Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[C:10]=1[CH2:36][CH2:37][CH3:38])([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[C:10]([CH2:36][CH2:37][CH3:38])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:39])=[O:3])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCCc1c(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cccc1OC(C)(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cccc1OC(C)(C)C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-{3-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-propyl-phenoxy}-2-methyl-propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the desired product. Rf=0.22 in 70% ethyl acetate/hexanes; 1H NMR (400 MHz, d6-DMSO) δ7.92 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.67 (d, J=7.6 Hz, 3H), 7.43 (t, J=7.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 2H), 6.95 (t, J=8.4 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.24 (d, J=8.4Hz, 1H), 4.13 (t, J=6.4Hz, 2H), 2.87 (t, J=6.4Hz, 2H), 2.41 (t, J=7.6Hz, 2H), 2.32 (s, 3H), 1.40 (s, 6H), 1.23 (sextet, J=7.2 Hz, 2H), 0.71 (t, J=7.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:26])[N:6]2[C:11]1[CH:12]=[C:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.[O:27]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:37]1[CH:38]=[CH:39][C:34]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=1)[C:5](=[O:26])[N:6]2[C:11]1[CH:12]=[C:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 37 °C

Procedure:
To a mixture of tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (600 mg, 1.68 mmol) and 4 A MS (800 mg) in dry DMF (10 mL) were added 4-phenoxyphenylboronic acid (1.08 g, 5.06 mmol), Cu(OAc)2 (307 mg, 1.68 mmol) and pyridine (1 mL). The reaction mixture was heated to 37° C. overnight under O2 atmosphere, and filtered through a Celite pad. The filtrate was diluted with water (30 mL), extracted with EtOAc (10 mL×3). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in methylene chloride) to give tert-butyl 3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl(methyl)carbamate as a light yellow solid (31) (450 mg, 51%). LC-MS (ESI): m/z (M+1) 525.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>>[C:8]1(=[O:9])[N:4]([CH2:3][CH2:2][O:1][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Product: O=Cc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
The title compound, mp 138° C., was prepared from N-(2-hydroxyethyl)phthalimide (9.6 g) and 4-fluorobenzaldehyde (6.2 g, 5.3 ml) by a procedure similar to that described in Procedure 2.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:29]([CH:31]=[CH2:32])=[O:30]>O1CCCC1>[OH:30][CH:29]1[NH:2][C:1](=[O:3])[C:4]2([C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:32][CH2:31]1
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Reactant: C=CC=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1NC(O)CCC12c1ccccc1-c1ccccc12
Temperature: 50 °C
Yield: 112.7 %

Procedure:
Following the general procedure of Example 1, 20.9 g (0.1 mole) of 9-carbamoylfluorene were added to 300 ml of tetrahydrofuran. The solution was heated to 50° C. and stirred while 6 ml of benzyltrimethylammonium hydroxide were added in one portion. After stirring the reaction mixture at 50° C. for thirty minutes, 6.2 g (0.11 mole) of acrolein were added and the mixture was then heated at reflux for four hours. The reaction mixture was cooled to 25° C. and the solvent was removed by evaporation under reduced pressure to provide 29.9 g of 6'-hydroxyspiro(9H-fluorene-9,3'-piperidine)-2'-one and its tautomeric isomer 9-carbamoyl-9-(3-oxo-propyl)fluorene, m.p. 199°-201° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C(=O)C)=[CH:17][CH:16]=2)C(O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.Cl>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)Oc1ccc(C=C(C(=O)O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Temperature: 95 °C

Procedure:
A portion (36.75 grams) of α-p-nitrophenyl-p-acetoxycinnamic acid from A. above, ethanol (300 mL) and concentrated hydrochloric acid (300 mL) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere. Heating commenced and a reflux is achieved at 93° C. Refluxing continued over the next 262 minutes at which time the temperature has increased to 95° C. At this time, the contents of the reactor are poured into deionized water (one liter) and the resultant precipitate recovered by filtration. The wet filter cake is washed with two portions (500 mL) of deionized water then dissolved in stirred ethanol (750 mL) maintained at 82° C. The resultant solution is maintained at 4° C. for 15 hours. The precipitate is recovered by filtration and dried at 75° C. under a vacuum of 2 mm Hg to a constant weight of 22.70 grams of light orange colored crystalline needles. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of a portion of the product revealed the presence of the expected hydroxyl group O--H stretching centered at 3422 cm-1 (broad), conjugated nitro group absorbances at 1516 and 1337 (1317 shoulder) cm-1 (sharp) and the ethylene C--H out-of-plane deformation at 972 cm-1.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C@:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C@:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][C@@H:20]2[C@H:19]1[O:9]2)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@]1(C)C=CCCC1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H]2O[C@H]21
Reaction time: 20 h

