Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([N:19]1[C:23](=O)[CH:22]([CH2:25][O:26][CH3:27])[O:21][CH-]1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>O>[CH3:27][O:26][CH2:25][CH:22]([OH:21])[CH2:23][NH:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:15]=1
Reactant: COCC1O[CH-]N(c2ccc3cc(OCc4ccccc4)ccc3c2)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCC(O)CNc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A mixture of 2.0 g of 3-(6-benzyloxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone, 20 ml of ethanol, 4 ml of water and 1.08 g of potassium hydroxide is stirred at 100° C. for one hour. The reaction mixture is evaporated under reduced pressure to remove the ethanol. The residue is extracted with ethyl acetate, and the extract is washed with water, dried and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from ethyl acetate-hexane to give 1.64 g of N-(3-methoxy-2-hydroxypropyl)-6-benzyloxy-2-naphthylamine as colorless needles.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(F)c4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3cccc(F)c3F)c2O1

Procedure:
The title compound was prepared (0.094 g, 84%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.23 mmol) and methylamine (0.072 g, 2.3 mmol); mp 166-168° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:22]12[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]#[C:35][Si](C)(C)C)([O:26][CH2:27]1)[O:24][CH2:23]2)[CH2:20][CH3:21]>O1CCCC1>[CH2:30]([C:25]12[CH2:28][CH2:29][C:22]([CH2:19][CH2:20][CH3:21])([CH2:23][O:24]1)[CH2:27][O:26]2)[CH2:31][CH2:32][CH2:33][C:34]#[CH:35]
Reactant: CCCC12CCC(CCCCC#C[Si](C)(C)C)(OC1)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCCCCC12CCC(CCC)(CO1)CO2
Reaction time: 1 h

Procedure:
Tetrabutylammonium fluoride solution (1.0M., solution 4.0 ml.) was added to a stirred solution of 4-n-propyl-1-(6-trimethylsilylhex-5-ynyl)-2,6,-dioxabicyclo[2.2.2]octane in dry tetrahydrofuran (40 ml.) at 20° and the mixture was stirred for 1 hour. The solvent was removed in vacuo and the residue was extracted with diethyl ether and water. The ethereal extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was chromatographed on alumina eluting with dichloromethane:hexane 1:9, saturated with ammonia. 1-(Hex-5-ynyl)-4-n-propyl-2,6-dioxabicyclo[2.2.2]octane was obtained as a colourless oil (0.45 g.)
Reaction SMILES: Cl.[NH2:2][OH:3].CO.[CH3:6][N:7]1[C:11]([CH:12]=O)=[CH:10][N:9]=[C:8]1[N+:14]([O-:16])=[O:15].C(O)C>C(N(CC)CC)C>[CH3:6][N:7]1[C:11]([CH:12]=[N:2][OH:3])=[CH:10][N:9]=[C:8]1[N+:14]([O-:16])=[O:15]
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCN(CC)CC
Product: Cn1c(C=NO)cnc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 0.400 g. of hydroxylamine hydrochloride in 15 ml. of methanol, 0.400 g. of 1-methyl-2-nitro-5-imidazolcarboxaldehyde in 20 ml. of ethanol and 0.810 ml. of triethylamine are added at room temperature. After standing overnight, the solution is concentrated to a small volume and the solid which precipitates is collected on the filter. After crystallization from water, 0.10 g. of the title compound is obtained which melts at 203°-205° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[C:8](=O)([O-:10])[O-:9].[K+].[K+].C(=O)=O.Cl>O>[CH3:1][C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c[nH]c(C)n1
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: Cc1nc(C(=O)O)c(C)[nH]1
Yield: 74.2 %

