Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([C:14](=O)[CH3:15])=[CH:9][CH:10]=2)[CH:5]=1)(=O)[CH3:2].[NH2:17][C:18]1[C:19]([CH:28]=O)=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2.[OH-].[K+]>C(O)C>[N:17]1[C:18]2[C:19](=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:28]=[CH:2][C:1]=1[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([C:14]3[CH:15]=[CH:28][C:19]4[C:18](=[C:27]5[C:22](=[CH:21][CH:20]=4)[CH:23]=[CH:24][CH:25]=[N:26]5)[N:17]=3)=[CH:9][CH:10]=2)[CH:5]=1
Reactant: CC(=O)c1ccc2ccc(C(C)=O)cc2c1
Reactant: Nc1c(C=O)ccc2cccnc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1cnc2c(c1)ccc1ccc(-c3ccc4ccc(-c5ccc6ccc7cccnc7c6n5)cc4c3)nc12
Yield: 42.1 %

Procedure:
54.0 g of 2,7-dihydroxynaphthalene was dissolved in a mixture of 680 ml of dichloromethane and 136 ml of pyridine, and to this, 228 g of trifluoromethanesulfonic anhydride (produced by TOKYO CHEMICAL INDUSTRY CO., LTD.) was added dropwise at 0° C. After the resulting mixture was reacted at 5° C. for 2 hours and then at room temperature for one day, a reactant was treated by a normal method to obtain 143 g of 2,7-bis(trifluoromethane sulfonyloxy)naphthalene. 143 g of this 2,7-bis(trifluoromethane sulfonyloxy)naphthalene was mixed with 216 ml of n-butyl vinyl ether, 113 ml of triethylamine, 2.78 g of 1,3-bis(diphenylphosphino)propane, 0.76 g of palladium acetate and 680 ml of dimethylformamide and the resulting mixture was reacted at 70 to 85° C. for two days. The reactant was treated by a normal method to obtain 40 g of 2,7-diacetylnaphthalene. 4.62 g of this 2,7-diacetylnaphthalene was reacted with 7.87 g of 8-amino-7-quinoline carboaldehyde and 7.9 g of potassium hydroxide in 220 ml of ethanol at 60° C. and a reactant was treated by a normal method to obtain 4.44 g of 2,7-di(1,10-phenanthroline-2-yl)naphthalene. 5.48 g of this 2,7-di(1,10-phenanthroline-2-yl)naphthalene was reacted with 22.6 ml of phenyl lithium (2.0 M cyclohexane-ether solution) in 200 ml of toluene at room temperature for 2 days and a reactant was treated by a normal method. The obtained product was reacted with 100 g of manganese dioxide in 400 ml of dichloromethane at room temperature for 2.5 hours and a reactant was treated by a normal method to obtain 0.93 g of E-57.
Reaction SMILES: [NH2:1][CH2:2]/[CH:3]=[CH:4]/[CH:5]=[CH2:6].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1>>[OH:10][CH2:11][CH:7]1[CH2:6][CH:5]=[CH:4][CH:3]2[CH:8]1[CH2:9][NH:1][CH2:2]2
Reactant: C=C/C=C/CN
Reactant: C1CCOC1
Product: OCC1CC=CC2CNCC21

