Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=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>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)[CH:11]=2)[C:6]([Cl:13])=[CH:7][N:8]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1cnc(Cl)c2cc(Br)ccc12
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: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc3c(Cl)cnc(Cl)c3c2)cc1
Yield: 48 %

Procedure:
A mixture of 7-bromo-1,4-dichloroisoquinoline (276 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (60 mg, 5 mol %), 4-methyphenylboronic acid (137 mg, 1.00 mmol), and aqueous Na2CO3 (2.0 mL, 1.0 M, 2.0 mmol) in DME (6 mL) was heated at reflux under N2 for 20 h. The mixture was diluted with EtOAc (100 mL), washed with water (30 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexanes-EtOAc (99:1 to 97:3) as eluant to give 1,4-dichloro-7-(4-methylphenyl)isoquinoline (139 mg, 0.48 mmol) as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[NH:39]([CH2:43][CH2:44][OH:45])[CH2:40][CH2:41][OH:42].O>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:39]([CH2:43][CH2:44][OH:45])[CH2:40][CH2:41][OH:42])=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCN(CCO)CCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 52 mg), potassium carbonate (138 mg), and diethanolamine (53 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 41 mg (yield 82%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:18][C:17]4([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:16]3)[C:9]2=[O:25])=[CH:4][CH:3]=1.Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:18][C:17]4([CH2:19][CH2:20][N:21]([CH2:34][C:35]5[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=5)[CH2:22][CH2:23]4)[CH2:16]3)[C:9]2=[O:25])=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCNCC2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccc(C(F)(F)F)cc3)CC2)C1
Temperature: 40 °C

Procedure:
To 3,3-bis(4-fluorophenyl)-1-(2-oxo-2-(2,7-diazaspiro[3.5]nonan-2-yl)ethyl)pyrrolidin-2-one (0.050 g, 0.114 mmol; Example 153A) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.030 g, 0.125 mmol) in dichloromethane (0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.171 mmol), and the reaction was heated to 40° C. for 1 hour. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences), and the title compound eluted with a gradient of 0.8% methanol/dichloromethane containing 0.2 N NH3 to 5.6% methanol/dichloromethane containing 0.2 N NH3(Flow=25 mL/minute) over 30 minutes. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.1, 2H), 7.42 (d, J=8.0, 2H), 7.34-7.27 (m, 4H), 7.04-6.94 (m, 4H), 3.97 (s, 2H), 3.72 (d, J=19.3, 4H), 3.52 (dd, J=5.5, 12.0, 4H), 2.75 (t, J=6.5, 2H), 2.31 (s, 4H), 1.74 (d, J=4.9, 4H); MS (ESI+) m/z 598.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[Na+].Cl[CH2:13][CH2:14][OH:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:13][CH2:14][OH:15]
Reactant: OCCCl
Reactant: COc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1OCCO
Yield: 41.6 %

Procedure:
A solution of 43.2 g (0.35 mole) of 2-methoxyphenol (guaiacol, Aldrich) in 200 ml of ethanol was stirred and treated with 29 ml (0.36 mole) of 50% sodium hydroxide solution. To this solution was added a solution of 28.2 g (0.35 mole) of 2-chloroethanol (Aldrich) in 50 ml of ethanol and the reaction mixture was heated at reflux for 2 hr. The solids were removed by filtration. The filtrate was evaporated under reduced pressure and the viscous residue was partitioned between 300 ml of 15% sodium hydroxide solution and 500 ml of ethyl ether. The organic layer was washed with 200 ml of 15% sodium hydroxide solution, 300 ml of water, dried (magnesium sulfate) and the solvent evaporated under reduced pressure to give 24.5 g (42%) of the title compound as a lightly colored viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O[CH:15](OC(C)C)[N:16]([CH3:18])[CH3:17])(C)C>>[CH3:15][N:16]([CH3:18])/[CH:17]=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)OC(OC(C)C)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 1-(4-chlorophenyl)ethane-1-one (35.0 g, 226 mmol) and N,N Dimethylformamide diisopropylacetal (35 mL) was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and treated with hexanes (50 mL). The resulting solid was collected via filtration and washed with hexanes to provide the title compound as a yellow solid (47.12 g, 99% yield): HPLC Retention Time; 6.45 min (Method B). M+1; 209.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][OH:22])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:22][CH2:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[N:14]=3)[CH:37]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.5 %

