Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:25]I.NC(N)=O.S(=O)(=O)(O)O.[N+]([O-])(O)=O>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[I:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[C:13]([C:8]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:20][CH:21]=1
Reactant: c1ccc(-c2ccccc2-c2ccccc2-c2ccccc2)cc1
Reactant: II
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: ClC(Cl)(Cl)Cl
Product: Ic1ccc(-c2ccccc2-c2ccccc2-c2ccccc2)cc1
Temperature: 116 °C
Reaction time: 2.5 h
Yield: 35 %

Procedure:
To a first mixture containing 5.0 g of quaterphenyl, 8.28 g of iodine, 75 ml of glacial acetic acid, 10 ml of carbon tetrachloride and 2.51 g of urea, a second mixture containing 7.5 ml of concentrated sulfuric acid and 2.00 ml of nitric acid (d=1.4) was added over a period of 0.5 hours while the first mixture was stirred at 115-117° C. Heating continued for another 2.5 hours. The product then was cooled, filtered, washed with sodium bisulphite (NaHSO3), water and methylene chloride. The reaction yield was 35%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: Brc1ccccn1
Reactant: OCC1CCC2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OCC1CCC2CN(c3ccccn3)CCN2C1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 1.0 g (5.9 mmol) of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874); 4.6 9 (29 mmol) of 2-bromopyridine, 1.5 g (14 mmol) of sodium carbonate and 50 mL of isoamyl alcohol were refluxed for 18 h. The mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium carbonate. The organic layer was dried (magnesium sulfate), filtered and evaporated, and the crude product was purified by flash chromatography on silica gel eluting first with chloroform followed by 95:5 chloroform:methanol to give 0.61 g (42%) of the title compound. 13C NMR (base, CDCl3): δ 26.8, 29.0, 39.0, 45.1, 50.7, 54.8, 58.7, 60.8, 66.0, 107.1, 113.3, 137.5, 147.9, 159.3.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]=[CH2:5].Br[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21](=O)CC>>[CH2:20]([CH:7]([CH2:8][C:9]([OH:11])=[O:10])[N:2]([CH3:1])[CH2:3][CH:4]=[CH2:5])[CH3:21]
Reactant: C=CCNC
Reactant: CCC(C)=O
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCN(C)C(CC)CC(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
A mixture of N-methyl-2-propen-1-amine (2.7 ml), ethyl 3-bromo-propanoate (4.5 ml) and potassium carbonate (5.8 g) in 2-butanone (20 ml) was stirred at 50° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate evaporated. The residue was dissolved in water, extracted with CH2Cl2 and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 9.75/0.25). The pure fractions were collected and evaporated, yielding 3 g (63%) of ethyl N-methyl-N-2-propenyl-β-alanine (interm. 3).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[CH3:14][CH:15]([CH3:35])[CH2:16][NH:17][C@@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][C@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:19]1.C(=O)([O-])[OH:37].[Na+].O>C1COCC1>[NH:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[C:2]([N:17]([CH2:16][CH:15]([CH3:35])[CH3:14])[C@@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][C@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:19]1)=[O:37]
Reactant: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3[nH]2)CN(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
2-(Trichloromethyl)-1H-benzimidazole (19 g) and 1-tert-butyl 3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (25 g) were dissolved in THF (1200 ml), sodium hydrogen carbonate (67 g) and water (600 ml) were added, and the mixture was stirred at room temperature for 1 hr and at 50° C. for 1 hr. After evaporation of the solvent, the residue was extracted 3 times with ethyl acetate (700 ml). The extract was washed successively with 10%-aqueous citric acid solution (500 ml) and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (1000 ml), subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (30.6 g).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:10]([C:21]#[N:22])=[C:9]([SH:23])[N:8]=1.[CH3:24][O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>CN(C=O)C>[NH2:6][C:7]1[N:8]=[C:9]([S:23][CH2:33][C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:26]([O:25][CH3:24])=[O:35])[C:10]([C:21]#[N:22])=[C:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCO1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSc2nc(N)c(C#N)c(C3CCCCO3)c2C#N)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
48 mg (0.58 mmol) of sodium bicarbonate are added to a solution of 50 mg (0.19 mmol) of the compound from Example 31A and 48 mg (0.21 mmol) of 3-(bromomethyl)benzoic acid methyl ester in 2 ml of dry DMF, and the mixture is stirred at RT for 20 h. The mixture is then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][CH2:56][OH:57]>>[Cl:46][C:41]1[CH:42]=[C:43]([CH3:45])[CH:44]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH2:54][CH2:55][CH2:56][OH:57])=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:10][CH:9]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Reactant: OCCCc1ccccc1Br
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCCO)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and commercially available 3-(2-bromophenyl)propan-1-ol as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: CS(O)(=O)=[O:3].[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:14](O)[CH:15]=[CH2:16])[CH:11]=[CH:12][CH:13]=1.C1(C)C=CC=CC=1>O1CCCC1.O>[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH2:16][OH:3])[CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)O
Reactant: C=CC(O)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCC=Cc1cccc(C(F)(F)F)c1