Procedure:
Initially introduce 83.2 g (1.0 mol) of (E)-1-amino-2,4-pentadiene (title compound from Example B.2.) in 250 ml of THF, and add 0.1 g of 4-hydroxyanisole. Subsequently, at an internal temperature of 20°-30° C., add 229.2 g (1.05 mol) of di-tert-butyl dicarbonate dissolved in 250 ml of THF dropwise. After addition is complete, stir at room temperature for 20 h. Add 103.0 g (1.05 mol) of maleic anhydride, and heat to reflux for 5 h. Concentrate and take up the residue in 500 ml of methanol, add 30 ml of p-toluenesulphonic acid, and then heat once again to reflux for 5 h. After cooling with ice, and stirring, rapidly add a solution of 20 g of sodium carbonate dissolved in 500 ml of water dropwise, allow the mixture to stand for a further 30 min in an ice bath, and filter off the precipitate with suction, wash it with a little water, and dry it at 50° C. to constant weight.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[C:19]2[NH:18][C:17](=[O:20])[CH2:16][CH2:15][C:14]=2[C:13]([CH:21]=[O:22])=[CH:12][CH:11]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)=[O:26]>C(OCC)(=O)C.O>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:18]2[C:19]3[C:10]([O:9][CH3:8])=[CH:11][CH:12]=[C:13]([CH:21]=[O:22])[C:14]=3[CH2:15][CH2:16][C:17]2=[O:20])=[CH:29][CH:28]=1)([O:24][CH3:23])=[O:26]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(C=O)c2c1NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN2C(=O)CCc3c(C=O)ccc(OC)c32)cc1
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
Sodium hydride (60% in oil) (2.87 g) was added at 0° C. to a DMF solution (100 ml) of 8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde (13.4 g), followed by stirring for 30 minutes. Methyl 4-bromomethyl benzoate (18.0 g) was added, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4→1:2). The purified product was recrystallized from a chloroform-diisopropyl ether mixed solvent to thereby obtain 14.43 g (yield: 62%) of 1-(4-carbomethoxybenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[CH3:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[NH:1]([C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[CH3:15])[C:16]([CH3:17])=[O:18]
Reactant: Cc1nc2ccccc2c2c(N)cnn12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cnn2c(C)nc3ccccc3c12
Yield: 89 %

Procedure:
1-Amino-5-methylpyrazolo[1,5-c]quinazoline is treated with acetic anhydride as described in Example 5 to give 1-acetamino-5-methylpyrazolo[1,5-c]quinazoline. M.p.: 258°-260° C. Yield: 89%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.Cl.[NH2:20][CH2:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:14]([NH:20][CH2:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:16])[CH:10]([CH3:11])[CH2:12][CH3:13])([CH3:2])[CH3:3]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCc1nc2ccccc2[nH]1
Yield: 88.4 %

Procedure:
The title compound is prepared by the procedure of Example 1 using 0.505 g of N-(tert-butoxycarbonyl)-L-isoleucine in 10 ml of methylene chloride, 0.500 g of 2-(aminomethyl)benzimidazole dihydrochloride hydrate, 1.07 g of BOP, and 0,850 g of triethylamine. Purification by chromatography (75 g Silica gel; 70% ethyl acetate/hexane) gives 0.669 g of the desired product.
Reaction SMILES: [Br:1][CH2:2][CH:3](OC)OC.[CH2:8]([OH:13])[CH2:9][CH:10]([OH:12])[CH3:11].C1(C)C(S(O)(=O)=O)=CC=CC=1>>[Br:1][CH2:2][CH:3]1[O:12][CH:10]([CH3:11])[CH2:9][CH2:8][O:13]1
Reactant: COC(CBr)OC
Reactant: CC(O)CCO
Agent: Cc1ccccc1S(=O)(=O)O
Product: CC1CCOC(CBr)O1
Temperature: 25 °C

