Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][N+:13]=1[O-].CCN(CC)CC.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:14]1[N:13]=[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH:17]=[C:16]([CH3:18])[C:15]=1[CH3:19]
Reactant: Cc1cc(N2C(=O)c3ccccc3C2=O)[n+]([O-])cc1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1cc(N2C(=O)c3ccccc3C2=O)nc(Cl)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of 2-(1,3-dioxoisoindolin-2-yl)-4,5-dimethylpyridine 1-oxide (1.5 g, 0.01 mol) in POCl3 (50 mL) was added Et3N (680 mg, 0.01 mol) at room temperature. The mixture was stirred at 80□ for 2 hr, and then carefully poured into the mixture of saturation NaHCO3 solution and ice water. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give a crude residue that was purified by column chromatography on silica gel (10-15% ethyl acetate in petroleum ether) to give 2-(6-chloro-4,5-dimethylpyridin-2-yl)isoindoline-1,3-dione (650 mg, 41%). 1H NMR (300 MHz, CDCl3) δ 7.97-7.92 (m, 2H), 7.82-7.78 (m, 2H), 7.16 (s, 1H), 2.41 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[C:8]([CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[C:18]1[N:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=2)[C:20](=[O:23])[NH:21][N:22]=1.ClCCCl>CCCCCC>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[C:18]1[N:19]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:20](=[O:23])[NH:21][N:22]=1
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1-c1ccc(OC)cc1
Solvent: CCCCCC
Solvent: ClCCCl
Product: CC(C)c1cc(-c2n[nH]c(=O)n2-c2ccc(O)cc2)c(O)cc1O
Temperature: 80 °C
Reaction time: 24 h
Yield: 14.7 %

Procedure:
Crystals (3.30 g, 7.68 mmol) of 5-(2,4-bis(methoxymethoxy)-5-isopropyl phenyl)-4-(4-methoxyphenyl)-4H-[1,2,4]triazol-3-one (F60-03: an intermediate of Example 2-7) was added to a suspension of tribromoborane dimethylsulfide complex (11.65 g, 37.26 mol) and 1,2-dichloroethane (250 mL) in 300 mL eggplant shaped flask and stirred at room temperature for 2 hours and further at an external temperature of 80° C. for 24 hours. After completing the reaction, the reaction mixture was returned to room temperature and mixed with n-hexane (250 mL). The precipitates were collected by filtration, washed with diethyl ether and then purified by DIAION HP-20 column chromatography (water-methanol gradient elution), followed by CHP-20 column chromatography (water-methanol gradient elution) to obtain the title compound (OH-all: 370 mg, 14.8%). The fractions which were not sufficiently separated and purified were purified by HPLC fractionation to obtain the title compound (OH-all: 300 mg, total 670 mg, 26.8%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylate (i.e. product of Step B) (0.92 g, 2.8 mmol) in methanol (15 mL) was added water (5 mL), which caused the reaction mixture to become cloudy. An aqueous solution of sodium hydroxide (50%, 1.5 g, 19.2 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 30 minutes, during which time the reaction mixture became again clear. Water (20 mL) was added and the reaction mixture was extracted with ethyl ether, which was discarded. The aqueous phase was acidified to pH 2 using concentrated hydrochloric acid and then extracted with ethyl acetate (50 mL). The ethyl acetate extract, which was washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate and concentrated to give the title compound, isolated as a white solid (0.8 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C@H:3]1[C:13]([OH:15])=[O:14].[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C@H:3]1[C:13]([O:15][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=1)=[O:14]
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1cccc(Oc2ccccc2)c1
Product: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylic acid and 3-phenoxy-benzyl alcohol were reacted to obtain 3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]([F:13])([F:12])[F:11])=[C:6]([NH2:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.[CH3:23][N:24]1[CH2:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH2:26][CH2:25]1>CN(C=O)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]>[CH3:23][N:24]1[CH2:25][CH:26]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]([O:9][C:10]([F:13])([F:12])[F:11])=[C:6]([NH2:8])[CH:7]=2)[CH2:28][CH2:29]1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1cc(Br)ccc1OC(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CC=C(c2ccc(OC(F)(F)F)c(N)c2)CC1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
5-Bromo-2-trifluoromethoxy-phenylamine (0.43 g, 1.68 mmol), cesium carbonate (1.65 g, 5.06 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(ii) dichloride, complex with dichloromethane (1:1) (0.08 g, 0.1 mmol) in dry DMF (20 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. A solution of 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine (0.45 g, 2.01 mmol) in dry DMF (10 mL) were added to the suspension and the reaction mixture warmed at 80° C. for 3 hours. The reaction mixture was then allowed to cool to room temperature, diluted with water (100 mL) and extracted with DCM (2×50 mL) and the combined organic phases were extracted with 1N HCl solution (50 mL). The aqueous layer was basified by addition of sodium bicarbonate and extracted with EtOAc (2×50 mL). The combined organic phases were dried over anhydrous Na2SO4, the solvent removed under reduced pressure and the crude solid purified by flash chromatography on silica gel (eluant: DCM/MeOH 90/10) to afford the intermediate as a light brown solid (0.3 g, 65% yield)
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[C:15]([C:6]2=[C:5]([C:16]([O:18]C)=[O:17])[CH:4]=[C:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[OH-].[K+].Cl>C(O)C.O>[O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[C:15]([C:6]2=[C:5]([C:16]([OH:18])=[O:17])[CH:4]=[C:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccccc3c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2ncc3ccccc3c12
Temperature: 25 °C

