Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]=[O:11].[OH-].[K+].Cl.[CH3:15]O>O>[C:10]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)(=[O:11])[CH3:15]
Reactant: CO
Reactant: C=O
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OCc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
Into a solution of 321 g. of 3-bromo benzaldehyde, 220 cm3 of 30% formaldehyde and 600 cm3. of methanol one-third of the solution of 300 g. of potassium hydroxide in 300 cm3. of water are dropped at 50° C. while stirring then the reaction mixture is stirred at this temperature for 1 hour. The temperature is raised to 60° C. and at this temperature the second third part of the base solution are dropped into the reaction mixture. After stirring the reaction mixture 1 hour at 60° C. the temperature is rised to 70° C. and at this temperature the last part of the base solution is dropped into the reaction mixture. The reaction mixture is stirred 1 hour at 70° C. then cooled to ambient temperature. The pH-value of the reaction mixture is adjusted with concentrated hydrochloric acid solution between 7.5 to 8 while maintaining the temperature at 40° C. From this reaction mixture 500 cm3. of methanol is distilled off, 500 cm3. of water are added to the residue then extracted twice with 150 cm3 of 1,2-dichloro ethane. From the united organic phase the water is removed by azeotropic distillation then 200 cm3. of acetic acid anhydride are dropped into the dichloro ethane solution while boiling and stirring. After boiling for 6 hours the reaction mixture is cooled, washed with 500 cm3. of water and 500 cm3. of 10% sodium hydrogen carbonate solution then evaporated. The residue is distilled in vacuo. 287.2 g. of 3-bromobenzyl acetate are obtained. Boiling point 123°-125° C./1200 Pa, nD24 : 1.5406, yield 72%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH3:12][NH:13][CH3:14].[CH2:15]=O>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:7]([OH:11])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: C=O
Reactant: CNC
Solvent: CO
Product: CC(=O)Nc1ccc(CN(C)C)c(O)c1
Yield: 66.6 %

Procedure:
To a solution of 30.5 g (202 mmol) of 3-acetamidophenol in 27.5 g (244 mmol) of 40% dimethylamine and 25 ml of methanol, was added 16.4 g (202 mmol) of 37% formalin. The reaction mixture was placed in an ice bath just after the precipitate formed (ABOUT 15 minutes). The white precipitate was filtered after 15-30 minutes, washed with cold water, and air-dried to give 28.0 g (67% yield) of 5-acetamido-2-[(N,N-dimethylamino)-methyl]phenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[N:26]=[N:27][NH:28][N:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[N:26]=[N:27][NH:28][N:29]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccc(-c3nn[nH]n3)c21
Product: CC1c2c(cccc2-c2nn[nH]n2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@H:27]3[CH2:30][C@H:29]([CH2:31][OH:32])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[O:33](S(C1C=CC(C)=CC=1)(=O)=O)[S:34]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=O)=[O:35]>C(Cl)Cl.N1C=CC=CC=1.O.C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@H:27]3[CH2:28][C@H:29]([CH2:31][O:32][S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:35])=[O:33])[CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3cc(-c4ccc5ccc(-c6ccccc6)nc5c4)c4c(N)ncnc43)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of trans-{3-[4-amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol (105.7 mg, 0.251 mmol) in CH2Cl2 (5 mL) and pyridine (1 mL), cooled in a dry ice/acetone bath, was added a solution of Ts2O (92 mg, 0.28 mmol) in CH2Cl2 (2 mL) over 5 min, then the reaction mixture was warmed up to ambient temperature and stirred for 16 h. More Ts2O (70 mg, 0.21 mmol) was added, and stirring at ambient temperature was continued for 4.5 h. The reaction solution was diluted with CH2Cl2 (25 mL), water and saturated NaHCO3 sol. were added, the layers were separated, the aqueous layer was extracted with CH2Cl2 (3×25 mL), and the combined CH2Cl2 extracts were washed with water and brine and dried over MgSO4. Filtration and concentration after adding toluene (10 mL; to remove remaining pyridine as azeotrop) gave the desired product. No purification before the next step. 1H NMR (CDCl3, 400 MHz) δ 2.43-2.51 (m, 2H), 2.47 (s, 2H), 2.67-2.86 (m, 3H), 4.22 (d, J=6.6 Hz, 2H), 5.19 (brs, 2H), 5.36 (quint, J=8.0 Hz, 1H), 7.29 (s, 1H), 7.37-7.41 (m, 2H), 7.46-7.51 (m, 1H), 7.52-7.58 (m, 2H), 7.68 (dd, J=1.8, 8.4 Hz, 1H), 7.83-7.87 (m, 2H), 7.92 (d, J=8.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.17-8.22 (m, 2H), 8.25-8.29 (m, 2H), 8.33 (s, 1H). MS (ES+): m/z 576.1 (54) [MH+], 338.2 (10) [MH+-cyclobutene-CH2OTs]. HPLC: tR=2.8 min (OpenLynx, nonpolar—5 min).
