Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:9][O:10][C:11](=[O:31])[C@@H:12]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:14][O:15]N2C(=O)CCC2=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[C:3]1([CH2:9][O:10][C:11](=[O:31])[C@@H:12]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:13][CH2:14][OH:15])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a mixture of NaBH4 (1.4 g, 37 mmol) in THF (80 mL) and H2O (20 mL) was added a solution of (2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-butanoic acid phenylmethyl ester (10 g, 24 mmol) in THF at 0° C. After 15 min, the reaction mixture was quenched with NH4Cl (sat.), and extracted with EtOAc, dried over Na2SO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc, 7:3 to 6:4) afforded the product as colorless oil. LC-MS: 310 (M++1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[C:19](=O)[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16](COCC[Si](C)(C)C)[S:15]2(=[O:34])=[O:33])[CH2:10][CH2:9]1)=O)(C)(C)C.[BH4-].[Na+].O.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([OH:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1>CO>[C:38]1([CH3:48])[CH:39]=[CH:40][C:41]([S:44]([OH:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1.[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15](=[O:33])(=[O:34])[NH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2C(=O)c3ccccc3N(COCC[Si](C)(C)C)S2(=O)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S1(=O)Nc2ccccc2C=C1C1CCNCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
4-[2,2,4-Trioxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2,3,4-tetrahydro-2λ6-2,1-benzothiazin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (865 mg, 1.7 mmol) was dissolved in methanol (25 mL). Mixture was cooled to 0° C. Sodium borohydride (100 mg, 2.6 mmol) was added to the mixture in three portions. Reaction stirred at 0° C. for 3 hours. Mixture was concentrated by roto-vap. Residue was treated with 1N hydrochloric acid. Material was extracted twice with ethyl acetate. Organic phase was dried (magnesium sulfate), filtered and concentrated to dryness. Residue was dissolved in benzene (20 mL). p-Toluenesulfonic acid monohydrate (475 mg, 2.5 mmol) was added to the mixture. Reaction was heated to reflux and held with stirring for 1 hour. Mixture was cooled to room temperature. Solids were filtered off. The sticky solid was treated with hot isopropyl alcohol (10 mL). Mixture was cooled to room temperature and allowed to stand overnight. Solids were filtered off, washed with isopropyl alcohol and then dried under high vacuum. Title compound was obtained as tan solid in 65% yield. MS m/e (M+H)+=265.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[CH:22]([CH3:24])[CH3:23]>>[CH3:23][CH:22]([O:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2)CC1
Reactant: CC(C)I
Product: CC(C)Oc1cccc(N2CCNCC2)c1

Procedure:
Prepared from 1,1-dimethylethyl 4-(3-hydroxyphenyl)-1-piperazinecarboxylate (Description 21) and 2-iodopropane according to the method of Description 22. 1H NMR (250 MHz, CDCl3) δ1.34 (6H, d, J 6 Hz), 3.63-3.78 (8H, m), 4.51-4.60 (1H, m), 6.78-6.84 (2H, m), and 7.30-7.37 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6](N)[CH:5]=1.C(I)[I:20].[N+]([O-])([O-])=O>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([I:20])[CH:5]=1
Reactant: ICI
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Agent: O=[N+]([O-])[O-]
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1

Procedure:
3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester was treated with methylene iodide and isoamy nitrate using the procedure of step 5 of preparation 5, to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=353.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](CC(O)=O)=[CH:4][C:3]=1[N+:12]([O-])=O.[CH2:15]([OH:17])[CH3:16]>[Pd]>[CH:5]1[CH:4]=[C:3]([NH2:12])[C:2]([NH:1][C:15]([C:16]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[O:17])=[CH:7][CH:6]=1
Reactant: CCO
Reactant: Nc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccc(C(=O)Nc2ccccc2N)cc1

Procedure:
4-Amino-3-nitrophenylacetic acid (0.97 g) and the product from Example 15 (1.0 g) were treated by the procedure described in Example 19. The intermediate product was hydrogenated over palladium in ethanol to yield the intermediate dianiline. Treatment of this intermediate with 2,3-dihydroxy-1,4-dioxane, followed by conversion to the methanesulfonate addition salt yielded 0.88 g. of the desired product. m.p. 192° C. 1H NMR (DMSO-d6, 300 MHz) δ1.7-2.0 (m, 4H), 2.3 (s, 3H), 2.4-3.6 (m, 9H), 3.03 (d, 3H), 3.79 (s, 3H), 6.84 (d, 1H), 6.90 (d, 1H), 7.16 (t, 1H), 7.85 (dd, 1H), 8.1 (m, 2H), 8.96 (m, 2H), 9.1 (bs, 1H). Anal calcd for C24H31N3O4S: C, 62.99; H, 6.83; N, 9.18. Found: C, 62.79; H, 6.96; N, 9.00.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(#N)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:5][C:6]1([CH3:11])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1(C)CCCC1)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](CC1(C)CCCC1)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 25 %