Procedure:
2-Bromo-1,1-dimethoxyethane (0.1 mole) and 1,3-butanediol (0.1 mole) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, Dean Stark trap and reflux condenser. Toluene sulfonic acid (0.1 grams) is added and the reaction mixture is heated and alcohol removed. When alcohol evolution ceases, the reaction mixture is then cooled to room temperature, treated with sodium carbonate (5 grams) and filtered. Volatiles are stripped from the filtrate using a rotary evaporator to yield the desired product 2-bromomethyl-4-methyl-1,3-dioxane as the residue.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].Br[CH2:9][CH:10]=[O:11].[OH-].[Na+]>CO>[CH2:1]([NH:7][CH2:9][CH:10]=[O:11])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6]
Reactant: O=CCBr
Reactant: CC=CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC=CCCCNCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Hex-4-enylamine (2.0 mole), the diethyl acetal of 2-bromoacetaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 2-hex-4-enylaminoacetaldehyde.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([OH:12])[CH:11]=1)=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)=[O:5]
Reactant: CC(=O)c1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a mixture of sodium hydride (4.5 g of 80% mineral oil dispersion, 0.15 mol), which had been washed free of mineral oil, in DMF (25 ml) was added, dropwise with cooling, a solution of 3-hydroxyacetophenone (20.5 g, 0.15 mol) in DMF (25 ml). Upon completion of the addition, the mixture was allowed to stir at room temperature for 15 min, at which time was added benzyl bromide (25.6 g, 0.15 mol). The resulting mixture was allowed to stir at room temperature overnight, then was partitioned between EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 1M NaOH, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to afford the title compound (33 g, 97%), which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[CH:14]1[CH2:19][C:18](=[O:20])[C:17]([C:21](=[O:24])[CH2:22][CH3:23])=[C:16]([OH:25])[CH2:15]1.N1C=CC=CC=1.O>ClCCl>[C:1]([O:12][C:10]1[CH:11]=[C:6]([CH3:5])[C:7]([CH:14]2[CH2:15][C:16](=[O:25])[C:17]([C:21](=[O:24])[CH2:22][CH3:23])=[C:18]([OH:20])[CH2:19]2)=[C:8]([CH3:13])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(O)cc2C)CC1=O
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(OC(C)=O)cc2C)CC1=O
Reaction time: 24 h
Yield: 42.4 %

Procedure:
Acetyl chloride (0.39 g; 4.9 mmole) in dichloromethane (5 ml) was added to a solution of 5-(2,6-dimethyl-4-hydroxyphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (1.29 g; 4.5 mmole) and pyridine (0.39 g; 4.9 mmole) in dichloromethane (100 ml) at room temperature. The mixture was stirred for 24 hours, then poured into water and extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give an oily residue. Purification by column chromatography over silica gel (eluant dichloromethane) gave 5-(4-acetyloxy-2,6-dimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (0.63 g; 42.0%) as a pale cream solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2.Br[CH2:20][CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+].Cl>C(Cl)Cl.CCOC(C)=O.C1COCC1>[Br:1][C:2]1[C:3]([O:18][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2
Reactant: Oc1ccc2cnn(-c3ccc(F)cc3)c2c1Br
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)CCOc1ccc2cnn(-c3ccc(F)cc3)c2c1Br
Temperature: 0 °C
Reaction time: 15 h
Yield: 141.3 %