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[N:14][CH:13]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[Br:22][C:15]1[C:16]([C:18]([O:20][CH3:21])=[O:19])=[N:17][C:12]([NH:11][C@@H:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][C@@H:2]2[OH:1])=[CH:13][N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cncc(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Solvent: ClCCl
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of methyl 6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate (1.0 g, 3.5 mmol) in CH2Cl2 (35 mL) was added N-bromsuccinimide (0.69 g, 3.86 mmol). Stir at t for 2 hr. Wash the reaction with sat. aq. NaHCO3. The organic extract was dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 20% ethyl acetate/hexanes) to afford 380 mg (30%) of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate as a solid: 1H NMR (CDCl3) δ 3.01-3.06, 3.24-3.29, 4.00, 4.75-4.78, 5.45-5.46, 7.25-7.32, 7.94; MS (ESI+) for C15H14BrN3O3 m/z 386 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>ClCCl>[C:7]([C:9]1[CH:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:17][CH2:16]2)=[N:11][CH:10]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone (crude, 2.6 mmol assumed) and triethylamine (780 mg, 7.8 mmol) in dichloromethane (10 mL) was added benzyl chloroformate (663 mg, 3.9 mmol). The reaction mixture was stirred at room temperature for 2 hours, and diluted with dichloromethane (100 mL). The organic phase was washed with water (100 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (etroleum ether/ethyl acetate=4:1˜2:1) to give benzyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (600 mg, 57%) as a yellow solid. MS (ES+) C23H22N4O3 requires: 402, found: 403 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])=[CH:21][C:20]=2[Cl:32])=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].Cl.[CH3:34][O:35][NH2:36]>N1C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:20]([Cl:32])=[CH:21][C:22]([O:26][CH2:27][CH:28]=[C:29]([Cl:30])[Cl:31])=[CH:23][C:24]=2[Cl:25])=[CH:10][CH:9]=1)[C:5](=[N:36][O:35][CH3:34])[CH3:6]
Reactant: CON=C(C(C)=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(C)C(=NOC)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
0.23 g of 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-propane-1,2-dione 1-(O-methyl-oxime) and 44 mg of O-methylhydroxylamine hydrochloride are stirred in 5 ml of pyridine at 80° C. for 2 hours. The reaction mixture is concentrated; the residue is taken up in ethyl acetate and washed with water. After concentration of the organic phase and purification over silica gel, the title compound is obtained. 1H-NMR (CDCl3) 300 MHz: 2.12 (s, 3H), 2.30 (m, 2H), 3.88 (s, 3H), 3.94 (s, 3H), 4.17 (t, 2H), 4.29 (t, 2H), 4.59 (d, 2H), 6.11 (t, 1H), 6.83 (s, 2H), 6.91 (d, 2H), 7.29 (d, 2H)
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[CH3:58][NH:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=1>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:59]([CH3:58])[CH2:60][CH2:61][O:62][C:63]3[CH:64]=[CH:65][N:66]=[CH:67][CH:68]=3)=[O:26])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCCOc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)CCOc3ccncc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (50 mg, 0.13 mmol), EDCI (50 mg, 0.26 mmol), HOBt monohydrate (40 mg, 0.26 mmol), DIPEA (90 μL, 0.52 mmol), N-methyl-2-(pyridin-4-yloxy)ethanamine (20 mg, 0.13 mmol) and DMF (1 mL). The resulting crude compound was purified using prep method D.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>CN(C=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]=[C:26]([N:3]2[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]2=[O:1])[CH:27]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2cc(Cl)ncn2)c2ccccc21