Procedure:
2-Benzyloxycarbonylamino-3-(1-methylcyclopentyl)propionic acid methyl ester (7.6 g, 23.8 mmol) was dissolved in a mixture of acetonitrile (82 ml) and 0.2 M aqueous NaHCO3 (158 ml) and Alcalase 2.4 L (1.1 ml) was added and the reaction mixture was stirred vigorously for 8 h. The reaction mixture was then evaporated at 30° C. to remove acetonitrile, and the aqueous residue was washed with ether. The ethereal layer was concentrated to yield (R)-2-benzyloxycarbonylamino-3-(1-methylcyclopentyl)propionic acid methyl ester (1.9 g). The aqueous phase was filtered with Celite®, the pH was adjusted to 3 with 6N HCl, and the solution was extracted with ethylacetate. The ethyl acetate layer was dried and evaporated to yield 2(S)-benzyloxycarbonylamino-3-(1-methylcyclopentyl)propionic acid (1.4 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:18][C:19]1[CH:26]=[C:25](F)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[C:14]([O:13][C:3](=[O:12])[CH:4]([C:25]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Br:18])[CH:26]=1)[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C#N)c(Br)c1
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.37 g, 15.4 mmol, 60.0% dispersion in oil) in DMF (40 mL) was added a solution of di-t-butyl malonate (3.6 g, 16 mmol) in DMF (10 mL) at 0° C. and this was stirred for 15 minutes. Subsequently, 2-bromo-4-fluorobenzonitrile (3.0 g, 15.0 mmol) was added in one portion and the reaction mixture was stirred for 8 hours at 80° C. and three hours at room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4 and filtered. After evaporation in vacuo, the residue was purified by flash chromatography (20% EtOAc in hexane) to give di-tert-Butyl(3-bromo-4-cyanophenyl)malonate as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.60 (d, J=8 Hz, 1H), 4.95 (s, 1H), 1.42 (s, 18H). LC-MS (IE, m/z): 398 [M+1]+.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Br[CH2:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[O:16][C:15]1=[O:23]>C(Cl)(Cl)Cl>[NH2:2][CH2:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[O:16][C:15]1=[O:23]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=c1oc2cccnc2n1CCBr
Solvent: ClC(Cl)Cl
Product: NCCn1c(=O)oc2cccnc21

Procedure:
0.013 mol of hexamethylenetetramine, dissolved beforehand in 20 cm3 of chloroform, and 0.01 mol of 3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolved beforehand in 15 cm3 of chloroform, are introduced into a round-bottomed flask placed under argon and surmounted by a condenser. The mixture is heated to reflux for one week. The product is drained and dried. The precipitate is introduced into a ground-necked 250-cm3 flask equipped with a reflux condenser, and 50 cm3 of absolute alcohol and 10 cm3 of concentrated hydrochloric acid are added. The mixture is heated to reflux for two hours with magnetic stirring. The solvent is evaporated off on a water bath under vacuum and the product is recrystallized in alcohol at 95° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.C1C(=O)N([Br:41])C(=O)C1.CCOCC>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Temperature: -60 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
A solution of 15 (137 mg, 0.366 mmol) in freshly distilled THF (7.3 mL) and cooled to -78° C. under Ar was treated with 10 μL of a 1 μL/mL solution of H2SO4 in THF and the solution was stirred for 20 min before the addition of NBS (78 mg, 439 mmol, 1.2 equiv). The reaction mixture was allowed to warm to -60° C. and was stirred for 4 h at which time the reaction was complete by TLC. Et2O (7.3 mL) was added and the resulting organic phase was washed with 5% aqueous NaHCO3 (1×10 mL), saturated aqueous NaCl (1×10 mL), dried (MgSO4), and concentrated in vacuo. Chromatography (SiO2, 2×20 cm, 10% EtOAc-hexane) afforded 16 (145 mg, 166 mg theoretical, 87%) as a white crystalline solid: mp 179° C. dec (white needles, 10% EtOAc-hexane); 1H NMR (CDCl3, 250 MHz) δ8.40 (s, 1H, C8-H), 8.26 (d, 1H, J=8.5 Hz), 8.23 (s 1H, C3-H), 7.5-7.3 (m, 6H), 5.23 (s, 2H), 1.58 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ154.4, 152.4, 137.0, 136.0, 132.2, 132.0, 128.7, 128.6, 128.4, 128.0, 124.9, 124.8, 124.2, 119.1, 111.9, 102.0, 81.9, 70.8, 28.3; IR (KBr) vmax 3416, 2978, 2230, 1738, 1623, 1603, 1570, 1498, 1405, 1364, 1335, 1229, 1158, 990, 970, 878, 850, 823, 758, 696 cm-1 ; FABHRMS (NBA-CsI) m/z 584.9793 (M+ +Cs, C23H21BrN2O3 requires 584.9790).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:15][CH2:16][CH2:17][N:18]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:19][CH2:20][C:21](O)=[O:22])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:27]([O:26][C:24]([N:18]1[CH2:19][CH2:20][C:21](=[O:22])[N:15]([C@H:4]([C:3]([O:2][CH3:1])=[O:34])[CH2:5][CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:16][CH2:17]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NCCN(CCC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Reaction time: 15 h