Procedure:
12 g (0.125 mole) of 2,4-dimethylimidazole, 42.5 g (0.3 mole) of potassium carbonate and 100 ml of liquid carbon dioxide were stirred for 5 hours at 150° C. in an autoclave, the reaction pressure being 130 bar. The reacted mixture was pulverized and suspended in 100 ml of water, and the stirred suspension was brought to pH 5-6 with hydrochloric acid. The precipitate which separated out was filtered off and dried to give 13 g (74% of theory) of pure 2,5-dimethylimidazole-4-carboxylic acid of melting point 234° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([N:4]1[C:3](=[O:9])[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[N:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a round bottom flask was added 4,5-dichloropyridazin-3(2H)-one (50 gm, 303.03 mmol), DMF (150 ml), K2CO3 (46 gm, 333.33) and benzyl bromide (51.83 gm, 303.03 mmol). The reaction was stirred at rt for 16 hrs. After this time, the reaction mixture was slowly poured into water (500 ml) and a solid precipitate formed. The slurry was stirred at rt for 1 hr. After this time, the reaction mixture was filtered and the solid was collected. The solid was dried under vacuum to give product 2-benzyl-4,5-dichloropyridazin-3(2H)-one as tan-colored solid (74 gm, 97% yield). HPLC retention time (method A)2.788 min; LCMS (M+1)=255.1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=2)[CH:10]=[N:9][CH:8]=1)(=O)=O.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44](B3OC(C)(C)C(C)(C)O3)=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=4)[CH:10]=[N:9][CH:8]=3)=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cncc4ccc(C(=O)OCC[Si](C)(C)C)cc34)cc2)CC1
Yield: 79.5 %

Procedure:
Using 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (1.00 g, 2.38 mmol) and tert-butyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (998 mg, 2.57 mmol), the desired title compound (1.01 g, yield 79%) was obtained by the same method as in Example 4 (4a).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11]([O:13][CH3:14])=[O:12].Cl>ClCCl>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:9])[C:2]=1[NH:1][C:11](=[O:12])[O:13][CH3:14]
Reactant: Nc1c(O)cccc1F
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)Nc1c(O)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-amino-3-fluorophenol (2.07 g) and dichloromethane (100 mL) were added TEA (2.29 mL) and methyl chloroformate (1.27 mL) under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was ice-cooled, and 0.5 M hydrochloric acid solution was added thereto, followed by stirring for 10 minutes. Then, the organic layer was separated. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=100/0-75/25) to obtain methyl (2-fluoro-6-hydroxyphenyl)carbamate (2.55 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:51])[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][C:10]([NH:12][C@:13]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:44])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:11]>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[O:51]=[S:2]1(=[O:1])[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][C:10]([NH:12][C@:13]12[CH2:47][CH2:46][C@@H:45]([CH:48]([CH3:49])[CH3:50])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:44])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:42][CH:43]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:11]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H]1CC[C@]2(NC(=O)CN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 6 h
Yield: 76.2 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (15 mg, 0.021 mmol) in a mixture of THF (4 mL) and MeOH (1 mL) under a N2 (g) atmosphere was added palladium hydroxide on carbon (3.67 mg, 5.23 μmol). The reaction mixture was purged with H2 (g) and was stirred under a H2 (g) atmosphere. After 6 h, the reaction mixture was filtered and washed with DCM and concentrated to give brown solid. The material was then plugged through a silica gel column (3 g), eluted with 90:10 DCM:MeOH, concentrated and dried to give 4-((1S,3 aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-3a-(2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)acetamido)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (11.5 mg, 76% yield) as a light brown solid. LC/MS: m/e 719.3 (M+H)+, 2.61 min (method 3). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 7.90 (d, J=7.3 Hz, 2H), 7.30-7.21 (m, 1H), 7.18 (d, J=7.3 Hz, 2H), 5.28 (d, J=4.9 Hz, 1H), 4.09 (br. s., 1H), 3.77 (br. s., 1H), 3.65 (d, J=6.6 Hz, 2H), 2.59 (d, J=12.7 Hz, 4H), 2.32 (d, J=11.2 Hz, 1H), 2.13 (dd, J=17.0, 5.7 Hz, 1H), 1.97-1.82 (m, 3H), 1.78-1.67 (m, 3H), 1.60-1.42 (m, 12H), 1.39 (br. s., 1H), 1.24 (br. s., 4H), 1.13 (br. s., 1H), 1.07 (br. s., 3H), 1.00 (br. s., 6H), 0.92 (br. s., 6H), 0.88 (d, J=6.4 Hz, 3H), 0.78 (d, J=6.4 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][C:14]([CH3:23])([CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][NH2:21])[CH2:15][NH2:16]>CO>[CH3:13][C:14]([CH3:23])([CH2:17][CH:18]([CH3:22])[CH2:19][CH:20]([C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[NH2:21])[CH:15]([C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[NH2:16]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CC(CCN)CC(C)(C)CN
Solvent: CO
Product: CC(CC(N)C(=O)CN1CCCC1=O)CC(C)(C)C(N)C(=O)CN1CCCC1=O

