Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:27][CH3:28])=[O:4]
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(Oc2ccccc2)cc1)O3
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.9 %

Procedure:
(S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (30 mg), Cu(OAc)2, (25 mg), phenyl boronic acid (32 mg) and molecular sieves suspended in 5 mL DCM. TEA (0.064 mL) added, reaction flushed with oxygen and stirred at room temperature for 20 hours. The resulting mixture poured onto EtOAc and 10% sodium carbonate. Organic layer washed 3 times with 10% sodium carbonate, dried over sodium sulfate and concentrated. Residue purified over silica (hexanes to 9:1 hexanes/EtOAc) to give (3S,8S)-3-(4-phenoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (22 mg). LCMS (m/z): 537.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:27])[C:10]=2[C:28]([OH:30])=O)=[CH:5][CH:4]=1.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:25][CH2:26]3)[C:11](=[O:27])[C:10]=2[C:28](=[O:30])[NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:5][CH:4]=1
Reactant: NCc1ccccn1
Reactant: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)NCc3ccccn3)c2-c2ccc(OC)cc2)cc1

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-one and 2-(aminomethyl)pyridine as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained quantitatively.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3]1.Cl>CO.O1CCOCC1>[F:21][C:2]1([F:1])[CH2:7][CH2:6][NH:5][CH:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC1(F)CCNC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4,4-difluoro-2-phenylpiperidine-1-carboxylate (0.17 g, 0.57 mmol) in methanol (5 mL) was added 4M hydrogen chloride in dioxane (5 mL). The reaction mixture was stirred at room temperature for 4 hours then concentrated and the residue was triturated with diethyl ether. The white solid was collected by filtration and dried to give 4,4-difluoro-2-phenylpiperidine as the hydrochloride salt (93 mg, 70%). GC-MS (EI) for C11H13F2N: 197 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1>>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([OH:17])=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)=[CH:25][C:26]=1[C:32]([F:33])([F:35])[F:34]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: COc1ccc(CCl)cc1C(F)(F)F
Product: COc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F

Procedure:
From tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and 4-(chloromethyl)-1-methoxy-2-(trifluoromethyl)benzene, the title compound was prepared using a similar method to the one described in Example 1.48, Step B. LCMS m/z=420.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.31-2.39 (m, 1H), 2.50 (dd, J=16.3, 9.9 Hz, 1H), 2.75 (dd, J=16.3, 4.4 Hz, 1H), 2.83-2.93 (m, 1H), 3.59-3.67 (m, 1H), 3.85 (s, 3H), 3.95-4.05 (m, 2H), 4.06-4.14 (m, 2H), 5.30 (s, 1H), 6.67-6.74 (m, 2H), 6.86 (d, J=8.6 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]([CH3:13])[CH2:3][CH:4]=[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[S:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Sc1ccccc1
Reactant: CN(C)C=CC(=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC=C(Sc1ccccc1)c1ccccc1

Procedure:
By using a method similar to that described in Example 35, but starting from 3-dimethylaminoacrylophenone (80 g), phosphorus oxychloride (40 cc), thiophenol (50.3 cc) and sodium cyanoborohydride (16 g), and crystallising the (Z)-isomer, a yellow solid is isolated after evaporation of the mother liquors under reduced pressure (2.7 kPa) at 30° C. followed by crystallisation of the residue obtained from a mixture of acetone and ethyl ether (25/75 by volume); the solid is recrystallised from methyl ethyl ketone (230 cc). 1-Dimethylamino-3-phenyl-3-phenylthio-2-propene (E) hydrochloride (14.3 g) is thus obtained in the form of a white solid melting at 146°-147° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Br:18])=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)ccc2c1cnn2Cc1ccccc1
Reaction time: 4 h
Yield: 4.2 %