Procedure:
11 g of methyl 4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxylate are taken up in 300 ml of ethanol under argon, whereupon a solution of 3.7 g of potassium hydroxide in 30 ml of water is added thereto and the mixture is heated under reflux until the reaction has finished. The reaction mixture is then cooled to room temperature and poured into 2200 ml of water. The mixture is adjusted to pH 7 by adding 1N aqueous hydrochloric acid and impurities are removed by two-fold extraction with 300 ml of methylene chloride each time. The aqueous phase is acidified to pH 1 with 2N aqueous hydrochloric acid and the crystals formed are removed by filtration under suction. After repeated washing with water and drying in vacuo, there is obtained 4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxylic acid as yellow crystals of m.p. 236°-237° (dec.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CS(C)=O.C(OCC)(=O)C>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(F)c1
Temperature: 90 °C
Yield: 92.2 %

Procedure:
A solution of 2.14 g (31.4 mmol) of imidazole and 10.9 g (62.8 mmol) of dibasic potassium phosphate in 190 mL DMSO was treated with 5.25 g (3.7 mL, 32.9 mmol) of 3,4-difluoronitrobenzene followed by warming at 90° C. for 18 h. The solution was diluted with ethyl acetate and was extracted with water. The water layer was back-extracted with ethyl acetate and the combined organic layers were then extracted with water (2×). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford a brown solid. This material was chromatographed over 250 g of 230-400 mesh silica gel, eluting with dichloromethane, and then with 1% (v/v) methanol in dichloromethane, and finally with 2% (v/v) methanol in dichloromethane. These procedures afforded 6.0 g (92%) of the title compound as a bronze colored solid. 1H NMR (CDCl3): δ 8.17, 7.96, 7.63, 7.35, 7.26.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[OH:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[O:22][CH2:27][CH:26]=[CH2:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN1CCC(O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC1CCN(CC)c2c(CO[Si](C)(C)C(C)(C)C)cccc21
Reaction time: 2.5 h
Yield: 74.3 %