Procedure:
A solution of 4.40 g (8.64 mmol) of (S)-4-benzyloxy-2-{2-[benzyloxycarbonyl-(2-carboxy-ethyl)-amino]-ethylamino}-butyric acid methyl ester; hydrochloride in 85 ml dichloromethane was treated with 1.20 (8.64 mmol) of triethylamine and at 0° C. with 1.99 g (10.37 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. The cooling bath was allowed to come to room temperature and after 15 h the reaction was extracted with 10% aq. potassium hydrogensulfate solution/diethyl ether (3×). The organic phases were washed with 10% aq. potassium hydrogensulfate solution, 10% sodium chloride solution and dried over Na2SO4 to yield after evaporation of the solvent 3.74 g (95%) of the titled compound as light yellow oil. MS: 455.2 (MH+).
Reaction SMILES: [CH:1]([C@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=1)[CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[CH:1]([C@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=1)[CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc(C(=O)[C@@H](C/C=C/C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCCCOc1cc(C[C@@H](C/C=C/C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of (2S,7S)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropyloxy)-benzoyl]-8-methylnon-4-enoic acid (90 mg; 0.21 mmol) in trifluoroacetic acid (1 ml) was added triethylsilane (250 μl; 1.5 mmol). After stirring the solution at RT for 1 day, a second portion of triethylsilane (250 μl; 1.5 mmol) was added, and the solution was stirred at RT for a further 2 days and then added to water. The aqueous layer was extracted 3× with tert-butyl methyl ether and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel; hexane/acetone 4:1) to obtain (2S,7R)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnon-4-enoic acid (53 mg, 0.126 mmol, 61% yield).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[C:30]#[CH:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.ClCCl.CO.N>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[C:30]#[C:31][C:2]3[CH:14]=[CH:13][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: Ic1ccc(CN2CCCCC2)cc1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(CN2CCCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)piperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 6 mg (4% of theory); melting point: 179.5° C.; C27H25ClN2O (M=428.96); calc.: molecular ion peak (H+ H)+: 429/431; found: molecular ion peak (M+H)+: 429/431; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][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][OH:27].O>CN(C)P(N(C)C)(N(C)C)=O>[OH: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][CH2:14][CH2:13][CH2:12][CH2:11][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCCCCCCCCBr
Reactant: N#Cc1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: N#Cc1ccc(NCCCCCCCCCCCCCCCCO)cc1
Temperature: 120 °C