Procedure:
A solution of 1-benzyl-1H-indazol-4-amine (0.087 g, 0.39 mmol) in DMF (2 mL) was treated with N-bromosuccinimide (0.069 g, 0.39 mmol) at ambient temperature and stirred for 4 hours. The mixture was diluted with water, extracted with EtOAc, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (10-50% EtOAc in hexanes) to provide 1-benzyl-5-bromo-1H-indazol-4-amine (0.005 g, 4% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5])C.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][O:15][C:13]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:14]=1
Reactant: CCOC(=O)c1cc(OCCc2ccc(Cl)cc2Cl)c2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(OCCc2ccc(Cl)cc2Cl)c2c(c1)OCO2
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.41 g (1.07 mmol) of 7-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxole-5-carboxylic acid ethyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: C1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:12]C=O)=CN=1.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:12][C:11]#[C:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: O=CC=Cc1cncc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc2c(s1)CCN(CC#Cc1ccccc1)CC2

Procedure:
Prepared from 3-(4-isoquinolinyl)acrolein and 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine by reductive amination with sodium cyanoborohydride (in methanol in the presence of I equivalent of glacial acetic acid). The crude product is purified by column chromatography on silica gel (acetone/methanol/conc. ammonia =50:12:0.5). At first the title compound (A) is eluted. Yield: 4% of theory, Melting point: 205°-208° C. (ether).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([C:16]#[N:17])([CH3:15])[CH3:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:18][C:19]1[N:20]=[CH:21][N:22](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=1>C(#N)C>[C:16]([C:13]([C:11]1[CH:12]=[C:3]([CH2:2][N:20]2[C:19]([CH3:18])=[CH:23][N:22]=[CH:21]2)[CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])([CH3:15])[CH3:14])#[N:17]
Reactant: COC(=O)c1cc(CBr)cc(C(C)(C)C#N)c1
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Product: COC(=O)c1cc(Cn2cncc2C)cc(C(C)(C)C#N)c1

Procedure:
A mixture of methyl 3-bromomethyl-5-(1-cyano-1-methylethyl)benzoate (0.7 g), 4-methyl-1-tritylimidazole (0.8 g) and acetonitrile (2 ml) was heated under reflux for 48 h, then evaporated to dryness. The residue of 3-[3-(1-cyano-1-methylethyl)-5-methoxycarbonylbenzyl]-4-methyl-1-tritylimidazolium bromide was washed with diethyl ether (2×10 ml), and the residue was treated with glacial acetic acid (4 ml) and water (1 ml) and heated at 90° for 15 minutes. The mixture was diluted with water (20 ml), and washed with diethyl ether, and the aqueous phase was basified with 10N aqueous sodium hdroxide and extracted three times with ethyl acetate. The extracts were combined and evaporated to dryness, and the residue was purified by flash column chromatography, eluting with methanol:chloroform (1:49 by volume), to give methyl 5-(1-cyano-1-methylethyl)-3-(5-methylimidazol-1-ylmethyl)benzoate, mp 101°-104°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[NH:11][C:12]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25]([CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][CH2:29]Br)=[O:26])[CH3:23].O>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:28][CH2:29][N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[N:11]=[C:10]1[CH2:9][O:8][C:7]1[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C(CCBr)Cc1ccccc1
Reactant: Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21)Cc1ccccc1
Temperature: 25 °C
Yield: 117.8 %

Procedure:
A sodium hydride solution (60% in oil, 810 mg, 20.3 mmol) was washed with hexanes (2×50 ml) and then diluted with N,N-dimethylformamide (100 ml). At room temperature, under a nitrogen atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (5.0 g, 18.3 mmol) was then added in one portion. The resulting mixture was then stirred at room temperature for thirty minutes, and then 3-(ethoxycarbonyl)-4-phenylbutyl bromide (5.79 g, 20.3 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. Upon completion of this addition, the reaction mixture was stirred for about six hours at a temperature of 70-80° C. The reaction mixture was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 10.28 grams of a dark oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 9:1 methylene chloride:ethyl acetate. The fractions containing the desired title product were combined and concentrated in vacuo to yield 8.08 grams (93%) of a viscous yellow oil.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].CC1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]1O>C(O)C>[N+:15]([C:13]1[CH:12]=[CH:11][N:10]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:14]=1)([O-:17])=[O:16]
Reactant: CC1C=C([N+](=O)[O-])C=CN1O
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)OCc1cc([N+](=O)[O-])ccn1
Temperature: 110 °C
Reaction time: 0.03 h