Temperature: 140 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (130 mg, 0.52 mmol, described in Intermediate 7) in DMF (0.7 mL) was added sodium hydride (15 mg of a 60% dispersion in mineral oil, 0.38 mmol). The mixture was stirred for 5 min, then 4,6-dichloropyrimidine (234 mg, 1.57 mmol) was added and argon was bubbled through the mixture for 5 min. The reaction mixture was heated at 140° C. for 10 min in a microwave reactor. The cooled mixture was partitioned between CHCl3 (10 mL) and saturated aqueous NaHCO3 (5 mL). The aqueous phase was extracted further with CHCl3 (10 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 75:25, to give the title compound. MS: m/z=361 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](I)=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([NH:29][C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])[CH:26]=[CH:27][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:35][C:34]([F:36])([F:37])[CH2:33][NH:32][C:30](=[O:31])[NH:29][C:25]1[CH:24]=[C:23]([C:11]2[N:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]3=[N:13][CH:12]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(C(=O)O)ccn23)c1
Temperature: 80 °C

Procedure:
To a solution of 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (3.02 g, 10 mmol) in DME (200 ml) was added 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (4.13 g, 12 mmol), 1M Na2CO3 (80 ml) [reaction degassed by bubbling N2 through] followed by tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol). The mixture was heated at 80° C. overnight, then diluted with water and extracted with CH2Cl2. The aqueous layer was neutralised and loaded onto a reverse phase (C18) SPE (Solid Phase Extraction) cartridge. The cartridge was washed with H2O (2 column volumes) and eluted with MeOH (2 column volumes), the organic solvent removed in vacuo to afford the product as an off-white solid: 1H NMR (400 MHz, DMSO-d6): 12.31 (1H, s), 9.77 (1H, s), 8.85 (1H, d), 8.12 (1H, d), 8.04 (1H, s), 7.94 (1H, s), 7.84 (1H, s), 7.76 (1H, d), 7.39 (1H, t), 7.21 (1H, d), 4.05-3.90 (2H, m). MS: [M+H]+ 379.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([OH:31])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:40]([CH:42]1[O:44][CH2:43]1)Cl>CN(C=O)C.C(OCC)(=O)C.C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:31][CH2:40][C@@H:42]5[CH2:43][O:44]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCC1CO1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC[C@@H]1CO1

Procedure:
To a solution of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (120 mg, 0.267 mmol) in DMF (4 mL), Cs2CO3 (0.32 mmol) and (S) (+) epichlorohydrin (104 μL, 1.33 mmol) was added. The reaction mixture was reacted at 80 C under microwave condition for 2 h. The mixture was diluted with a ethyl acetate/THF (15/5) mixture and washed with water, brine and dried over MgSO4. After removal of the solvent, the titled compound was obtained as an off-white solid. Yield: 135 mg (100%). LC-MS (ESI) m/z 506 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[N:45][CH:46]=[N:47][CH:48]=2)=[CH:38][C:37]=1[CH3:49].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:49][C:37]1[CH:38]=[C:39]([C:43]2[CH:48]=[N:47][CH:46]=[N:45][CH:44]=2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(-c2cncnc2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cncnc6)cc5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (100 mg), 5-(4-bromo-3,5-dimethylphenyl)pyrimidine (85 mg), K3PO4 (90 mg) are suspended in toluene (1 mL) and water (100 μL) and purged for 10 minutes with argon. Palladium-(II)-acetate (2.4 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (8.8 mg) are added, the vial is sealed and the mixture is stirred at 100° C. for 12 hours. The mixture is diluted with tetrahydrofuran and purified by HPLC on reversed phase to give the title compound. Yield: 40 mg; Mass spectrum (ESI+): m/z=525 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:3]=1[O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].CN(CCN(CCN(C)C)C)C.C([Li])CCC.[CH:38](N1CCOCC1)=[O:39].Cl>C1COCC1>[F:1][C:2]1[C:3]([O:4][Si:5]([CH:6]([CH3:7])[CH3:8])([CH:12]([CH3:13])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[CH:15][C:16]([O:19][CH3:20])=[CH:17][C:18]=1[CH:38]=[O:39]