Procedure:
p-Aminobenzonitrile (12 g.) and 16-bromo-1-hexadecanol (15 g.) are dissolved in hexamethylphosphoramide (200 ml.) and heated under nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water (50 ml.) is added gradually. The mixture is then chilled in an ice-bath. The precipitate separated is filtered, washed thoroughly with water, and dried. It is then washed repeatedly with hexane and dried. The pale brownish yellow granular solid is obtained as a homogeneous product. Recrystallization from ether-hexane affords 4-(16-hydroxyhexadecylamino)benzonitrile as pale yellow prisms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.CCN(CC)CC.[Cl:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH:19][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][Cl:28])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A solution of 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) (1.2 g, 4.3 mmol, 1 equiv) in CH2Cl2 (10 ml) was treated with NEt3 (525 mg, 5.2 mmol, 1.2 equiv). The solution was cooled to 0° C. and 4-chlorobutyryl chloride (733 mg, 5.0 mmol, 1.2 equiv) was added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. The solution was washed with 2N aqueous HCl solution (20 ml), dried over MgSO4 and concentrated in vacuo to give 5-(4-chloro-butanoylamino)-N,N-dipropyl-isophthalamic acid methyl ester (D89) (1.7 g, 104%) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11]O)[CH2:6]2)[C:3]1=[O:13].S(Cl)([Cl:17])=O.O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11][Cl:17])[CH2:6]2)[C:3]1=[O:13]
Reactant: CC1(C)C(=O)C2CCC1CC2CCO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)C(=O)C2CCC1CC2CCCl
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a stirred solution of 50 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octan-2-one (produced according to Example II) in 200 ml of dry pyridine is added 30 g of thionyl chloride. The mixture is stirred at 50° C. for 2 hours and then poured into 50 g of water. The resulting aqueous solution is extracted with three 200 ml portions of ether. The combined ether layers are washed with two 100 ml portions of 5% aqueous HCl and dried over anhydrous sodium sulfate. The ether is stripped and the residue is vacuum distilled, yielding about 42 g of 3,3-dimethyl-6-(2-chloroethyl)-bicyclo(2.2.2)-octan-2-one, having the structure: ##STR28##
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16]C=C[N:13]=3)=[N:11][C:7]=2[CH:6]=1.[NH:36]1C=CC(C=O)=N1>>[F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16][NH:36][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: O=Cc1cc[nH]n1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2F)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cc[nH]n4)nc3cc2Oc2ccccc2F)cn1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 202 or in accordance with the method or by combining it with an ordinary method but using 4-(2-fluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 223 and 1H-pyrazole-3-carboxaldehyde.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=2)O1>>[OH:19][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:7]=2)[C:2]=1[C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=1
Reactant: CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Product: CC(=O)Nc1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Reaction time: 2 h
Yield: 77 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)naphthalene-2-ol (150 mg, 0.48 mmol, 1 eq) with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (124.3 mg, 0.48 mmol, 1 eq) according to method A in 2 h. Purification by column chromatography with hexane/ethyl acetate 8/2 yields the desired compound in a yield of 77%, 136 mg.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:11][C@@H:12]1[C@H:17]2[CH2:18][O:19][C@H:15]([O:16]2)[C@H:14]([CH:20]=C)[C@H:13]1[OH:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[BH4-].[Na+]>C(O)C.C(O)C.O>[CH2:4]([O:11][C@@H:12]1[C@H:17]2[CH2:18][O:19][C@H:15]([O:16]2)[C@H:14]([CH2:20][OH:1])[C@H:13]1[OH:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[O+][O-]
Reactant: C=C[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@@H]1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@@H]1O
Reaction time: 0.5 h

Procedure:
A stream of ozone (0.36 mmol/min) was passed through a solution of 1,6-anhydro-4-O-benzyl-2-deoxy-2-C-vinyl-β-D-glucopyranose (8, 3.36 g, 12.8 mmol) in ethanol (100 ml) for 43.5 minutes. The solution of the ozonide was transferred to a three-necked round bottomed flask equipped with a thermometer and a dropping funnel containing a solution of NaBH4 (3.87 g, 102 mmol) in ethanol/water 1:1 (35 ml). The solution of NaBH4 was added dropwise in such a manner to keep the temperature below 20° C. (cooling on ice bath). After stirring for 45 min Amberlite IR 120, H+ (100 ml) was added. After stirring for another 30 minutes, the ion exchange resin was filtered off and rinsed with water. The solution was evaporated and co-concentrated with methanol (3×80 ml). The residue was a colorless syrup obtained in 96% (3.28 g) yield. This syrup was flash chromatographed using ethyl acetate/pentane 2:1 and ethyl acetate as eluent to give 9 in a 63% (2.14 g) yield as a crystalline compound. In some runs the crude syrup crystallized and was recrystallized from chloroform: mp. 111°-113°; [α]D20 =41.4° (c; 2.05, CH3OH). 13C-NMR (50 MHz, D2 O):δ139, 130.1, 129.8 (Ph); 102.0 (C-1);, 80.5 (C-4), 76.1 (C-3), 72.9 (OCH2Ph), 67.4 (C-5), 66.2 (C-6), 61.7 (C-2'), 49.0 ppm (C-2). Anal. Calc. for C14H18O5 : C, 63.15; H, 6.81. Found: C, 63.14; H, 6.79.