Procedure:
Methanesulphonic acid (59.4 g) was added to a solution of 1-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (50 g) in tetrahydrofuran (200 mL) and de-ionized water (100 mL) at room temperature. Reaction mixture was refluxed at 65° C. to 70° C. for about 20-22 hours. After completion of the reaction, de-ionized water (50 mL) and toluene (200 mL) were added to organic layer. Organic layer was separated and neutralized to pH 7.5-8.0 using solution of sodium bicarbonate (7%), and concentrated under vacuum to give 3-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol as oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].P([O-])([O-])([O-])=O.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.P([O-])([O-])([O-])=O>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: CCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To ethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.5 ml of a solution containing 1 mg/ml in a phosphate or citrate-phosphate 0.1 M buffer) was added the enzyme (amount indicated below). The reaction mixture was shaken at room temperature and analysed at different times. The reaction mixture was analysed by the gradient HPLC method 1 and by chiral HPLC.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7]([OH:18])(=O)[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1>>[C:12]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][OH:5])(=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])=[O:18])=[CH:16][CH:15]=1
Reactant: OCCCCO
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: O=C(OCCCCO)c1ccc(C(=O)OCCCCO)cc1

Procedure:
In order to produce polyesters derived from 1,4-butanediol such as polybutyleneterephthalate, the reaction of one mole of terephthalic acid and/or a dialkyl ester with 1.1-2.2 moles of 1,4-butanediol is conducted at about 150°-230° C. for about 0.5-5 hours to produce bis(hydroxybutyl) terephthalate and oligomers thereof. Thereafter, the reaction is continued, heating at a temperature of about 230°-260° C. under a gradually reduced pressure of about 0.05-10 mmHg, until a polyester having a suitable degree of polymerization is produced. Depending upon the progress of the polycondensation, an excess of 1,4-butanediol is distilled out from the reaction system. It is quite important to recover and to reuse the distilled 1,4-butanediol mixture in the polycondensation system in order to lower the cost of the production of the polyester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C@H:7]([OH:21])[CH2:8][NH:9][C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=2)[CH2:12][CH2:11]1.[CH2:34](Cl)[CH2:35]Cl.[CH:38]1[CH:39]=C[C:41]2[N:46](O)N=[N:44][C:42]=2[CH:43]=1>CN(C=O)C>[N:46]12[CH2:35][CH2:34][CH:43]([CH2:38][CH2:39]1)[C@@H:42]([NH:44][C:26](=[O:28])[CH2:25][CH2:24][C:23]([NH:22][C@@H:6]([CH2:5][C:4]1[CH:30]=[C:31]([F:33])[CH:32]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:21])[CH2:8][NH:9][C:10]1([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=3)[CH2:12][CH2:11]1)=[O:29])[CH2:41]2.[CH:26]([OH:28])=[O:27]
Reactant: ClCCCl
Reactant: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCC(=O)O)CC2)c1
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCC(=O)N[C@H]3CN4CCC3CC4)CC2)c1
Product: O=CO
Temperature: 45 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of S-aminoquinuclidine (0.086 g, 0.434 mmol) TEA (0.302 ml, 2.17 mmol), and anhydrous DMF (2.5 ml) was added 4-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)amino]-4-oxobutanoic acid (0.200 g, 0.434 mmol), EDC (0.125 g, 0.651 mmol), and HOBT (0.088 g, 0.651 mmol) under nitrogen, with stirring at 45° C. overnight. Reaction mixture was quenched with 10% sodium bicarbonate (aq.) then extracted with ethyl acetate then concentrated in vacuo, yielding product (0.093 g). Prep-HPLC yielded the product as its formate salt. (ES+: 569.3)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][NH:7][C:6]2=[N:10][CH:11]=[CH:12][C:5]=12.[H][H].[C:15]([O:18][CH2:19][CH2:20][O:21][CH2:22]Br)(=[O:17])[CH3:16]>CN(C=O)C.O>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH2:22][O:21][CH2:20][CH2:19][O:18][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CC(=O)OCCOCBr
Reactant: [H][H]
Reactant: Clc1nc[nH]c2nccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Yield: 40.2 %