Procedure:
Under a nitrogen atmosphere, to a solution of (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (100 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (72 mg) in toluene (4.7 mL) were added 1,1′-(azodicarbonyl)dipiperidine (133 mg) and tributylphosphine (131 μL), and the mixture was stirred at room temperature for 14 hr. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (90 mg) as a colorless oil.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:2].CCN([CH2:20][CH3:21])CC.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CN(C)C1C=CN=CC=1.CS(C)=O.CCOC(C)=O>[CH2:1]([N:3]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@:4]([CH:20]=[CH2:21])([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: C=CN[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C=C[C@](Cc1ccccc1)(C(=O)O)N(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 166 %

Procedure:
To a suspension of (±)-vinylphenylalanine (560 mg. 2.9 mmol), NEt3 (1.6 mL, 12 mmol) and 4-dimethylaminopyridine (71 mg, 0.59 mmol) in dry DMSO (3 mL) at 10° C. was added benzyl chloroformate (1.9 mL, 13 mmol), dropwise and with stirring. After being stirred for 1.5 h at 50° C., the reaction mixture was diluted with EtOAc (150 mL) and extracted with NaHCO3 (aq, 50 mL). The organic layer was further extracted with 1N HCl (50 mL) and brine (50 mL). After drying (MgSO4), the volatiles were evaporated in vacuo and the residue purified by flash SiO2 chromatography (10% Et2O-hexane) to give 19 (1.0 g, 82%) as a white solid: mp 68°-70° C.; 1H NMR (500 MHz, CDCl3) δ 3.33 (d, J=13 Hz, 1 H); 3.62 (d, J=13 Hz, 1 H); 5.10-5.25 (m, 4 H); 5.27 (d, J=10 Hz, 1 H); 5.28 (d, J=17 Hz, 1 H); 5.68 (s, 1 H); 6.08 (dd, J=10, 17 Hz, 1 H); 6.90-6.91 (m, 2 H); 7.10-7.20 (m, 3 H); 7.26-7.43 (m, 10 H); 13C NMR (125 MHz, CDCl3) δ 40.4, 65.1, 66.5, 67.8, 116.2, 126.9, 128.1, 128.20, 128.23, 128.4, 128.5, 128.6, 130.0, 130.3, 135.0, 135.4, 136.6, 136.8, 154.4, 171.2; IR (film)3420-3330, 1723 cm-1 ; HRMS (FAB, 3-NOBA) calcd for C26H25NO4Na (M+Na)+ 438.1681, obsd 438.1685. Anal. Calcd for C26H25 NO4 : C, 75.16; H, 6.07; N, 3.37. Found: C, 74.98; H, 6.22; N, 3.37.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[C:27](=[O:28])[N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:32][CH:31]=4)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=3[CH2:47][CH3:48])=[CH:21][C:16]=2[CH2:15][CH2:14]1>O>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[C:27](=[O:28])[N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]5[NH:3][C:4](=[O:7])[O:5][N:43]=5)=[CH:32][CH:31]=4)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=3[CH2:47][CH3:48])=[CH:21][C:16]=2[CH2:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)c(-c2ccc3c(c2)CCO3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)c(-c2ccc3c(c2)CCO3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A mixture of hydroxylammonium chloride (2.36 g), sodium hydrogen carbonate (3.36 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-(2,3-dihydro-1-benzofuran-5-yl)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.95 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.49 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.46 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.69 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:14][CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2C(O)=O)[CH:7]=1.CS(C)=O.C(O)(C(F)(F)F)=O>CN(C=O)C.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH3:15])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1
Reactant: COc1nc(Cl)cn2ncc(C(=O)O)c12
Agent: [Pd+2]
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1nc(Cl)cn2nccc12
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
Crude 6-chloro-4-methoxypyrazolo[1,5-a]pyrazine-3-carboxylic acid from above (611 mg, 2.68 mmol) was dissolved along with palladium(II) trifluoroacetate (401 mg, 1.2 mmol) in DMF (24 mL). DMSO (1.6 mL) and TFA (2 mL, 26 mmol) were added and the resulting mixture was heated to 110° C. After stirring 2.5 h, the reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo and was partitioned between EtOAc, saturated aqueous NaHCO3 and water. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water and was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel (5-30% EtOAc in hexanes) to provide 6-chloro-4-methoxypyrazolo[1,5-a]pyrazine 5.36. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H7ClN3O: 184.0; found: 184.2.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:32][CH2:33][CH2:34][CH2:35][OH:36]>>[ClH:32].[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:33][CH2:34][CH2:35][OH:36])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCCCCl
Reactant: c1ccc(C(CCNCCC(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: Cl
Product: OCCCN(CCC(c1ccccc1)c1ccccc1)CCC(c1ccccc1)c1ccccc1