Procedure:
8-t-butyldimethylsilyloxymethyl-4-hydroxy-1-ethyl-1,2,3,4-tetrahydroquinoline (2.19 g) was dissolved in dimethyl formamide (15 ml), followed by addition of sodium hydride (60% in oil, 0.33 g), and allyl bromide (0.99 g) was added thereto under ice-cooling. The mixture was stirred for 2.5 hours at the same temperature. Furthermore sodium hydride (60% in oil, 0.16 g) and allyl bromide (0.48 g) were added to the reaction mixture and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate-toluene and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (6 : 1)]to give 8-t-butyldimethylsilyloxymethyl-4-allyloxy-1-ethyl-1,2,3,4-tetrahydroquinoline (1.83 g).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:8]=[CH:9][C:10]=1[CH2:11][NH:12]C(=O)C)(=O)C.[OH-].[K+]>C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH:8]=[CH:9][C:10]=1[CH2:11][NH2:12]
Reactant: CC(=O)NCc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CN)c(N)c2)CC1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
To a solution of compound 19 (1.5 g, 3.85 mmol) in ethanol (20 mL) at room temperature was added a solution of KOH (3M, 25 mL), and the reaction was refluxed for 12 h. The reaction was cooled to room temperature, ice cold water was added, and the solution was extracted with ethyl acetate (30 mL×2). The organic layer was washed with brine (15 mL), dried over Na2SO4 and evaporated to get a brown oil material, which was resolved over silica column, eluting with ethyl acetate:hexanes (8:2), and then changing to ethyl acetate (100%) to obtain 0.98 g (83%) of 20 as a dark brown gum. IR (KBr) νmax. cm−1: 3060 (Ar-H), 1690 (C═O), 1616, 1514, 1417 (C═C). 1H NMR (500 MHz, CDCl3) δ=1.46 (s, 9H, (CH3)3C); 2.90 (m, 4H, 2CH2); 3.49 (m, 4H, 2CH2), 3.90 (s, 2H, CH2); 5.30 (br. s, 4H, 2NH2); 6.59 (d, 1H, J=8.2 Hz, H-5); 6.68 (dd, 1H, J=2.6, 8.2 Hz, H-6); 6.80 (d, 1H, J=2.6, H-2); 13C NMR (125.7 MHz, CDCl3) δ=28.37 (CH3)3C), 42.10 (CH2), 44.01 (CH2), 50.87 (CH2), 79.64 (CH3)3C), 117.29 (C-2), 117.79 (C-6), 119.88 (C-4), 120.36 (C-5), 139.80 (C-3), 144.15 (C-1), 154.67 (C═O). Calculated (%) for C16H26N4O2(306.21); C, 62.72; H, 8.55; N, 18.29. found (%) C, 62.63; H, 8.63; N, 18.20.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]2[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[N:12][O:13][CH2:14][C:9]=2[CH:8]=1.[CH2:24]([NH:27][CH3:28])[CH:25]=[CH2:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:24]([N:27]([CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]2[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[N:12][O:13][CH2:14][C:9]=2[CH:8]=1)[CH3:28])[CH:25]=[CH2:26]
Reactant: BrCC=CCOc1ccc2c(c1)CON=C2c1ccc(Br)cc1
Reactant: C=CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C)C/C=C/COc1ccc2c(c1)CON=C2c1ccc(Br)cc1

Procedure:
1.35 g of 7-(4-bromo-but-2-enyloxy)-4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazine are dissolved in 50 ml of acetone and treated with 3.83 ml of N-allyl-methyl-amine and 1.28 g of potassium carbonate. The mixture is stirred and subsequently filtered. After concentration the filtrate is chromatographed over silica gel with toluene/acetone/triethylamine (92:7:1). There are obtained 1.09 g of (E)-allyl-[4-[4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazin-7-yloxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 427 (M+H+, 1 Br).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N+:12]([O-])=O.[ClH:15].O>C(O)C.[Pd]>[ClH:15].[ClH:15].[NH2:12][C:3]1[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:5][N:6]([CH3:7])[C:2]=1[NH2:1]
Reactant: Cn1nc(C(C)(C)C)c([N+](=O)[O-])c1N
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1nc(C(C)(C)C)c(N)c1N
Reaction time: 3 h

Procedure:
A suspension of 8.5 g (0.035 mol) of 5-amino-1-methyl-4-nitro-3-tert-butylpyrazole and 1.5 g of 5% by weight palladium-on-charcoal containing 50% water in 200 cm3 of ethanol was placed in a hydrogenator. After stirring for 3 hours under a hydrogen pressure of 10 bar, at a temperature of 75° C., the reaction medium was poured into a solution, precooled to 0° C., of 60 cm3 of ethanol and 20 cm3 of 12 N hydrochloric acid. The solution was clarified by filtration on a sinter funnel and then evaporated to dryness under reduced pressure. The brown solid obtained was taken up, at reflux, in 35 cm3 of 5 N hydrochloric ethanol and 11 cm3 of water and then cooled to room temperature. The white crystals obtained were filtered off on a sinter funnel and then dried under vacuum at room temperature. 4.9 g of the expected product were obtained in the form of white crystals, the melting point of which was 260° C. The elemental analysis for C8H10N4.2HCl was:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.[ClH:20].[N:21](=[CH:29][CH2:30]Cl)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].C(N(CC)CC)C>C(O)C>[ClH:28].[ClH:20].[N:21]1([CH2:29][CH2:30][N:14]2[CH2:15][CH2:16][C:11]3[C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ClCC=NCCCCCCCl
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCCCCC1)C3

