Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(NN)(C)C.N#CCl.[OH-].[Na+].[CH:12]([N:15]([C:17]#[N:18])[NH2:16])([CH3:14])[CH3:13].[C:19](Cl)(Cl)=[O:20]>O>[CH:12]([N:15]1[CH:17]=[N:18][C:19]([OH:20])=[N:16]1)([CH3:14])[CH3:13]
Reactant: O=C(Cl)Cl
Reactant: CC(C)N(N)C#N
Agent: CC(C)NN
Agent: Cl
Agent: N#CCl
Solvent: O
Product: CC(C)n1cnc(O)n1
Reaction time: 1 h
Yield: 90 %

Procedure:
Into a solution of isopropylhydrazine hydrochloride in a mixture of 3 partsof water and one part of alcohol there is introduced, at a temperature of 10° C, an equivalent amount of cyanogen chloride, with a pH-range of 6.5 to 7 being maintained by addition of sodium hydroxide solution and checking with a pH-meter. The duration of the reaction is 1 hour. During the reaction, there precipitates a yellow oil from which there is obtained, by extraction with ether, the crude 1-isopropyl-cyano-hydrazine in a yield of 90% as oil. The crude product obtained in this way can be used directly for the further reaction with phosgene to give 1-isopropyl-3-hydroxy-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:19][CH2:18][C@@H:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH:10]1[OH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C.CCCCCC>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[OH:31]
Reactant: CC(C)[Si](O[C@@H]1CCC(c2cccc(F)c2F)C(O)c2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 100 mL round-bottom flask was dissolved (9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (mixture of intermediates 2 and 3, 224.3 mg, 0.501 mmol) in tetrahydrofuran (4 mL) to give a colorless solution. TBAF (0.752 mL, 0.752 mmol) was added, and the mixture was stirred at room temperature for 2 h. LCMS indicated complete conversion of major component while the minor one did not change. Tetrahydrofuran was removed in vacuo and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Sodium sulfate, and concentrated to give a tan oil. FCC up to 50% ethyl acetate/hexane afforded intermediate 3 unchanged (38 mg, 17%) as a white crystalline solid, and intermediate 4 (95 mg, 65%) as a colorless oil (solidified upon standing). Intermediate 4 was further crystallized and single crystals were obtained. Its relative stereochemistry was proven by x-ray studies.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])[CH:2]([CH3:4])[CH3:3].[Br:15][CH2:16][C:17](Br)=[O:18]>C1COCC1>[Br:15][CH2:16][C:17]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])=[O:18]
Reactant: CC(C)CNCC(=O)N1CCOCC1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Product: CC(C)CN(CC(=O)N1CCOCC1)C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
2-Isobutylamino-1 -morpholin-4-yl-ethanone (1.43 g, 7.13 mmol) was dissolved in 15 mL of THF. To this solution at −78° C. was added a solution of bromoacetyl bromide (1.24 mL, 14.3 mmol) in 15 mL of THF. The mixture was warmed to room temperature and stirred for 2 h. Solvent was removed in vacuo. The residue was dissolved in 30 mL of methylene chloride, washed with saturated sodium bicarbonate, and brine, then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography eluting with 2% MeOH in methylene chloride to give 2-bromo-N-isobutyl-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide (1.37 g, 60%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1cc(C=O)ccc1F
Solvent: C1CCOC1
Product: COc1cc(C(O)Cc2ccccc2)ccc1F
Temperature: 50 °C
Yield: 60.2 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (25 g, 162 mmol) in THF (150 mL) was added a solution of benzyl magnesium chloride (2 M solution in THF, 122 mL, 243 mmol) in THF (50 mL). The reaction mixture was heated at 50° C. for 2 h. The reaction mixture was allowed to cool to rt and quenched by addition of sat. NH4Cl. The reaction mixture was extracted with EtOAc (3×) and the combined organic layers were washed with sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluting with 0-40% EtOAc/hexane) to yield 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanol as a yellow oil (24 g, 60% yield). NMR (500 MHz, CDCl3) δ ppm 7.27-7.32 (m, 2H), 7.21-7.27 (m, 1H), 7.16 (d, J=7 Hz, 2H), 7.01 (dd, J=11, 8 Hz, 1H), 6.92 (dd, J=8, 2 Hz, 1H), 6.82 (ddd, J=8, 4, 1 Hz, 1H), 4.80-4.88 (m, 1H), 4.66 (d, J=6 Hz, 1H), 3.84 (s, 3H), 2.91-3.04 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:18])([CH3:17])[CH2:5][CH2:6][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])O.