7, 143.1, 140.8, 134.2, 133.4, 133.2, 128.7, 122.5, 96.8 (d, J=170 Hz), 56.7 (d, J=9.5 Hz), 52.7 (d, J=21.4 Hz), 24.5; MS (ESI) m/z 290 (M+H)+; Anal. calcd for C14H16FN5O: C, 58.12; H, 5.57; N, 24.21. Found: C, 58.19; H, 5.54; N, 24.16.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:10][C:9]([NH2:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C@H:25]1[C:29](=[O:30])[NH:28][CH2:27][C@@H:26]1[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=3)=[CH:10][C:9]([NH:23][C:31]([C@@H:26]3[C@@H:25]([CH3:24])[C:29](=[O:30])[NH:28][CH2:27]3)=[O:32])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Reactant: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccccc2)n1
Yield: 57.3 %

Procedure:
To a solution of 1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (79 mg) in N,N-dimethylformamide (0.8 ml) were sequentially added (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (46 mg) prepared in Preparation 1, HOBt.H2O (57 mg) and WSC.HCl (71 mg), and the mixture was stirred at room temperature for 2 hours. To this reaction solution were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (63 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.CC1C=CC(N=[CH:25][C:26]2[C:27]([NH2:35])=[CH:28][C:29]3[O:33][CH2:32][O:31][C:30]=3[CH:34]=2)=CC=1>>[CH3:15][O:14][C:10]1[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[C:4]2[CH2:5][C:6]3[C:7]([C:8]=2[CH:9]=1)=[N:35][C:27]1[CH:28]=[C:29]2[O:33][CH2:32][O:31][C:30]2=[CH:34][C:26]=1[CH:25]=3
Reactant: COc1cc2c(c(OC)c1OC)CCC2=O
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Product: COc1cc2c(c(OC)c1OC)Cc1cc3cc4c(cc3nc1-2)OCO4
Yield: 0 %

Procedure:
Using the procedure of Example 1, 4,5,6-trimethoxyindan-1-one (1.10 mg, 4.8 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (1.22 g, 4.8 mmol) to yields 7,8,9-trimethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (0.84 mg, 49.9% of theory).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28](/[CH:29]=[CH:30]/[CH:31]=[O:32])=[C:27]([CH:33]([CH3:35])[CH3:34])[C:26]([CH2:36][OH:37])=[C:25]([CH:38]([CH3:40])[CH3:39])[N:24]=2)=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.[Br-].[Zn+2].[Br-]>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28](/[CH:29]=[CH:30]/[CH:31]([OH:32])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:27]([CH:33]([CH3:34])[CH3:35])[C:26]([CH2:36][OH:37])=[C:25]([CH:38]([CH3:40])[CH3:39])[N:24]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(/C=C/C=O)c(C(C)C)c1CO
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)nc(C(C)C)c(CO)c1C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 ml (4.5 mmol) of methyl acetoacetate are added dropwise at 0° C.-5° C. under argon to a suspension of 0.15 g(5 mmol) of 80% pure sodium hydride in 6.5 ml of tetrahydrofuran p.a. After 15 minutes in each case, 3.65 ml (6 mmol) of 15% strength butyllithium in hexane are first added dropwise at 0° C. during the course of 10 minutes then a solution of 1.01 g (4.5 mmol) of dry zinc bromide in 4.5 ml of tetrahydrofuran and finally 0.51 g (1.5 mmol) of the compound from Example 123. The mixture is stirred overnight at room temperature, saturated ammonium chloride solution is added slowly, the aqueous phase is extracted using ethyl acetate, and the combined organic phases are washed using saturated sodium chloride solution, dried over sodium sulphate and concentrated. After column chromatography (φ3 cm) on 20 g of silica gel (230-400 mesh) using petroleum ether-ethyl acetate (1:1), 0.17 g (25% of theory) of yellowish oil is obtained. Rf =0.35 (petroleum ether-ethyl acetate (1:1)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: Cc1ccccc1C
Product: Fc1ccc(Oc2ccnc3cc(Cl)ccc23)cc1
Yield: 615.9 %