Procedure:
8.55 g (0.05 mol) of ethyl 2-oxo-1-pyrrolidineacetate and 3.95 g (0.025 mol) of 2,2,4-trimethyl-1,6-diaminohexane are boiled in 5 ml of absolute methanol for 22 hours, moisture being excluded. After evaporating off the solvent, the residue is chromatographed on silica gel from methanol/water (80:30). Chromatography is then carried out a second time from methanol/water/acetic acid (20:7.5:2.5), and finally the water and the acetic acid are removed by chromatography on aluminium oxide. The product is syrupy with nD54 1.5095.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=[O:3].C(O)(=O)CO.[SH:11][CH2:12][C:13](O)=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:14]=[C:13]1[O:3][CH:2]([C:1]([OH:5])=[O:4])[S:11][CH2:12]1
Reactant: O=CC(=O)[O-]
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CO
Solvent: Cc1ccccc1
Product: O=C1CSC(C(=O)O)O1

Procedure:
In all cases, the 1,3-oxathiolane ring is prepared in one of the following ways: (i) reaction of an aldehyde derived from a glyoxylate or glycolic acid with mercaptoacetic acid in toluene in the presence of p-toluenesulfonic acid to give 5-oxo-1,3-oxathiolane-2-carboxylic acid (Kraus, J-L., et al., Synthesis, 1991, 1046); (ii) cyclization of anhydrous glyoxylates with 2-mercaptoacetaldehyde diethylacetal at reflux in toluene to give 5-ethoxy-1,3-oxathiolane lactone (U.S. Pat. No. 5,047,407); (iii) condensation of glyoxylic acid ester with mercaptoacetaldehyde (dimeric form) to give 5-hydroxy-1,3-oxathiolane-2-carboxylic ester or (iv) coupling of an acyloxyacetaldehyde with 2,5-dihydroxy-1,4-dithiane, the dimeric form of 2-mercaptoacetaldehyde to form a 2-(ayloxy)methyl-5-hydroxy-1,3-oxathiolane. The lactone, 5-oxo compound, has to be reduced to the corresponding lactol during the process to synthesize nucleosides. The 2-carboxylic acid or its ester also has to be reduced to the corresponding 2-hydroxymethyl derivatives with borane-methylsulfide complex.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH2:21][O:22][C:23]3[CH:38]=[CH:37][C:26]4[O:27][CH2:28][C:29]5[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=5[C:31](=[O:32])[C:25]=4[CH:24]=3)=[N:18]2)=[CH:13][C:12]=1F>CN(C)C=O>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH2:21][O:22][C:23]3[CH:38]=[CH:37][C:26]4[O:27][CH2:28][C:29]5[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=5[C:31](=[O:32])[C:25]=4[CH:24]=3)=[N:18]2)=[CH:13][C:12]=1[S:3][CH2:1][CH3:2]
Reactant: CCS
Reactant: O=C1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1cc2ccc(COc3ccc4c(c3)C(=O)c3ccccc3CO4)nc2cc1Cl
Temperature: 90 °C
Reaction time: 4 h