[Na+]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]([CH3:18])([CH3:17])[CH2:5][CH2:6][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)CCSc1cccc2nccn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCOS(C)(=O)=O)CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 304 mg (1.15 mmol) of 5-(5-hydroxy-3,3-dimethylpentylthio)imidazo[1,2-a]pyridine and 0.16 ml (1.15 mmol) of triethylamine in 5 ml of dichloromethane, 89 μl (1.15 mmol) of methanesulfonyl chloride was added at 0° C., followed by stirring at room temperature for 1 hour, after which saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and dried, after which the solvent was distilled off to yield 5-(5-methanesulfonyloxy-3,3-dimethylpentylthio)imidazo[1,2-a]pyridine.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.[Br:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30](I)=[CH:29][C:28]=1[F:35]>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Br:26][C:27]1[C:28]([F:35])=[CH:29][C:30]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)=[C:31]([CH3:33])[CH:32]=1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)C4CC4)ncc3c2)OC1(C)C
Reactant: Cc1cc(Br)c(F)cc1I
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c(F)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 120 °C
Yield: 65 %

Procedure:
A mixture of N-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolyl]cyclopropanecarboxamide (500 mg, 1.48 mmol), 1-bromo-2-fluoro-4-iodo-5-methyl-benzene (559 mg, 1.77 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (105 mg, 0.15 mmol) in ACN (6 mL) and saturated aqueous sodium carbonate (1 mL) was heated under microwave irradiation (Biotage) 120° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-60% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (385, 65%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11](Cl)[C@H:10]1[OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:21]([NH:26][C@H:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:10]1[OH:20])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CCN
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CCN[C@H]1c2ccccc2C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O

Procedure:
Under argon a solution of (1R,2S,3R)-3-tert-butoxycarbonylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol (BOC-amino-cis-chlorohydrin) (500 mg) in anhydrous tetrahydrofuran was refluxed with isoamylamine (1.0 ml) and triethylamine (250 μl ) for 5 hours at 90° C. The mixture was poured in aqueous 5% sodium bicarbonate and extracted with methylene chloride. The organic solution was dried over magnesium sulfate and evaporated under vacuum to yield an oil. Crystallization of this oil in hexane yielded the title compound as a white solid (270 mg).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[C:6]([O:19][CH3:20])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([CH:40]=[CH:41][CH:42]=2)[CH2:34][NH:35][S:36]([CH3:39])(=[O:38])=[O:37])O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]([C:7]1[O:8][C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[C:33]([CH:40]=[CH:41][CH:42]=3)[CH2:34][NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:22]=[CH:21][C:5]=2[C:6]=1[O:19][CH3:20])=[O:10]
Reactant: COc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Reactant: CC1(C)OB(c2cccc(CNS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(CNS(C)(=O)=O)c3)ccc12
Yield: 30.3 %

Procedure:
(6-Bromo-3-methoxybenzofuran2-yl)(2,4-dichloro-phenyl)methanone (110 mg, 0.264 mmol), prepared as described above was dissolved in toluene/ethanol (1:1 8 mL). To this solution was added N-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-methanesulfonamide (99 mg, 0.317 mmol) and aqueous sodium carbonate (2M, 1.59 mmol). The mixture was degassed with nitrogen for 30 minutes and then Pd(dppf)2Cl2 (19.32 mg, 0.03 mmol) was added. The resultant mixture was heated at 85 deg C for 18 hours at which time it was cooled to ambient and concentrated via rotary evaporation. The oil thus obtained was diluted with EtOAc and washed with water and brine and dried over MgSO4. The organic layer was filtered and concentrated and purified by HPLC to give the desired compound (40.4 mg, 29%) 1H-NMR (CDCl3): δ 7.84 (d, 1H), 7.63-7.25 (m, 9H), 4.85 (br t, 1H), 4.40 (d, 2H), 4.24 (s, 3H), 2.95 (s, 3H), (M+H) 506.1 RT=3.66 min.