Procedure:
To bis(3,3-diphenylpropyl)amine (1.2 g) was added 3-chloropropan-1-ol (20 ml) and the mixture was heated with agitation at 150° to 160°C for 4 hours. The reaction mixture was evaporated under reduced pressure, and to the resulting residue was added benzene (20 ml). The mixture was washed with 5% hydrochloric acid and water in order. The benzene layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give oily residue. The residue thus obtained was crystallized from acetone-petroleum ether and further recrystallized from ethanol-ether to give 3-[bis(3,3-diphenylpropyl)amino]propan-1-ol hydrochloride (0.5 g). M.P. 152° to 154°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])C(Cl)=O.[OH:24][C:25]1[CH:30]=[CH:29][C:28](C2C=CC(C(OC[C@@H](C)CC)=O)=CC=2)=[CH:27][CH:26]=1.C(Cl)Cl.[C:48](OCC)(=[O:50])C>N1C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:9]([CH:8]=[CH:4][CH:3]=1)[C:48]([O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:50]
Reactant: CC[C@H](C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1c(F)cccc1C(=O)Oc1ccccc1

Procedure:
3-Fluoro-4-dodecyloxybenzoic acid chloride (3.32 g: 10 mmols) and 2.84 g (10 mmols) of (S)-2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate were reacted in 10 ml of pyridine and 15 ml of methylene chloride for 3 hours under reflux. After the reaction mixture was left to cool, 50 ml of ethyl acetate was added, and washed twice with 10% hydrochloric acid and once with each of a saturated sodium bicarbonate aqueous solution, water and a saturated sodium chloride aqueous solution. After the reaction product was dried with anhydrous sodium sulfate, the solvent was concentrated. Crude crystals obtained were purified by silica gel column chromatography (solvent: chloroform-hexane), and recrystallized from ethanol to obtain 4.64 g of 4{(S)-2-methylbutyloxycarbonyl]phenyl)phenyl 3-fluoro-dodecyloxybenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][C:25]1[O:26][C:27]([CH3:33])=[C:28]([C:30](Cl)=[O:31])[N:29]=1.C(OCC)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:28]5[N:29]=[C:25]([CH3:24])[O:26][C:27]=5[CH3:33])=[O:31])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c(C)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (202 mg, 0.652 mmol) in N,N-dimethylacetamide (4.0 mL) was added a solution of 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (135 mg, 0.847 mmol) in N,N-dimethylacetamide (1.0 mL), and the mixture was stirred at 0° C. for 1 hr. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the mixture, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→490/10), and precipitated from ethyl acetate/hexane to give the title compound (213 mg, 76%) as a white powder. melting point 224° C.
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:13]([O:19][CH2:20][C:21]([CH3:33])([CH3:32])[CH2:22][N:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24])(=[O:18])[CH2:14][C:15]([CH3:17])=O.[NH2:34]/[C:35](/[CH3:42])=[CH:36]\[C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC(O)C>[CH3:17][C:15]1[NH:34][C:35]([CH3:42])=[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[F:1])[C:14]=1[C:13]([O:19][CH2:20][C:21]([CH3:33])([CH3:32])[CH2:22][N:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24])=[O:18]
Reactant: O=Cc1cccc([N+](=O)[O-])c1F
Reactant: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1F
Yield: 20.3 %