Procedure:
To acetic anhydride (60 mL, 0.635 mol) at 110° C. under a nitrogen atmosphere was added 2-methyl-4-nitro-pyridin-1-ol (15)(17.1 g, 111 mmol) portionwise over 1 minute. After approximately 2 minutes the solution began to darken and heating maintained at 100-120° C. for 30 minutes and then allowed to cool to 80° C. Ethanol (60 mL) was added and the solution was concentrated under vacuum; residue slurried in water (140 mL) and the mixture neutralised with NaHCO3 (ca. 40 g). The aqueous liquor was extracted with ethyl acetate (4×100 mL, combined extracts washed with brine (2×100 mL, dried over Na2SO4, concentrated in vacuo to a crude oil. The material was subjected to flash chromatography eluent hexane:TBME (2:1). A brown oil was isolated, single peak in LC-MS analysis, (6.44 g 30%); m/z (LC-MS, ESP), RT=3.65 mins, (M+H) 197.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([OH:12])=[O:11].[CH2:13](O)[CH2:14][CH3:15].CCN=C=NCCCN(C)C.O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11]
Reactant: Cc1cc(O)c(C(=O)O)c(=O)o1
Reactant: CCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOC(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.9 %

Procedure:
In 30 ml of toluene, 0.85 g of 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylic acid, 0.9 g of 1-propanol and 0.12 g of 4-dimethylaminopyridine were dissolved, and 0.96 g of WSC was added to the mixture, and the mixture was stirred at room temperature for 16 hours. Subsequently, water was poured into the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The resultant organic layer was washed with saturated a saturated solution of sodium chrolide, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to obtain 0.37 g of propyl 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylate (Compound No. 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C1COCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:15][CH:16]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of 2-(4-fluorophenyl)ethanol (0.568 g) in THF (10 mL) was added NaH (0.270 g, 60% in oil). The mixture was stirred at room temperature for 2 hours, before 2,5-dibromopyridine (0.8 g) was added. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (2×20 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column (Hex/EtOAc=100:5) to give 5-bromo-2-(4-fluorophenethoxy)pyridine (0.3 g). LCMS (M+H)=296.0.
Reaction SMILES: [OH:1][C:2]1[CH2:10][CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=32)[C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:20]1(O)[CH:25]=CC=[CH:22][CH:21]=1>>[C:18]1([O:17][C:15]([C:3]2[C:4]3=[N:5][C:6]4[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=4[N:8]3[CH2:9][CH2:10][C:2]=2[OH:1])=[O:16])[CH:22]=[CH:21][CH:20]=[CH:25][CH:19]=1
Reactant: CCOC(=O)C1=C(O)CCn2c1nc1ccccc12
Reactant: Oc1ccccc1
Product: O=C(Oc1ccccc1)C1=C(O)CCn2c1nc1ccccc12
Reaction time: 16 h

Procedure:
A mixture of the pyridobenzimidazo derivative VII prepared as in Example 1 (3.5 g, 13.6 mM) and phenol (7.0 g, 74.5 mM) in xylenes (350 mL) was heated to reflux under argon for 6 h and left at room temperature for 16 h. The resulting solid precipitate was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by HPLC, using methylene chloride and THF as eluents followed by recrystallization of the desired fractions from methylene chloride and acetone to give the title compound as a solid: mp 176-178° C.; MS: 307 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.[CH2:29]([O:31][CH2:32][CH2:33]O)[CH3:30].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:28][Si:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:30][CH2:29][O:31][CH2:32][CH3:33])=[O:23])=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CCOCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOCCOC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Reaction time: 120 h

Procedure:
A solution of 11.5 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred at reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:19]([S:21][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)(=[O:22])[CH3:20]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 105 °C
Reaction time: 4 h
Yield: 905.4 %