Procedure:
To a 50 mL flask equipped with a condenser, drying tube and thermometer, was added 1.98 g (0.01 moles) of 4,7-dichloroquinoline, 1.07 g (0.0015 moles) of polyDMAP™and 20 mL of xylene. The mixture was stirred to reswell the polymer and 1.57 g (0.0014 moles) of 4-fluorophenol were added. The reaction mixure was heated to reflux and maintained at that temperature for 18 hr. The reaction mixture was filtered hot to remove the polymer. After cooling, the filtrate was washed with 50 mL of 5N NaOH. The caustic layer was extracted with 2×25 mL of diethyl ether. The xylene and the ether layers were combined and dried over Na2SO4. Removal of the solvent provided 2.36 g (86 percent yield) of product, mp=89°-91° C.
Reaction SMILES: [CH3:1][C:2]12[CH:9](Br)[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>C(O)(=O)C.[Cu]Cl>[CH3:1][C:2]12[CH:9]([O:15][C:12](=[O:14])[CH3:13])[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2
Reactant: CC12CCCC(C)(CC1)C2Br
Reactant: CC(=O)[O-]
Agent: Cl[Cu]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC1C2(C)CCCC1(C)CC2

Procedure:
5 g of 1,5-dimethyl-8-bromobicyclo[3,2,1]octane was boiled under reflux for 18 hours in acetic acid in the presence of sodium acetate and copper(I) chloride. The reaction mixture was cooled and filtered, diluted with water and extracted with pentane. The pentane solution was washed with water and an aqueous sodium bicarbonate solution, dired, evaporated and fractionally distilled. 1,5-dimethyl-8-acetoxy-bicyclo[3,2,1]octane was obtained in good yield. 1,5-dimethyl-8-acetoxybicyclo[3,2,1]octane was also obtained in a similar manner starting from the 8-iodo compound described in Example 3.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:8][NH:7]1)=[O:5].BrC([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=[O:37])=[CH:27][C:26]=1[F:38])C(N)=O>CN(C=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:8][N:7]1[CH2:14][C:12](=[O:13])[NH:11][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=[O:37])=[CH:27][C:26]=1[F:38])=[O:5]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1
Reactant: NC(=O)C(Br)c1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1CC(=O)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
11.4 Using general procedure A with DMF as solvent (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester hydrochloride was reacted with 2-bromo-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamide to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid methyl ester. White solid. MS 533.2 ([M+H]+)
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8]([O:16]CC)(=[O:15])[CH2:9][C:10](OCC)=O.ClC1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>C(O)(=O)C>[Cl:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:27]([O-:29])=[O:28])[C:10]=1[CH2:9][C:8]([OH:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)Cc1c(Cl)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 31.4 %