Procedure:
THF (100 mL) was added to a mixture of 7-bromo-1-(4-fluorophenyl)-1H-indazol-6-ol (4.54 g, 14.8 mmol) (97, R1=4-Fluorophenyl) and 3-bromopropionic acid (34.0 g, 222 mmol). The mixture was cooled to about 0° C. NaOH (2 M aqueous solution, 150 mL, 300 mmol) was added over about 15 min. The ice bath was removed. After about 15 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. 3-Bromopropanoic acid (6.00 g, 39.2 mmol) was added in portions over about 5 min. After about 6 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. After about 14 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. After about 2 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. After about 15 h, the solution was cooled to about 0° C. 2 M aq. HCl (250 mL) and EtOAc (400 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organics were washed with water (400 mL) and sat. aq. NaCl (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (220 g) using a gradient of 0-50% EtOAc in DCM. The fractions containing the product were combined and concentrated under reduced pressure to afford a light tan solid. DCM (50 mL) was added. The solid was collected by filtration rinsing with 2×10 mL DCM (2×10 mL) then dried under reduced pressure to afford 3-((7-bromo-1-(4 fluorophenyl)-1H-indazol-6-yl)oxy)propanoic acid (98, R1=4-Fluorophenyl) (7.93 g, 30% yield) as an ivory solid. LC/MS, method 3, Rt=1.97 min, MS m/z 379 and 381 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 8.30 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.56-7.46 (m, 2H), 7.39-7.30 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 4.34 (t, J=6.0 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][CH:3]=1.[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@H:35]([CH:44]([CH3:46])[CH3:45])[C:36]([NH:38][C@H:39]([CH3:43])[C:40](O)=[O:41])=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:45][CH:44]([CH3:46])[C@H:35]([NH:34][C:32](=[O:33])[O:31][CH2:30][CH:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:29]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:36](=[O:37])[NH:38][C@@H:39]([CH3:43])[C:40](=[O:41])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:11])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4-Aminophenylboronic acid pinacol ester was added (146.9 mg, 0.67 mmol) was added to a solution of HO-Ala-Val-Fmoc 20b (330 mg, 0.8 mmol), DCC (166 mg, 0.8 mmol) and DMAP (5 mg, cat.) in dry DCM (8 mL) previously stirred for 30 minutes at room temperature in a flask flushed with argon. The reaction mixture was then allowed to stir at room temperature overnight. The reaction was followed by LCMS and TLC. The reaction mixture was diluted with CH2Cl2 and the organics were washed with H2O and brine before being dried with MgSO4, filtered and the solvent removed by rotary evaporation under reduced pressure. The crude product was dryloaded on a silicagel chromatography column (Hexane/EtOAc, 6:4) and pure product 20 was isolated as a white solid in 88% yield (360 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[C:13]([O:17][C:18](=[O:21])[CH2:19][NH2:20])([CH3:16])([CH3:15])[CH3:14].C([BH3-])#N.[Na+].C(O)(=O)C>C(Cl)Cl.CO.C(Cl)Cl.O>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([CH:3]([NH:20][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[CH2:2][OH:1])=[CH:6][CH:7]=1)#[N:10]
Reactant: N#Cc1ccc(C(=O)CO)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CNC(CO)c1ccc(C#N)cc1
Reaction time: 18 h

Procedure:
A solution of 4-(2-hydroxyacetoyl)benzonitrile (0.730 g; 4.53 mmol) and glycine tert-butyl ester (0.896 mg; 6.80 mmol) in DCM/MeOH (1:1; 12 mL) was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (0.342 g; 6.80 mmol) and acetic acid (0.389 mL; 6.80 mmol) were added to the reaction mixture and the mixture stirred for 18 hours. The reaction mixture was diluted with DCM and water and then poured through a hydrophobic frit. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography eluting with iso-hexane/EtOAc (3:2) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.65 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 3.88-3.85 (m, 1H), 3.76-3.72 (m, 1H), 3.59-3.55 (m, 1H), 3.32 (d, J=17.6 Hz, 1H), 3.15 (d, J=17.6 Hz, 1H), 1.49 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=S)[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>O1CCCC1>[O:17]1[CH2:18][CH2:19][N:14]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=3[N:9]=2)[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc2oc(N3CCOCC3)nc2c1
Yield: 92.3 %