Reactant: O=CN1CCOCC1
Reactant: COc1ccc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To a 240 ml THF solution containing 113 g of (2-fluoro-5-methoxyphenoxy)triisopropylsilane and 70 g of N,N,N′,N′,N″-pentamethyldiethylenetriamine there was added dropwise 150 ml of n-butyllithium (2.66 M, hexane solution) over a period of 50 minutes, at −74° C. After stirring for 3 hours at −60° C., 70 ml of N-formylmorpholine was added. The temperature of the reaction mixture was slowly raised to 6° C. Next, 1N hydrochloric acid was added to the reaction mixture while cooling on ice, and then the mixture was extracted with a mixture of hexane and t-butylmethyl ether and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (t-butyl methyl ether-heptane) to give the title compound (113.26 g) as an oil.
Reaction SMILES: [OH-].[K+].[C:3]([OH:20])(=[O:19])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:3]([OH:20])(=[O:19])/[CH:4]=[CH:5]/[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC/C=C/C=C/C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCC=C/C=C/C(=O)O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 90.9 %

Procedure:
To the trans-2-tetradecenal (2.3 g) dissolved in methylene chloride (80 ml ) was added (carbomethoxymethylene) triphenylphosphorane (4.4 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). Potassium hydroxide (2.8 g) was dissolved in a mixed solvent of ethanol-water (1:1), and the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). After the mixture was stirred at 60° C. for 40 minutes, it was cooled, adjusted to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans, trans-2,4-hexadecadienoic acid (2.0 g). The product was dissolved in N,N-dimethylformamide (DMF, 50 ml), and para-nitrophenol (1.1 g) and N,N'-dicyclohexylcarbodiimide (1.6 g) were added. The mixture was stirred for 12 hours. After the reaction, precipitates produced were removed by filtration, DMF was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-hexadecadienoic acid (0.8 g). To the active ester (340 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (500 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK283 in the yield of 270 mg.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22](NC2C=CC=CC=2O)=[O:23])[C:11]1=[O:40].C(N1C=CN=C1)(N1C=CN=C1)=[O:42].[Cl:53]CCl>>[ClH:53].[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22]([OH:42])=[O:23])[C:11]1=[O:40]
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(C)nc1C
Reactant: ClCCl
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1ccc(C)nc1C
Product: Cl
Reaction time: 20 h
Yield: 56 %

Procedure:
2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)acetamide (24.25 g, 45 mmol) (intermediate 2) and 1,1′-carbonyidiimidazole (11.7 g, 72 mmol) were dissolved in dry dichloromethane (200 ml) and left to stand under nitrogen for 20 hours. The solvent was removed in vacuo and the residue was dissolved in acetone (200 ml) and 2N hydrochloric acid (20 ml). After stirring for 20 hours the solvent was removed in vacuo and the residue was dissolved in methanol (50 ml). The solution was applied to an aminopropyl cartridge (2×70 g) and eluted with methanol (250 ml) and then 10% acetic acid in methanol (250 ml). The required fractions were combined and evaporated in vacuo. The residue was treated with 2N hydrochloric acid and the resulting solution evaporated in vacuo to give the title compound {(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2,6-dimethyl-3-pyridinyl)acetic acid hydrochloride as a tan solid (12.21 g, 56%).