Procedure:
8.08 g (202 mmol) of 60% sodium hydride was added to 30 ml of tetrahydrofuran, and while cooling on a freezing mixture, 60 ml of tetrahydrofuran solution containing 32.0 g (200 mmol) of diethyl malonate was dropped to the solution below 20° C. over 1 hour, then the solution was stirred for 1 hour. 60 ml of Tetrahydrofuran solution containing 19.2 g (100 mmol) of 2,3-dichloronitrobenzene was dropped to the solution below 10° C. over 10 minutes. After the solution was stirred for 3.5 hours at room temperature, it was heated at reflux for 48 hours. 18 ml of acetic acid was added to the solution, and the solvent was removed by distillation. The solution was extracted over 200 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, 30 ml of 4N hydrochloric acid and 25 ml of acetic acid were added, and the solution was heated at reflux for 24 hours. After air-cooling, the deposited crystals were filtered off and washed with water, and they were dissolved in 250 ml of ethyl acetate. The filtrate was extracted with 250 ml of ethyl acetate. The organic layers were combined, and after drying over magnesium sulfate, the solvent was removed by distillation. The crystals were washed with n-hexane to obtain 6.78 g of the subject compound (137) in a 31% yield.
Reaction SMILES: [C:1]1(=[O:6])O[C:3](=[O:4])[CH2:2]1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: Nc1ccccc1
Reactant: O=C1CC(=O)O1
Product: O=C(CC(=O)Nc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To the cold solution of malonic anhydride, prepared as above, was added aniline (700 μl, 6 equivalents). The reaction mixture was allowed to warm to room temperature. It was then extracted with 5 ml saturated aqueous NaHCO3, and the aqueous extract was washed with 5 ml ether, acidified with H2SO4, and extracted with 3 4-ml portions of ether. The ether extracts were combined and dried over Na2SO4, and the ether was removed under reduced pressure, to leave a residue of malonanilide (mp 127°-130° C., 180 mg, 72% isolated yield, based on diketene).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24]>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([NH:25][CH3:26])=[O:24])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2nc(Cl)ncc2F)c1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (1 g, 5.98 mmol) in isopropanol (18 mL, 3 mL/mmol) was added DIPEA (1.6 mL, 8.9 mmol) and 3-amino-N-methylbenzamide (900 mg, 5.98 mmol) and the mixture was heated at 80° C. for 7 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL) and water (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography provided 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-N-methylbenzamide (800 mg, 50%) as a solid. Observed mass (M+1): 281.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([NH:37][CH3:36])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: CNC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Yield: 63 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with methylamine to give the title compound as a white solid (126 mg, 63%) except that the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum 1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.71 (s, 2H), 7.00 (d, 1H), 7.04-7.10 (m, 3H), 7.36 (dd, 2H), 7.71-7.77 (m, 3H), 8.17 (s, 1H), 8.37 (m, 1H), 8.53 (s, 1H), 8.55 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 471.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:16][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:18]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
N-({1-[4-(6-Methoxy-pyridin-3-yl)-cyclohex-3-enyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in the previous step, 500 mg, 1.02 mmol) from step B in MeOH (40 mL) was driven through an H-Cube® Continuous-flow Hydrogenation reactor (ThalesNano, Budapest, Hungary) under full hydrogen mode at room temperature using a 5% Pd/C cartridge. The resulting solution was concentrated and purified by silica gel column on a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the two title compounds as white solids.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.N1C=CC=CC=1>ClCCl>[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
p-Toluenesulfonyl chloride (29.8 g, 157 mmol) was added portionwise to a mixture of tetrahydro-2H-pyran-4-yl-methanol (20.0 g, 172 mmol) and pyridine (25.2 ml, 313 mmol) in dichloromethane (200 ml). The mixture was stirred at room temperature for 17 h, then quenched with aqueous hydrochloric acid (2 M; 100 ml). The layers were separated and the aqueous layer extracted 2 with dichloromethane (2×100 ml). The organic layers were combined and concentrated in vacuo. Recrystallisation from dichloromethane:n-heptane (5:1) afforded toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. The mother liquors were further purified by silica gel column chromatography eluting with 50% dichloromethane in n-heptane to yield a further quantity of toluene-4-sulfonic acid tetrahydropyran-4-ylmethyl ester (total yield 41.6 g, 154 mmol).
Reaction SMILES: [F-].[K+].[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([C:17]3([C:24]#[C:25][Si](C)(C)C)[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]3)[CH:12]=[CH:13][C:14]=2OC)CCCC1.CN(C)[CH:32]=[O:33]>>[CH:32]1([O:33][CH2:3][O:8][C:9]2[CH:10]=[C:11]([C:17]3([C:24]#[CH:25])[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]3)[CH:12]=[CH:13][CH:14]=2)[CH2:13][CH2:14][CH2:9][CH2:10]1
Reactant: COc1ccc(C2(C#C[Si](C)(C)C)CCCC(=O)C2)cc1OC1CCCC1
Reactant: CN(C)C=O
Agent: [F-]
Agent: [K+]
Product: C#CC1(c2cccc(OCOC3CCCC3)c2)CCCC(=O)C1
Reaction time: 18 h