Procedure:
5-nitrobenzo[d]oxazole-2(3H)-thione (98.1 mg, 0.5 mmol) and morpholine (66 μL, 0.75 mmol) in tetrahydrofuran (3 mL) were heated at 150° C. for 15 min in the microwave. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4 and absorbed on silica. Purification by column chromatography, eluting with ethyl acetate/hexanes 25:75 v/v affords 115 mg (92%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])(C)(C)[CH3:29]>>[CH2:28]([O:32][C:33]([N:35]1[CH2:36][CH2:37][N:38]([C:11](=[O:12])[C:10]2[CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)[CH:9]=2)[CH2:39][CH2:40]1)=[O:34])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CCOC(=O)N1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 79.9 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.234 g, 1.26 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.18 (3H, t), 3.52 (8H, m), 4.15 (2H, q), 7.00 (2H, s), 7.07 (1H, s), 7.28 (2H, d), 7.88 (2H, d).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.O>C1COCC1.CCCCCCC>[C:14]([Si:11]([CH3:13])([CH3:12])[O:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([B:23]([OH:28])[OH:24])[CH:7]=[CH:6][CH:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
50.0 g of [2-(3-bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane were dissolved in 500 ml of anhydrous THF. 64.6 ml of a 2.7 M solution of n-butyllithium in n-heptane were added dropwise at −70° C. The mixture was stirred for 1 h at −70° C. Then 40.2 ml of triisopropyl borate were added dropwise at −70° C. Stirring was continued for 30 min at −70° C. and the mixture allowed to warm up to −20° C. 500 ml of water were added and the mixture was extracted three time with 500 ml each of DCM. The combined organic layers were dried with magnesium sulfate and evaporated to yield 43.6 g of the title compound.
Reaction SMILES: [Na].[CH2:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl[CH2:12][CH:13]([OH:16])[CH2:14][OH:15]>C(OCC)C>[CH2:2]([O:10][CH2:12][CH:13]([CH2:14][OH:15])[OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:12][CH2:13][O:10][CH2:2][CH3:3]
Reactant: CCCCCCCCO
Reactant: OCC(O)CCl
Agent: [Na]
Solvent: CCOCC
Product: CCCCCCCCOCC(O)CO
Temperature: 105 °C

Procedure:
23 g (1 mol) of sodium were added in portions over the course of 4 hours to 325 g (2.5 mol) of 1-octanol while stirring at 105° C. (the temperature did not rise above 120° C. during this). The mixture was stirred at 115° C. for 1 hour. Subsequently, 110.5 g (1 mol) of 3-chloro-propane-1,2-diol were added over the course of 2 hours, and the mixture was stirred at 120° C. for 3 hours. After cooling, the mixture was taken up in 400 ml of diethyl ether and extracted 3× with a total of 700 ml of water. The ethereal phase was dried over sodium sulphate and concentrated. The residue was distilled in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[N+](C1C=CC([O:29][C:30]([NH:32][CH2:33][C@@H:34]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=O)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>CC#N.C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:30]([NH:32][CH2:33][C@@H:34]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:35][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:29])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CC1CCCCC1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)NC[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.8 %

Procedure:
To a stirred solution of (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (31 mg, 0.10 mmol) and (S)-tert-butyl 1-(p-nitrophenoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (40 mg, 0.10 mmol) in MeCN (1 mL) and CH2Cl2 (1 mL) was added DIEA (50 μL, 0.28 mmol). The mixture was stirred at rt for 20 h, diluted with ether (90 mL), washed with 5% aq HCl (20 mL) and 1 M aq NaOH (20 mL) and dried over MgSO4. Removal of the solvent left an oil (82 mg) which was applied to a 2-g silica SPE cartridge which was eluted sequentially with 10, 25, 50, 75 and 100% ethyl acetate in hexanes (15 mL of each) to afford 5 fractions. The 4th fraction was concentrated to afford tert-butyl (S)-1-((R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-3-cyclohexylpropan-2-ylcarbamate (29 mg, 49%) as an oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[C:9](Br)Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].CCCCCC.C([Li])CCC.O>O1CCCC1>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]#[CH:9])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=C(Br)Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#Cc1ccc(CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
Under nitrogen flow, the 27 g of 4-propyl-β,β-dibromostyrene was dissolved in 44 ml of tetrahydrofuran and cooled to -78° C. Two hundred ml of a butyl lithium hexane solution (1.6 mol/1 was added dropwise therein over a period of one hour. The solution was then agitated at room temperature for one and a half hours. After completion of the reaction, 200 ml of water was added. The crystals then were extracted with chloroform and washed three times with water. The remaining chloroform was distilled off, after which vacuum distillation (70° to 75° C./20 mmHg) was carried out to obtain 3.5 g of 4-propylphenylacetylene.