Procedure:
A mixture of 184 mg of 2-fluoro-3-nitrobenzaldehyde, 324 mg of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate and 138 mg of ethyl 3-aminocrotonate in 1 ml of 2-propanol was reacted and then purified in the same way as in Example 8 to yield 120 mg of the desired compound (162).
Reaction SMILES: [SiH4].[CH:2]([O:5][SiH:6]([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9])([CH3:4])[CH3:3].[CH:15]([Si:17]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])[O:18][CH:19]([CH3:21])[CH3:20])=[CH2:16]>>[CH:8]([O:7][Si:6]([O:5][CH:2]([CH3:4])[CH3:3])([O:11][CH:12]([CH3:14])[CH3:13])[CH2:16][CH2:15][Si:17]([O:18][CH:19]([CH3:20])[CH3:21])([O:22][CH:23]([CH3:25])[CH3:24])[O:26][CH:27]([CH3:28])[CH3:29])([CH3:10])[CH3:9].[CH:8]([O:7][Si:6]([O:18][CH:19]([CH3:21])[CH3:20])([O:5][CH:2]([CH3:4])[CH3:3])[O:11][CH:12]([CH3:14])[CH3:13])([CH3:10])[CH3:9]
Reactant: C=C[Si](OC(C)C)(OC(C)C)OC(C)C
Reactant: CC(C)O[SiH](OC(C)C)OC(C)C
Agent: [SiH4]
Product: CC(C)O[Si](CC[Si](OC(C)C)(OC(C)C)OC(C)C)(OC(C)C)OC(C)C
Product: CC(C)O[Si](OC(C)C)(OC(C)C)OC(C)C
Reaction time: 3 h
Yield: 3 %
Yield: 2 %

Procedure:
The reaction was carried out as in Comparative Example 5 except that the starting silane used was triisopropoxysilane, a secondary alkoxysilane, and the reaction temperature was maintained at 140° C. After three hours the reaction was complete as monitored by GPC. The major product formed was vinyltriisopropoxysilane (95%). 1,2-bis(triisopropoxysilyl)ethane (3%) and tetraisopropoxysilane (2%) by-products were also formed.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][CH:17]=1)(=O)=O>CN(C)C=O>[O:9]([CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OCC1=CCCCO1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(COc2ccccc2)OCCC1
Reaction time: 0.5 h

Procedure:
6.0 g (0.25 mol) of sodium hydride are added a little at a time at room temperature to 20.5 g (0.22 mol) of phenol in 200 ml of dimethylformamide. Stirring is carried out for 30 minutes at room temperature, after which 42 g (0.22 mol) of 2,3-dihydropyran-6-ylmethyl methanesulfonate (Example 7b) are added dropwise with slight cooling. Stirring is carried out for 4 hours at room temperature, after which the reaction mixture is poured onto water. The aqueous phase is extracted three times with diethyl ether and the organic phase is dried over MgSO4 and evaporated down under reduced pressure. The residue is distilled. 27 g (0.14 mol=57%, based on 6-formyl-2,3-dihydropyran) of the title compound are obtained as a pale yellow oil.
Reaction SMILES: C([O:4][CH:5]1[C:10]2[CH:11]=[CH:12][S:13][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.[Br:14]N1C(=O)CCC1=O.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:4])[C:10]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC1CCCc2sccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: OC1CCCc2sc(Br)cc21
Yield: 82 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1-benzothien-4-yl acetate (5.1 g, 26 mmol) in chloroform (30 ml) was added N-bromosuccinimide (5 g, 28 mmol) at 0° C. with stirring, and the resulting mixture was stirred at room temperature for 3 hours. After stirring, the reaction mixture was poured into water (40 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in a mixed solvent of tetrahydrofuran (20 ml) and water (20 ml) was added sodium hydroxide (2.3 g, 57 mmol) with stirring, and the resulting mixture was stirred for 2 hours. After stirring, the reaction mixture was poured into water (50 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7) as the eluent to afford the title compound (5.0 g) in a yield of 82% as a colourless oily product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCSCc1cccnn1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCSCc1cccnn1)c1ccccc1

Procedure:
By the procedure of Example 18, 3-[(2-aminoethyl)-thiomethyl]pyridazine is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(3-pyridazinylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(3-pyridazinylmethylthio)ethyl]thiourea.