Reaction SMILES: BrCCBr.[C:5]([O:9][C:10]([N:12]1[CH2:15][CH:14](I)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].FC(F)(F)S(O[C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH:27]([NH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]([CH2:39][C:40]3[CH:45]=[CH:44][C:43](Cl)=[C:42]([Cl:47])[CH:41]=3)[C:25]=2[CH:24]=1)(=O)=O.O>CC(N(C)C)=O.[Zn].[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:5]([O:9][C:10]([N:12]1[CH2:15][CH:14]([C:23]2[CH:32]=[CH:31][C:30]3[CH2:29][CH2:28][CH:27]([NH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([Cl:47])[CH:41]=4)[C:25]=3[CH:24]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CCOC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)NC1CCc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2C1Cc1cccc(Cl)c1
Temperature: 67.5 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
A suspension of zinc powder (152 mg, 2.3 mmol) in 1 ml of DMA in a dry flask was heated under N2 to 65-70° C. A mixture of TMS-CI (28 mg, 0.26 mmol) and 1,2-dibromoethane (49 mg, 0.26 mmol) was added dropwise, stirred for 30 min, followed by slow (15 min) addition of 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (510 mg, 1.8 mmol) in 1 ml DMA. The reaction was cooled slowly (3 h) to room temperature, added to a mixture of 8-(3,4-chlorobenzyl)-7-[(ethoxycarbonyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (633 mg, 1.3 mmol, prepared in analogy to example 29), CuI (74 mg, 0.39 mmol) and PdCl2(dppf) (63 mg, 0.08 mmol) in 4 ml DMA preheated to 70° C. and stirred for 7 h at 70° C. Water and MTB (1:1 20 ml) were added and the resulting mixture filtered. The organic layer was separated, dried (Na2SO4) and the solvent evaporated. Purification by chromatography afforded 560 mg of product (white foam).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][CH:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[CH2:42][CH2:41]4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:41][CH2:42][CH:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[CH2:44][CH2:45]4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C1CCC(c2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: OCCO
Product: COC1=C(C)C(C2CCC(c3ccccc3)CC2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/2 v/v, 60 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(4-phenylcyclohexyl)-1H-pyrrol-2(5H)-one (1.0 g, 2.58 mmol, 1 eq) and MeOH (20 ml); yield: 0.100 g (10%); MS m/z: 402.2 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.53 (s, 1H), 8.32 (s, 1H), 7.64 (m, 2H), 7.25-7.08 (m, 7H), 4.81 (s, 1H), 3.87 (s, 3H), 2.20-2.20 (m, 2H), 2.01 (s, 3H), 1.78-1.4 (m, 5H), 1.37-1.14 (m, 7H); HPLC (METHOD [A]): rt 14.80 min (96.02%)
Reaction SMILES: CO[C:3]([C:5]1[C:6](Cl)=[N:7][CH:8]=[N:9][C:10]=1[Cl:11])=[O:4].[SH:13][CH2:14][C:15]([O:17][CH2:18]C)=[O:16].C(N(CC)CC)C.Cl>C(#N)C.O>[CH3:18][O:17][C:15]([C:14]1[S:13][C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[C:3]=1[OH:4])=[O:16]
Reactant: COC(=O)c1c(Cl)ncnc1Cl
Reactant: CCOC(=O)CS
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1sc2ncnc(Cl)c2c1O
Temperature: 50 °C
Yield: 92 %

Procedure:
To a solution of 4,6-Dichloropyrimidine-5-carboxylic acid methyl ester (0.5 g, 2.5 mmol) (prepared as disclosed in Lee, C.-H., et. al. Bioorganic & Medicinal Chemistry Letters (2001), 11(18), 2419) and mercaptoacetic acid, ethyl ester (0.29 g 2.5 mmol) in acetonitrile (50 mL) was added triethylamine (2 mL) and the solution warmed to 50° C. for one hour. The reaction mixture was diluted with water (100 mL), made acidic (pH 2) with 2N HCl and the precipitate collected by filtration, giving product as a white solid, (0.6 g, 2.3 mmol, 92 percent) yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:32])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH2:20][N:21]3C(=O)C4[C:23](=CC=CC=4)[C:22]3=[O:31])[N:11]=2)=[CH:5][CH:4]=1.Cl.ClCC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=CC=2)N=1.C([O-])([O-])=O.[K+].[K+].C1(=O)NC(=O)C2=CC=CC=C12.[K]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:32])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH2:20][NH:21][C:22](=[O:31])[CH3:23])[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccccc23)cc1