Procedure:
A mixture of potassium fluoride (900 mg, 15.6 mmol) and 3-(3-cyclopentyloxy-4-methoxyphenyl)3-trimethylsilylethynyl cyclohexan-1-one (0.3 g, 0.78 mmol) was stirred in dry N,N-dimethylformamide (3 mL) under an argon atmosphere. After 18 h, the solvent was removed in vacuo, the residue was partitioned between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, the combined extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 4:1 hexanes/ethyl acetate provided a clear colorless oil . Anal. (C20H24O3 ·1/10H2O) calcd: C 76.45,H 7.76; found: C 76.32,H 7.60.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([NH:8][C:9](=O)[CH2:10][C:11]2[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:25][C:9]([CH2:10][C:11]3[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[N:16]=3)=[N:8][C:6]=2[CH:7]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(F)ccc3o2)[nH]1

Procedure:
The product is prepared according to the procedure described in Stage 2 of Example 2, using 700 mg of N-(5-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide and 292 mg of 4-methylbenzenesulphonic acid hydrate, and replacing the toluene with xylene. After purification by silica gel column chromatography, elution being carried out with a mixture of CH2Cl2/MeOH: 98/02, then CH2Cl2/MeOH: 95/05, followed by recrystallization from methanol, 188 mg of 2-[(5-fluoro-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[O:9]1[CH:13]=[CH:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[O:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: C1=COCC1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1nccn1C1CCCO1
Yield: 75.3 %

Procedure:
A suspension of 0.338 g (3.0 mmol) of 2-nitroimidazole and 0.7 ml of 2,3-dihydrofuran in 35 ml of acetonitrile was stirred at 35°-45° C. in the presence of 5 mg of p-toluenesulfonic acid for 2 hr. under nitrogen and then evaporated. The residue was dissolved in chloroform, filtered, and evaporated to yield a syrup which was purified by preparative TLC with ethyl acetate-benzene (1:1) to provide 0.41 g (75.3%) of the title compound, mp 91° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH:13]1([C:16](=[O:24])[CH2:17][CH2:18][N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH2:15][CH2:14]1.[Cl-].[NH4+]>O.CCOCC.CC(=O)C>[CH:13]1([C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)([OH:24])[CH2:17][CH2:18][N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH2:15][CH2:14]1
Reactant: CC(=O)N(C)CCC(=O)C1CC1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)N(C)CCC(O)(c1cccc(C(F)(F)F)c1)C1CC1
Temperature: 25 °C

Procedure:
An ether solution of a Grignard reagent prepared from 50.0 g. (0.35 mole) of 3-bromobenzotrifluoride, 400 ml. of ether and 8.6 g. (0.354 mole) of magnesium was treated at -20°C. to -30°C. with 12.5 g. (0.059 mole) of crude 1-cyclopropyl-3-(N-methyl-acetamido)-1-propanone (calculated to contain 80% of the propanone by the nuclear magnetic resonance spectrum) in 100 ml. of ether. The reaction mixture was warmed to room temperature and treated with 7.4 g. (0.14 mole) ammonium chloride followed by 20 ml. of water. The ether layer was separated, concentrated to a dark oil and distilled under reduced pressure. The yield was 6.2 g.; b.p. 110°-114°C./0.1 mm.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[C:9](OC)[C:10]=1OC)[CH:6]=[O:7].[CH3:15][C:16]([C:18]1[CH:23]=[C:22](OC)[C:21](OC)=[C:20](OC)[CH:19]=1)=O.Cl>C(=O)([O-])[O-].[K+].[K+].O>[C:18]1([CH:16]=[CH:15][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:3][CH:4]=2)=[O:7])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
To a stirred solution of 3,4,5-trimethoxybenzaldehyde (190 mg, formula 5) in 10% methanolic potassium carbonate (15 mL), 3,4,5-trimethoxyacetophenone (200 mg) was added. It was stirred for 3 hours. On completion, the reaction mixture was diluted with water, acidified with dil. HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated to get a residue. The residue was purified through silica gel column to get chalcone of formula 6 (240 mg)