Procedure:
3-chlorobenzenecarboperoxoic acid (2.47 g, 11.00 mmol) was added in one portion to a stirred solution of (R)-tert-butyldimethyl(1-methylcyclohex-2-enyloxy)silane, 50b, (1.98 g, 8.87 mmol) and sodium hydrogen carbonate in 30 mL of dry dichloromethane at room temperature under nitrogen. The resulting mixture was stirred for 20 hours. Then, 25% sodium sulfite solution (30 mL) was added and the resulting biphasic mixture was stirred for 15 minutes. The 2 layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were washed with aqueous saturated NaHCO3, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% EtOAc-hexanes gradient) to provide 647 mg of compound 50c.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CN1C2C(=CC=C(N)C=2)C=C1)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (6-amino-indol-1-yl)-acetic acid ethyl ester (prepared in two steps from 6-nitroindole) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.33 (1H, s), 7.92 (1H, s), 7.45 (3H, m), 7.28 (1H, m), 7.02 (2H, m), 6.58 (1H, dd), 6.47 (1H, t), 4.84 (2H, s), 4.68 (2H, m), 4.40 (1H, d), 4.18 (1H, d), 2.78 (1H, m), 2.02-1.15 (19H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 58.25; H, 7.41; N, 10.61%; C32H37N5O5.C7H17NO5.2.0H2O requires: C, 58.38; H, 7.28; N, 10.47%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14]O)[C:8](=[O:16])[C:7](=[O:17])[NH:6]2.S(Cl)([Cl:22])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][Cl:22])[C:8](=[O:16])[C:7](=[O:17])[NH:6]2
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n(CCO)c1=O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n(CCCl)c1=O

Procedure:
1.3 g (4.7 mmol) of 2-[(6 trifluoromethylquinoxaline-2,3-dion-1-yl)ethyl alcohol is stirred in 20 ml of thionyl chloride for 4 hours at room temperature. After concentration by evaporation and subsequent distillation with toluene, 1.34 g (97% of theory) of 2-[(6 trifluoromethylquinoxaline-2,3-dion-1-yl)ethyl chloride is obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:23]([CH3:24])[CH:22]3[CH2:25][CH:18]([CH2:19][CH2:20][N:21]3[CH3:26])[C:17]=2[CH:27]=1)(=[O:11])[CH3:10].C(=O)(O)[O-].[Na+]>CO.ClCCl>[C:9]([O:12][C:13]1[CH:14]=[C:15]([Br:1])[C:16]2[N:23]([CH3:24])[CH:22]3[CH2:25][CH:18]([CH2:19][CH2:20][N:21]3[CH3:26])[C:17]=2[CH:27]=1)(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc2c(c1)C1CCN(C)C(C1)N2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Oc1cc(Br)c2c(c1)C1CCN(C)C(C1)N2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.5 %

Procedure:
N-Bromosuccinimide (2.40 g) was added in three portions to a solution of 3.50 g of crude 1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol acetate in 135 ml of deoxygenated methanol. The resulting solution was stirred at room temperature for five minutes and then diluted with dichloromethane and a saturated sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane, and the combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. Column chromatography of the oil (silica gel elution with triethylamine-methanol-ethyl acetate) afforded 1.80 g (33%) of 10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocine-8-ol acetate as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11][CH3:12]>C(O)(=O)C.O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: CSc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(N)cc1F
Reaction time: 2 h
Yield: 97 %