Procedure:
0.37 ml of ethyl mercaptan and 1.12 g of potassium carbonate were added to 2.0 g of 2-(7-chloro-6-fluoroquinolin-2-yl)methoxy-11-oxo-6,11-dihydrodibenz[b,e]oxepine dissolved in 80 ml of dimethylformamide and the mixture was stirred at 90° C. for 4 hours.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][N:13]1[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]1=[O:23])[C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[N:7]2.CC(C)=O.Cl.N([O-])=O.[Na+].[I-:40].[K+]>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:8]1[C:9]([CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[N:10][C:11]2[C:6]([N:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[I:40]
Reactant: Nc1cccc2nc(-c3ccccc3Cl)c(CN3C(=O)c4ccccc4C3=O)nc12
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2c(I)cccc2nc1-c1ccccc1Cl
Temperature: 0 °C

Procedure:
2-((8-amino-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)isoindoline-1,3-dione (1.1337 g, 2.733 mmol) was dissolved in acetone (39.04 mL, 2.733 mmol) and cooled to 0° C. While being stirred, the solution was treated first with 2 M hydrochloric acid (7.652 mL, 15.30 mmol) and then dropwise with 1 M aq. sodium nitrite (5.466 mL, 5.466 mmol) while maintaining the temperature of the mixture at 0° C. After the additions were complete, the mixture was stirred for 15 min and then treated with 5 M aq. potassium iodide (5.411 mL, 27.06 mmol) maintaining the temperature below 5° C. The mixture was then allowed to warm to 15° C. over 3.5 h. The acetone was removed under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic solution was washed with 10% aqueous sodium bisulfite (100 mL×1) and saturated aqueous sodium bicarbonate (100 mL×1), brine (100 mL×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give a dark violet syrupy solid. The dark violet syrupy solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 15 min and then 50% isocratic of EtOAc in hexane for 25 min as eluent to give 2-((3-(2-chlorophenyl)-8-iodoquinoxalin-2-yl)methyl)-isoindoline-1,3-dione as a solid: LC-MS (ESI) m/z 526.0 [M+H]+.
Reaction SMILES: NN.[O:3]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO>[O:3]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCCC(COc2ccccc2)C1
Agent: NN
Solvent: CCO
Product: NCCCN1CCCC(COc2ccccc2)C1
Reaction time: 3 h
Yield: 61.7 %

Procedure:
2.9 ml (0.06 mol) of hydrazine are added to 11.3 g (0.03 mol) of 2-{3-[3-(phenoxymethyl)-1-piperidyl]propyl}-1H-isoindole-1,3(2H)-dione in 226 ml of EtOH. The mixture is heated to the refluxing temperature while stirring for 3 h. It is left to cool and filtered, the filter is rinsed with EtOH and the filtrate is concentrated. The residue is taken up with ether. The filtrate is concentrated and 4.6 g of yellow oil are obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=3)=[O:19])[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[N:33]1([CH2:32][CH2:31][CH2:30][NH:29][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][C:20]([C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:7]4[C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:13][CH2:14]3)=[O:19])=[N:21][CH:22]=2)[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: NCCCn1ccnc1
Reactant: CC(C)CNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CC(C)CNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCn3ccnc3)cn2)CC1
Yield: 66 %

Procedure:
By the same procedure as described in the example 81, synthesis was carried out starting with 6-[1-[3-(isobutylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 1-(3-aminopropyl)imidazole. And then, the product was recrystallized with isopropanol to give a desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH2:12](O)[CH3:13]>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(Cl)Cl>[CH:12]([C:2]1[CH:11]=[CH:10][C:9]2[C:7](=[O:8])[O:6][CH2:5][C:4]=2[CH:3]=1)=[CH2:13]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: CCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)COC2=O