Agent: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)c2nc(CNC(C)=O)nc3ccccc23)cc1
Temperature: 70 °C
Yield: 68 %

Procedure:
2-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione: A suspension of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (10.367 g, 16.2 mmol) and K2CO3 (2.25 g, 16.3 mmol) in DMF (50 mL) was heated to 70° C. for 1 h. The reaction was cooled to rt, potassium phthalimide (6.004 g, 32.5 mmol) was added and the reaction heated to 70° C. for 2 h. The reaction was cooled to rt, diluted with EtOAc, washed with H2O and 5% NaOH, dried (MgSO4), filtered and concentrated. The residue was purified by gradient MPLC (SiO2, EtOAc/hexanes 0-100%) to yield 8.56 g (68%) of the title compound. 1H NMR (DMSO-d6) δ 7.95-8.02 (m, 2H), 7.87-7.94 (m, 2H), 7.55-7.60 (m, 2H), 7.18-7.22 (m, 2H), 7.02-7.12 (m, 1H), 6.94-7.01 (m, 2H), 6.88 (dt, 1H), 4.95 (s, 2H), 3.77 (s, 3H), 3.26 (s, 3H); HRMS (ES) calcd for C25H21N4O3 (M+H) 425.1608, found 425.1604.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:9])[CH:7]=[CH2:8]>[OH-].[Na+]>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
7.5 g (0.1 mol) mol) glycine was dissolved in 100 ml 2 N NaOH. The solution was cooled to 0° C. and 10.8 g (0.12 mol) acryloyl chloride was added dropwise over 45 minutes, while the temperature was kept below 10° C. The reaction was allowed to continue for one hour at 10° C. The reaction mixture was extracted 2 times with 50 ml tert. butyl methyl ether. The pH was adjusted to pH=3, using a concentrated hydrochloric acid solution and the reaction mixture was saturated with sodium chloride. The mixture was extracted 5 times with 100 ml n.-pentanol. The pooled n.-pentanol fractions were dried over Na2SO4 and evaporated under reduced pressure, after addition of a small fraction BHT as stabilizer. 4.2 g (32.5%) of N-acryloyl-glycine was isolated (m.p. 124-126° C.). N-acryloyl-glycine is Comparative Monomer 5 (see below).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[O:23][N:22]=1.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:42][CH2:43][CH2:44][N:45]=2)=[CH:37][CH:36]=1>O1CCCC1>[O:42]1[CH2:43][CH2:44][N:45]=[C:41]1[C:38]1[CH:39]=[CH:40][C:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:26][C:24]2[O:23][N:22]=[C:21]([CH3:20])[CH:25]=2)=[CH:36][CH:37]=1
Reactant: Cc1cc(C)on1
Reactant: BrCCCCCCOc1ccc(C2=NCCO2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a stirring solution of 48.6 g (0.48 moles) diisopropylamine in 520 ml tetrahydrofuran (THF) at -5° C. (ice/acetone bath) was added 185 ml of 2.6M n-butyllithium (0.48 moles) under nitrogen. The addition was complete after 30 minutes and the pale yellow solution was maintained at -5° to +5° C. for an additional 30 minutes. The ice/acetone bath was replaced by Dry Ice/acetone and when the internal temperature reached -55° C., 46.6 g (0.48 moles) 3,5-dimethylisoxazole was added dropwise over 20 minutes. This solution was allowed to stir an additional 30-40 minutes at -55° C. or lower. A solution containing 135 g (0.41 moles) 2-[4-(6-bromohexyloxy)phenyl]-4,5-dihydro-oxazole dissolved in 400 ml THF was added dropwise (via nitrogen pump) over 35 minutes. The temperature during the addition was kept below -50° C. by carefully controlling the rate of the addition. The heavy suspension was stirred for an additional hour. The Dry Ice bath was removed and the reaction was quenched