Procedure:
A mixture of 0.02m of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one, 0.022m of 2-(hexamethyleneimino)-ethyl chloride HCl and 0.022m of triethylamine in 200ml of ethanol was refluxed for 6 hours. The mixture was filtered while hot and immediately treated with excess HCl gas. Crystallization of the crude product from methanol gave 2.5g of material, m.p. 233°-4° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8]>>[CH2:6]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:1][CH:3]1[O:5][CH2:4]1)[CH2:7][CH3:8]
Reactant: ClCC1CO1
Reactant: CCCNCCC
Product: CCCN(CCC)CC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
A stirred solution of epichlorohydrin (20.0 g, 0.22 mole) is treated dropwise with dipropylamine (23.14 g, 0.23 mole) over a 1 hour period followed by continuous stirring at room temperature overnight. The reaction mixture is washed with 20% K2CO3 (50 ml). The organic layer is then stirred with 40% NaOH for 1 hour. The organic layer is separated and the aqueous layer is extracted with 3×100 ml portions of ether. The etheral extracts are pooled with the organic layer and washed with H2O (100 ml). The organic layer is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield the crude product (I) weighing 35.3 g. The crude product is distilled at 34°/0.1 mmHg to yield 7.23 g (21.0%) pure product to be used as an intermediate in Part B.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([C:7]1[CH:8]=[C:9](O)[CH:10]=[CH:11][CH:12]=1)#[N:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:4][C:11]1[CH:12]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:5]#[N:6]
Reactant: OCCBr
Reactant: N#Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(OCCBr)c1
Reaction time: 8 h

Procedure:
0.71 ml (10.0 mmol) of 2-bromoethanol, 1.43 g (12.0 mmol) of 3-cyanophenol and 3.15 g (12.0 mmol) of triphenylphosphine were dissolved in 100 ml of tetrahydrofuran. 5.22 g (12.0 mmol) of diethyl azodicarboxylate (40% solution in toluene) was added to the solution at room temperature, and they were stirred overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained. This product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:30]=[CH:29][O:28][N:27]=3)=[O:24])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:15][C@H:10]1[CH2:11][O:12][CH2:13][CH2:14][N:9]1[C:7]1[CH:8]=[C:3]([CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40])[N:4]=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:30]=[CH:29][O:28][N:27]=3)=[O:24])=[CH:20][CH:21]=2)[N:6]=1
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)Nc3ccon3)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccon3)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(1,2-oxazol-3-yl)urea (300 mg) was partially dissolved in DCM (10 mL) and triethylamine (0.153 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.086 mL) and the reaction was stirred for 45 mins at RT. The reaction was then washed with water (2 mL) and dried over magnesium sulphate. The solution was vacuumed to dryness to give the desired material as a yellow solid.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].O1CCCC1.Cl.[Cl:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17]>CO.ClCCl>[ClH:15].[NH:7]([C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17])[C:6]([NH2:8])=[NH:5]
Reactant: COc1ccc2nccc(-n3cc(C(=O)Cl)c4ccccc43)c2c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2nccc(-n3cc(C(=O)NC(=N)N)c4ccccc43)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 cm3 of methanol and 17 cm3 (8.5 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.812 g (8.5 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm3 of dichloromethane and evaporated to dryness under reduced pressure (2.7 kPa). 40 cm3 of tetrahydrofuran and 0.67 g (1.79 mmol) of 3-chlorocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride, suspended in 40 cm3 of dichloromethane, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the product obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.37 g of 3-guanidinocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 266° C. Mass spectrum (EI): m/e 359 (M+•), m/e 301.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:30].[K+]>O1CCCC1>[OH:30][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH2:9][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]([F:28])([F:29])[C:18]([F:26])([F:27])[C:19]([F:24])([F:25])[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCCCCCCCCOc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Yield: 67.2 %

Procedure:
In a flask, 1.7 g of 4-hydroxy-4'-[2-(perfluorobutyl)ethyloxy]biphenyl and 10 ml of tetrahydrofuran were placed. To this solution, 3.9 ml of a 1N aqueous solution of potassium hydroxide was added and stirred for a while. After the solvent was distilled away under a reduced pressure, 15 ml of methanol and 0.85 g of 8-bromooctanol were added to the solution and stirred under reflux for 12 hours. Next, the reaction solution was poured into water, and an organic layer was extracted with ether. The ether layer was washed with dilute hydrochloric acid and water in this order. After the solvent was distilled away, the residue was purified by silica gel column chromatography (eluent: benzene/ethyl acetate=9/1), and recrystallized from toluene to give 1.5 g of 4-(8-hydroxyoctyloxy)-4'-[2-(perfluorobutyl)ethyloxy]biphenyl (Y: 67.2%). The purity of the compound thus obtained was 98.8% by GC.