Procedure:
5-Bromophthalide (50 g, 235 mmol), potassium vinyl trifluoroborate (62.9 g, 469 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (9.58 g, 11.7 mmol) were added to ethanol (500 mL) then TEA (65.4 mL, 469 mmol) was added. The reaction mixture was degassed then heated at reflux for 8 h. The reaction was worked up by diluting with ethyl acetate and washing with brine twice. The organic layer was dried and evaporated to dryness. The crude product was purified by MPLC (silica, 600 g column) with 25% EtOAc/hexane (3 L) then with 30% EtOAc/Hexane (2 L) to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[N:3]=1.I>>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[N:3]=[CH:2]2
Reactant: Cc1nc(Cl)c2cccc(O)c2n1
Agent: I
Product: Cc1ncc2cccc(O)c2n1

Procedure:
4-Chloro-8-hydroxy-2-methyl-quinazoline (0.01 mol) was treated with hydriodic acid (100 mL; freshly distilled from red phosphorus) according to the method described6 in the literature. This provided 8-hydroxy-2-methyl-quinazoline (A3) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]=1[C:46]([F:49])([F:48])[F:47]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]=2[C:46]([F:48])([F:47])[F:49])[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ncccc12
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((12.8 g, 62.8 mmol) in dry DMF (400 ml) under an inert atmosphere of Argon is added dropwise, BEMP (18.1 ml, 62.8 mmol) over two minutes. After stirring at 10° C. for 40 minutes, the resulting solution is treated dropwise with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (23.8 g, 75.4 mmol) and allowed to warm to room temperature while stirring overnight. The reaction is concentrated in vacuo with toluene azeotroping and the resulting oil is partitioned between water (400 ml) and DCM (500 ml) and extracted with DCM (500 ml). The organic portions are combined and washed with water (2×200 ml). The resulting suspension is filtered and concentrated in vacuo with toluene azeotroping. The crude is purified by chromatography on silica eluting with iso-hexane/acetone (16:4) to yield the titled product. (MH+ 441)
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)/[CH:10]=[CH2:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:29][CH2:30][CH3:31])(=[O:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Si:5]([O:8][C:9]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:21]([C:20]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH:10]=1)([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:7])[CH3:6]
Reactant: C=C/C(=C/c1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)/C=C/C(=O)OCC
Product: CCOC(=O)C1CC=C(O[Si](C)(C)C(C)(C)C)C(c2ccc(F)cc2)C1C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 37 g (˜80% pure, 133.1 mmol, 1 equiv.) of 1E and 1Z-tert-butyl{[1-(4-fluorobenzylidene)prop-2-en-1-yl]oxy}dimethylsilane (Example 1, step C) and 17 mL (18 g, 104.6 mmol) diethyl(2E)-but-2-enedioate in 200 mL xylenes under nitrogen atmosphere was heated at 160° C. for 5 hr then cooled to RT. The solvent was evaporated under vacuum to give an oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)=[C:6]([CH3:8])[CH:7]=1.[CH3:19][O-:20].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:20][CH3:19])=[C:6]([CH3:8])[CH:7]=1
Reactant: C[O-]
Reactant: Cc1cc(Br)cc(C)c1OCCCCCCCBr
Agent: [Na+]
Solvent: CO
Product: COCCCCCCCOc1c(C)cc(Br)cc1C

Procedure:
A solution of crude 5-bromo-2-(7-bromoheptyloxy)-1,3-dimethylbenzene (7.81 g) in methanol (78 ml) was treated with 28% sodium methoxide in methanol (78 ml), and the solution was refluxed for 8 hours. After cooling, the reaction mixture was evaporated under reduced pressure, and the residue was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and magnesium sulfate was filtered off, and then the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixed solvent of n-hexane-ethyl acetate (from 0% to 7% gradient elution) to give 5-bromo-2-(7-methoxyheptyloxy)-1,3-dimethylbenzene (3.34 g) as a colorless oil.