by dropwise addition of 10 ml water. The reaction mixture was allowed to warm to about 5°-10° C. and then poured into 1 liter water and 1 liter ethyl acetate. The aqueous layer was set aside and the organic layer was washed once with water and brine. The extract was dried over magnesium sulfate and evaporated to near dryness under water vacuum. The crude crystalline product was dissolved in 600 ml warm acetonitrile, filtered thru a pad of solka floc and allowed to crystallize at room temperature. After two hours, the heavy crystalline precipitate was cooled to 10° C. and filtered to give 108 g (76%) 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole, m.p. 97°-98° C., after drying 24 hrs at 60° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1C=C)=[CH2:2].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(CC(C)(C)C)=C.C1(O)C=CC=CC=1.CC(CC(C)(C)C)=C>O>[CH2:2]([C:14]1[CH:15]=[CH:16][C:11]([OH:17])=[CH:12][CH:13]=1)[CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=Cc1ccccc1C=C
Reactant: Oc1ccccc1
Agent: C=C(C)CC(C)(C)C
Solvent: O
Product: CCCCCCCCc1ccc(O)cc1

Procedure:
The reaction is performed discontinuously in a stirred flask equipped with contact thermometer and reflux condenser, under the conditions indicated in Table 1. The flask is charged with 90 g of a sulfonated polystyrene ion exchange resin in the H-form, crosslinked with divinylbenzene to an extent of 8% by weight and having an activity of 4.6 meg/g catalyst, and 282 g of phenol and 168 g of diisobutene (molar ratio phenol: diisobutene=2:1) and 9 g of water (2% by weight, based on the mixture of phenol-diisobutene) is added thereto. After a reaction period of 15 minutes, the crude product is separated from the catalyst by filtration and worked up by distillation in a manner known per se without any pretreatment, thus obtaining a p-octyl phenol having a very high degree of purity (setting point 80.2° C.).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][C:12](=O)[CH3:13].Cl>C(COC)OC.C(O)C.O>[CH3:13][C:12]1[N:1]=[C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][N:9]2[CH:11]=1
Reactant: CC(=O)CBr
Reactant: Nc1ncccc1C=O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1cn2cccc(C=O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-aminonicotinaldehyde (92.8 g, 0.76 mol) and bromoacetone (114.5 g, 0.84 mol) in dimethoxyethane (980 ml) is stirred for 2 hr. at room temperature and then heated at 65° with stirring for 14 hr. The solid which separates is isolated by filtration, dissolved in 800 ml absolute ethanol and heated under reflux for 6 hrs. The ethanol solvent isremoved under reduced pressure and the residue treated with 138 ml 6 N hydrochloric acid in 750 ml water for 0.5 hr. The acidic aqueous layer is washed with ether (2×300 ml) and basified with cooling (78 ml 50% sodium hydroxide and 25 g sodium bicarbonate). The aqueous layer is extracted with dichloromethane. The extracts are combined and dried over anhydrous sodium sulfate. Following filtration, the solvent is removed under reduced pressure to afford 2-methyl-8-formylimidazo[1,2-a]pyridine, mp 136°-139.5° C.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[Cl:7][C:8]1[C:13]([NH:14][NH2:15])=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)C>[Cl:7][C:8]1[C:13]([NH:14][N:15]=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CCC(=O)CC
Reactant: NNc1cccnc1Cl
Solvent: CCO
Product: CCC(CC)=NNc1cccnc1Cl
Yield: 88.2 %

Procedure:
3-Pentanone (1.1 ml, 10.4 mmol) was added to a solution of (2-chloropyridin-3-yl)-hydrazine (1 g, 6.96 mmol) prepared in Step 1 in ethanol (35 ml). The reaction mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure and then purified with silica gel column chromatography to give 1.3 g of the titled compound as pale yellow oil. (Yield: 88%).