Procedure:
In 40 ml of dimethylformamide were dissolved 4.12 g (14.7 mmol) of 1-(tert-butoxycarbonyl)-4-(methanesulfonyloxy)piperidine, and 2.53 g (2.21 mmol) of potassium thioacetate were added to the solution, followed by stirring of the resulting mixture at 105° C. for 4 hours under nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water and then a saturated aqueous NaCl solution, followed by evaporation of the solvent. The thus obtained residue was subjected to silica gel column chromatography and the fractions eluted with a mixed solvent of hexane-ethyl acetate (5:1) were collected to obtain 5.19 g (yield: 81%) of the title compound as an oil.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[CH:11][CH:12]=4)=[CH:8][CH:7]=1)=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3>O>[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[CH:11][CH:12]=4)=[CH:8][C:7]=1[S:1]([OH:3])(=[O:5])=[O:2])=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3
Reactant: c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
As represented by the following reaction pathway, 30% fuming sulfuric acid (2.1-liter) was added to 300 g of acenaphtho[1,2-b]quinoxaline obtained by synthesis example 1 and the mixture was stirred at room temperature for 48 hours for reaction. While keeping the obtained solution at 40° C. to 50° C., 4.5-liter of ion exchange water was added for dilution, and the resultant was further stirred for 3 hours. The precipitate was filtered to obtain acenaphtho[1,2-b]quinoxaline-2-sulfonic acid as represented by the following formula (d).
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]([O:25][CH2:26]C)=[O:24])[C:18]([O:20][CH2:21]C)=[O:19])=[CH:13][CH:12]=1)C1C=CC=CC=1>CO.[Pd]>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]([O:25][CH3:26])=[O:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C(=O)OC)c1ccc(O)cc1

Procedure:
At room temperature and a hydrogen pressure of 5 bar, 94.3 g of diethyl (4-benzyloxyphenyl)malonate (J. Org. Chem. 46, 3007 (1981)) in 500 ml of methanol were hydrogenated in the presence of 5 g of palladium/carbon catalyst (5%). The catalyst was filtered off and the mixture was concentrated, to give the title product as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23]([O:27][C:28](=[O:58])[N:29]([CH2:31][CH:32]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)[CH3:30])([CH3:26])([CH3:25])[CH3:24]>O1CCOCC1.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>[C:23]([O:27][C:28](=[O:58])[N:29]([CH2:31][CH:32]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:52])[CH3:53])[CH2:33][O:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[N:3]=[C:4]([Cl:16])[CH:5]=[C:6]([N:8]([CH3:15])[CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:7]=2)[CH:40]=1)[CH3:30])([CH3:24])([CH3:26])[CH3:25]
Reactant: CN(c1cc(Cl)nc(Cl)n1)C1CCOCC1
Reactant: CN(CC(COc1cccc(B2OC(C)(C)C(C)(C)O2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(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: C1COCCO1
Product: CN(CC(COc1cccc(-c2nc(Cl)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of (2,6-dichloro-pyrimidin-4-yl)-methyl-(tetrahydro-pyran-4-yl)amine (0.4 g, 1.5 mmol) in degassed dioxane and H2O (4/1, 25 mL) was added Na2CO3 (315 mg, 3.0 mmol); Pd(PPh3)4 (86 mg, 0.075 mmol) and {2-(tert-Butyl-dimethyl-silanyloxy)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propyl}-methyl-carbamic acid tert-butyl ester (703 mg, 1.35 mmol). The system was purged with N2 stream and the mixture was stirred at 100° C. for 2 h., cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to give [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-chloro-6-[methyl-(tetrahydro-pyran-4-yl)-amino]-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (373 mg, 40% yield) as major product. ESI-LCMS (m/z): 411.2 [M+1]+along with the minor product [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{2-chloro-6-[methyl-(tetrahydro-pyran-4-yl)-amino]-pyrimidin-4-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (140 mg, 15% yield). ESI-LCMS (m/z): 411.2 [M+1]+.
Reaction SMILES: [C:1]1([C:7]([OH:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][CH2:12][C:13](Cl)=[O:14]>>[Br:11][CH2:12][C:13]([O:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])=[O:14]
Reactant: O=C(Cl)CBr
Reactant: CC(C)(O)c1ccccc1
Product: CC(C)(OC(=O)CBr)c1ccccc1

Procedure:
The sub-title compound was prepared analogously to the procedure described in Example 30(i) from 2-phenyl-2-propanol (3 g; 22 mmol) and bromacetylchloride (4.16 g, 26 mmol). Yield 1.2 g (44%).