Procedure:
Iron (33 g, 0.59 mol) was added to 2-fluoro-1-methylsulfanyl-4-nitro-benzene (18.5 g, 99 mmol) in a mixture of acetic acid (350 mL) and water (70 mL). The mixture was stirred for 2 h with periodic swirling, and then the solvents were evaporated. Ethyl acetate and aqueous sodium bicarbonate solution were added and the mixture was filtered through Celite. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 20% ethyl acetate/hexanes to give 3-fluoro-4-methylsulfanyl-phenylamine (15.1 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[C:7]=2[CH:24]=1.[CH3:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31]CBr>>[CH3:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[C:7]=2[CH:24]=1
Reactant: COc1ccc2nc(-c3ccccc3)n(-c3ccccc3C)c2c1
Reactant: COC(=O)CCCCCBr
Product: COC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3C)c2c1

Procedure:
6-Methoxy-1-(2-methylphenyl)-2-phenyl-1H-benzimidazole was reacted according to general operating instructions 6. The crude product was reacted with 6-bromohexanoic acid methyl ester according to general operating instructions 8.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:25])[O:17][CH2:18]C3CCCCO3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:25]=[C:16]([N:7]1[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[O:17][CH:18]1[CH2:29][CH2:28][CH2:27][CH2:26][O:33]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N=C(OCC1CCCCO1)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(N=C(OC1CCCCO1)N1Cc2ccccc2-c2ccccc2C1)c1ccccc1

Procedure:
starting from 2-tetrahydro-2H-pyranylmethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and benzoyl chloride, there is obtained tetrahydro-2H-pyran-2-yl N-(benzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6 carboximidate, m.p, 114.5°-117° C.;
Reaction SMILES: [NH2:1][C:2]([C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1)([C:4]#[N:5])[CH3:3]>C(O)C.[Ni].[H][H]>[NH2:1][C:2]([C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)([CH3:3])[CH2:4][NH2:5]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1(C(C)(N)C#N)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(C(C)(N)CN)CC1

Procedure:
To a solution (50 mL) of tert-butyl 1-(1-amino-1-cyanoethyl)-1-cyclopropanecarboxylate (1.12 g, 5.30 mmol) in ethanol was added a suspension (30 mL) of Raney nickel catalyst (R-100 manufactured by Nikko Rica Corporation, 10 mL) in ethanol, and the suspension was vigorously stirred at room temperature for 6 hours in hydrogen gas atmosphere. The catalyst was removed by filtration through celite, and the solvent was removed by distillation under reduced pressure to obtain 0.84 g (3.92 mmol, 74%) of the crude target compound as a colorless transparent oil. The thus obtained crude product was used in the subsequent reaction with no further purification.
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:11][C@@H:2]([CH3:1])[C@@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[OH:10])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)N[C@@H](C)[C@H](O)c2ccccc2)cc1
Yield: 37.8 %

Procedure:
Following a procedure similar to that described in Example 6, but using 3 g of (1R,2S)-(-)-norephedrine, 4.36 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 3.41 g of sodium cyanoborohydride, 2.65 g of the title compound were obtained as crystals, melting at 124° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25].ClCCl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C(/c1ccccc1)c1ccc(C#CCN(C)C)cc1

Procedure:
A solution of (Z)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester (1.200 g, 3.6 mmol), dimethyl-prop-2-ynyl-amine (0.9 ml, 10.88 mmol), bis(triphenylphosphine) palladium(II) chloride (0.102 g, 0.144 mmol), copper(I) iodide (2.06 mg, 0.0108 mmol) in dry triethylamine (10 ml) were heated to 100° C. by microwave irradiation for 20 min. The cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (10 g) and evaporated in vacuo. The resulting residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (Z)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acid ethyl ester as an oil.
Reaction SMILES: [C:1]1([N:10]=[C:11]=[O:12])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[CH2:13]([CH:15]([NH:18][OH:19])[CH2:16][CH3:17])[CH3:14]>ClCCl>[C:1]1([NH:10][C:11]([N:18]([OH:19])[CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:12])[CH:2]=[CH:3][C:4]([NH:7][C:8]([N:18]([CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[OH:19])=[O:9])=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccc(N=C=O)cc1
Reactant: CCC(CC)NO
Solvent: ClCCl
Product: CCC(CC)N(O)C(=O)Nc1ccc(NC(=O)N(O)C(CC)CC)cc1
Yield: 62.8 %