Procedure:
Sodium hydride (0.09 g, 60% in mineral oil) was added to a solution of 4-chloropyrrolo[2,3-d]pyrimidine (1) in dry DMF (6 mL) in small portions at 0-5 degrees C under a nitrogen atomosphere. When all hydrogen evolution has ceased, 2-acetoxyethoxymethyl bromide (2) (0.45 g) was added, dropwise with stirring, at room temperature. The reaction mixture was then stirred at room temperature for an additional 3 hours. After that period of time, water (50 mL) was added and the product was extracted with ethylacetate. The ethylacetate layer was separated, washed with cold water, dried over anhydrous, Na2SO4 and the solvent then evaporated under reduced pressure and temperature to afford a thick syrup. This syrup was applied to the top of a silica gel column (20×2 cm) and the column was eluted with 1% MeOH in CHCl3. All the fractions containing UV absorbing material were combined and the solvent from these fractions was evaporated to yield a colorless syrup was crystallized from methanol as colorless needles to yield 0.21 g of 3 (40.2%), mp 67-88 degrees C. 1H-NMR (DMSO-d6) δ: 8.5 (s, 1, C2-H), 7.88 (d, 1, J=3.5 Hz, C6-H), 6.72 (d, 1, J=3.6 Hz, C5-H), 5.7 (s, 2, N7-CH2), 4.03 (m, 2, OCH2), 3.52 (m, 2, CH2), 1.92 (s, 3, OAc): UVλmax nm (ε×104); (pH 7) 223 (1.2), 276 (2.4); (pH 1) 225 (1.2), 274 (0.25); (pH 11) 227 (0.8), 276 (0.2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].[C:30](=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl.C(#N)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]3[C:10]([CH2:11][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:30]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: O=C([O-])[O-]
Reactant: Brc1cnc2[nH]cc(-c3ccccc3)c2c1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(-c2cnc3[nH]cc(Cc4ccccc4)c3c2)cc1OC
Yield: 34 %

Procedure:
A vial was charged with 50 mg (0.18 mmol) of 5-bromo-3-phenylpyrrolo[2,3-b]pyridine, 43 mg (0.24 mmol) of 3,4-dimethoxyphenylboronic acid and 6.5 mg (9.31 mol, 5 mol %) of dichlorobis(triphenylphosphino)palladium(II). To this mixture was added 1 ml of acetonitrile and 1 ml of a 2 M aqueous solution of sodium carbonate. The vial was sealed and irradiated in a Personal Chemistry® microwave reactor with a temperature setting of 165° C. for 20 minutes. The resulting mixture was distributed between 75 ml of dichloromethane and 20 ml of a saturated aqueous solution of sodium bicarbonate in water. The organic phase was dried over sodium sulfate and evaporated. The residue obtained was recrystallized from a hot mixture of acetonitrile and ethanol to afford 20 mg (61 μmol, 34% yield) of 5-(3,4-dimethoxyphenyl)-3-phenylmethylpyrrolo[2,3-b]pyridine as a colorless crystalline solid. 1H-NMR (d6-DMSO) δ: 11.97 [1H] s, 8.55 [1H] d, 8.38 [1H] d, 7.90 [1H] d, 7.79 [2H] d, 7.45 [2H] t, 7.30 [1H] d, 7.26 [2H] t(m), 7.06 [1H] d, 3.87 [3H] s, 3.81 [3H] s. MS, m/z: 331 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:7][CH2:8]O.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:7][CH2:8][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: OCCOCc1cccc(Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCOCc1cccc(Br)c1

Procedure:
Mitsunobu reaction of 2-(3-bromobenzyloxy)ethanol and phthalimide following the method used in Example 134 gives 2-(2-(3-bromobenzyloxy)ethyl)isoindoline-1,3-dione.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:33][CH2:34][CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20]4[CH:21]=[C:22]([CH2:26][C:27]([O:29]C)=[O:28])[CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]1([C:7]2[O:8][C:9]([CH2:33][CH2:34][CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20]4[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2cccc(CC(=O)OC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2cccc(CC(=O)O)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a mixture of methyl 2-[3-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.44 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.35 g, 81%) of 2-[3-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C@@:12]12[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C@H:24]1[C@@H:15]([C:16]3[CH:17]=[CH:18][C:19]([OH:30])=[CH:20][C:21]=3[CH2:22][CH2:23]1)[CH2:14][CH2:13]2>N1C=CC=CC=1>[C:2]([O:30][C:19]1[CH:18]=[CH:17][C:16]2[C@@H:15]3[C@H:24]([C@H:25]4[C@@:12]([CH2:13][CH2:14]3)([CH3:11])[C:28](=[O:29])[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5cccnc5)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C

Procedure:
To nicotinoyl chloride hydrochloride (2.65 g, 0.015 mol) in pyridine (20 ml) at 0° C. was added estrone (2 g, 0.0074 mol). The mixture was refluxed for one hour and then poured over 100 ml of ice cold water, filtered, and dried over P2O5 under vacuum. Yield 72% (2.0076 g), m.p. 207°-210° C. NMR (CDCl3) δ 9.3-9.1 (br s, 1H, C2 pyridinium proton), 8.8-8.6 (br d, 1H, C6 pyridinium proton, 8.4-8.2 (br d, 1H, C4 pyridinium proton), 7.5-7.1 (m, 2-H,C5 pyridinium proton+C1. estrone proton), 7.0-6.7 (m, 2H, C2,4 estrone protons), 3.2-1.3 (estrone skeletal protons, 15), 1.0-0.9 (s, 3H, C18 estrone protons). IR (KBr) 1750-1730 cm-1 (broad C=O stretching). Anal. calculated for C24H25NO3 ; C, 76.76; H, 6.72; N, 3.73. Found: C, 76.37; H, 6.96; N, 3.67. The product is further characterized by the structural formula: ##STR1479##
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=3[O:28][CH3:29])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: COc1ccc(OC)c(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)c1
Yield: 77.4 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2,5-dimethoxyphenylboronic acid (174 mg, 0.96 mmol) were reacted. After purification the title compound (142 mg, 77% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (d, J=4.8 Hz, 1H), 8.51 (a dd, J=5.5, 9.3 Hz, 1H), 7.72 (t, J=9.0 Hz, 1H), 7.06 (a d, J=9.0 Hz, 1H), 7.00 (m, 1H), 6.86 (a d, J=3.0 Hz, 1 H), 3.72 (s, 3H), 3.58 (s, 3H), 2.93 (m, 1H), 0.68 (m, 4H). MS APCI, m/z=383.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].C[CH2:15][N:16](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH:16][CH3:15])=[O:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a roundbottom flask charged with 3-fluoro-5-nitrobenzoic acid (1.00 g, 5.40 mmol) was added DMF (6.75 mL), followed by Hunig's base (1.13 mL, 6.48 mmol), and HATU (2.157 g, 5.67 mmol). The flask was sealed with a septum and methanamine (2.0 M in THF) (13.5 mL, 27.0 mmol) was added via syringe. The resulting orange reaction mixture was stirred overnight at RT. After 16 h, the reaction mixture was diluted with CH2Cl2 (70 mL) and the resulting mixture was transferred to a separatory funnel and extracted with sat. aq. NaHCO3 (3×30 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. Purification with medium pressure silica gel chromatography using 70:30 Hex:EtOAc as the eluent afforded 3-fluoro-N-methyl-5-nitrobenzamide (961 mg, 4.85 mmol, 90%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[C:24]([Br:25])=[CH:23][N:22]([CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:25][C:24]1[C:20]([C:16]2[CH:15]=[C:14]([NH:13][C:10]([O:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])[CH:19]=[CH:18][CH:17]=2)=[N:21][N:22]([CH3:26])[CH:23]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)Nc2cccc(-c3nn(C)cc3Br)c2)cc1
Reaction time: 16 h
Yield: 52.2 %

Procedure:
To 4-methoxyphenylchloroformate (19 mg, 0.10 mmol) in CH2Cl2 (0.5 mL) was added dropwise a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (25 mg, 0.10 mmol) and triethylamine (14 μL, 0.10 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred for 16 h and concentrated. Chromatography on flash silica (40% EtOAc/hexane) gave the title compound as a colourless solid (21 mg, 52%), m.p. 140.3-141.8° C. (EtOAc/hexane).