Procedure:
The same general procedure as reported in Example 13 was followed. 1,4-Phenylene diisocyanate (3.2 g, 20 mmol), N-(1-ethylpropyl)hydroxylamine (4.3 g, 42 mmol), and dichloromethane (200 ml) were combined. The product formed as a precipitate. Purification by recrystallization from N,N-dimethylformamide.backslash.water yielded 4.6 g of the desired product as a white powder: MP: 202.0° C. (decomp); 1H NMR (300 MHz, DMSO): δ 9.13 (s, 2H), 8.72 (s, 2H), 7.44 (s, 4H), 3.96-3.87 (septet, J=4.7 Hz, 2H), 1.60-1.33 (m, 8H), 0.84 (t, J=7.3 Hz, 12 H); 13C NMR (75 MHz, DMSO): δ 157.9, 134.0, 119.3, 59.6, 24.6, 11.1; IR (KBr): 3401, 3134, 2964, 2923, 2873, 1634, 1541, 1462, 1412, 1269, 1218, 1159, 1103, 1060, 833, 755, 736 cm-1 ; MS (FAB): m/e 367.2331 (367.2345 calc'd for C18H31N4O4, M+H); Anal. calc'd for C18H30N4O4 : C, 59.00; H, 8.25; N, 15.29. Found: C, 58.72; H, 8.34; N, 15.28.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Yield: 33.4 %

Procedure:
A mixture of 10 g (0.06 mol) of 3,5-dihydroxybenzoic acid methyl ester, 16.2 ml (0.06 mol) of 1-bromotetradecane and 8.2 g (0.06 mol) of potassium carbonate in 200 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 24 hours, After the usual workup, the crude product was triturated with hot methylene chloride and filtered. The filtrate was concentrated at reduced pressure and the solid residue was recrystallized from methylene chloride-methanol to give the 3,5-dialkylated product. The filtrate was concentrated and the residue was purified by HPLC using 15% ethyl acetatehexane to give 7.3 g (34% yield, mp 92°-94°) of 3-hydroxy-5-(tetradecyloxy)benzoic acid methyl ester. The nmr spectra was consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[N:10]#[C:11]Br>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:11]([NH2:10])=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: NNc1cc(Br)ccn1
Reactant: N#CBr
Solvent: CC(C)O
Product: Nc1nnc2cc(Br)ccn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-bromopyridin-2-yl)hydrazine (0.710 g, 3.78 mmol) in 10 mL of 2-propanol was added cyanogen bromide (0.400 g, 3.78 mmol) at 25° C. The reaction was heated at 70° C. for 2 h and the reaction was monitored by LCMS. Additional cyanogen bromide (0.060 g) was added and the reaction was continued for another 2 h. The reaction was filtered while hot and the solid was washed with 2-propanol and pentane, and dried in vacuo to give the title compounds as a light orange amorphous solid. MS m/z: 214.9 [M+1].
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(CN2CCCC2)cc1
Yield: 96.6 %

Procedure:
Add pyrrolidine (0.89 mL, 10.74 mmol) to a stirred solution of 4-bromomethyl-benzonitrile (1 g, 5.1 mmol) and triethylamine (1.5 mL, 10.74 mmol) in anhydrous THF (26 mL). Stir reaction overnight at room temperature. Partition the reaction mixture between EtOAc and water. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over MgSO4, filter, and concentrate in vacuo to obtain the desired intermediate (918 mg, 97%) suitable for use without further purification. MS (APCI+) m/z: 187 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.C[SH+]C1C=CC(O[C:21](=[O:35])[C@H:22]([CH3:34])[NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=CC=1.[NH2:36][C@H:37]([C:41]([OH:43])=[O:42])[CH:38]([CH3:40])[CH3:39].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:36][C@H:37]([C:41]([OH:43])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[CH3:34])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: C[SH+]c1ccc(OC(=O)[C@H](C)NC(=O)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
In 50 ml of chloroform was dissolved 4.14 g of benzyloxycarbonylalanine p-methylsulfoniophenyl ester p-toluenesulfonate, and 20 ml of an aqueous solution of 0.91 g of valine and 1.1 ml of triethylamine was dropwise added thereto under stirring at room temperature. The reaction mixture was stirred for 8 hours at room temperature and then separated. The chloroform layer was washed with water, dried, and concentrated under reduced pressure, and ether was added to the residue to afford white crystals.