Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:13]=[CH:12][C:10](N)=[C:9]([CH3:14])[CH:8]=1.N([O-])=[O:16].[Na+].NC(N)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].C1(O)C=CC=CC=1>O>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([OH:16])=[C:9]([CH3:14])[CH:8]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: Oc1ccccc1
Solvent: O
Product: Cc1cc(Br)ccc1O
Temperature: 0 °C
Yield: 69.7 %

Procedure:
First, 70 ml of water, 25 ml of concentrated sulfuric acid, and 25.0 g of 4-bromo-2-methylaniline were put in a 500 ml flask. After 60 g of ice was added, 30 ml of water containing 10.9 g of sodium nitrite dissolved therein was dropped in 25 minutes keeping the temperature at 5° C. or less. Another 100 ml of water, 100 g of ice, and 1 g of urea were added and the resultant mixture was left for 30 minutes. Then, 50 g of anhydrous sodium sulfate, 70 ml of concentrated sulfuric acid, and 33 ml of water were put in a 500 ml flask provided with a distiller, and heated to a temperature of 130° C. to 135° C. The former reaction solution was dropped into the resultant mixture, and phenol generating was distilled together with steam. Ether was added to the distilled solution for extraction. The resultant ether layer was washed with water and a sodium hydrogencarbonate aqueous solution. A 10% sodium hydroxide aqueous solution was further added for extraction. Then, 35 ml of concentrated hydrochloric acid was added to the resultant sodium hydroxide aqueous solution to acidify the solution, and ether was added for extraction. The resultant ether layer was washed with water and dried with anhydrous sodium sulfate. The solvent was then distilled off under decompression. The residue was distilled (b.p.: 135° C. to 139° C./8 mmHg) to obtain 17.48 g (Y: 69.7%) of 4-bromo-2-methylphenol. The purity of the resultant compound was 98.8% as measured by GC.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Step 1. To a mixture of 4-(4-hydroxyphenyl)cyclohexanone (19.0 g, 0.1 mol) and triethylamine (40.4 g, 0.4 mol) in CH2Cl2 (700 ml) at 0° C. was added dropwise acetyl chloride (15.7 g, 0.2 mol). After the addition was finished, the reaction mixture was warmed to rt and stirred overnight. The reaction mixture was washed with water and brine, dried over MgSO4, and concentrated. The crude product was crystallized from 95% aq. ethanol to afford 4-(4-acetoxyphenyl)-cyclohexanone (17.6 g, 76%) as a colorless solid. mp 104-106° C. (95% aq. ethanol); 1H NMR (500 MHz, CDCl3) δ 1.88-1.98 (m, 2H), 2.20-2.26 (m, 2H), 2.48-2.54 (m, 4H), 2.30 (s, 3H), 3.00-3.07 (m, 1H), 7.03 (d, J=8.7 Hz, 2H), 7.25 (d, J=8.7 Hz, 2H). Step 2. A solution of O-methyl 2-adamantanone oxime (16.0 g, 89 mmol) and 4-(4-acetoxyphenyl)cyclohexanone (13.8 g, 59 mmol) in cyclohexane (400 ml) and CH2Cl2 (100 ml) was treated with ozone according to the general procedure. The crude product was triturated with ethanol (200 ml) to afford adamantane-2-spiro-3′-8′-(4′-acetoxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane (16.4 g, 70%) as a colorless solid. mp 149-151° C. (ethanol); 1H NMR (500 MHz, CDCl3) δ 1.64-2.08 (m, 22H), 2.29 (s, 3H), 2.50-2.60 (m, 1H), 7.00 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H). Step 3. A mixture of adamantane-2-spiro-3′-8′-(4′-acetoxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane (16.4 g, 41 mmol) and 15% aq. KOH (65 ml) in THF/MeOH (1:2, 500 ml) was heated at 50° C. for 4 h. After being cooled to rt, the reaction mixture was concentrated to 70 ml, diluted with water (70 ml), and acidified with acetic acid (30 ml). The precipitate was collected by filtration to afford trioxolane OZ288 (14.36 g, 98%) as a colorless solid. mp 136-138° C.; 1H NMR (500 MHz, CDCl3) δ 1.56-2.18 (m, 22H), 2.41-2.58 (m, 1H), 5.90 (br s, 1H), 6.76 (d, J=8.5 Hz , 2H), 7.05 (d, J=8.5 Hz, 2H); 13C NMR (125.7 MHz, CDCl3) δ 26.49, 26.89, 31.65, 34.75, 34.80, 36.41, 36.81, 42.05, 108.46, 111.35, 115.22, 127.71, 138.03, 154.26. Anal. Calcd for C22H28O4: C, 74.13; H, 7.92. Found: C, 73.90; H, 7.85.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:30]([O:37][C:38](ON1C(=O)CCC1=O)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:30]([O:37][C:38]([N:15]1[C:16]([CH3:29])=[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=2)[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(=O)OCc1ccccc1
Yield: 75.3 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole (1.3 g) in tetrahydrofuran (30 mL) was added N-(benzyloxycarbonyloxy)-succinimide (1.6 g), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(benzyloxycarbonyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][NH:20][CH3:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:20]([CH3:21])[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CNC
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Yield: 47.6 %

Procedure:
A solution of 2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.668 mmol) and excess dimethylamine (3.34 mL, 6.68 mmol) in MeOH (4 mL) was stirred at rt for 30 min. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-7-(4-chlorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (98 mg, 0.318 mmol, 47.6% yield). LC-MS (M+H)+=308.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1(O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: Oc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccccc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
Tetrahydropyran-4-carboxylic acid (1.00 g, 7.69 mmol), phenol (651 mg, 6.92 mmol), and PyBOP (4.40 g, 8.45 mmol) were dissolved in DMF (15 mL). To the solution was added triethylamine (2.36 mL, 16.9 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate aqueous solution and brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to give phenyl tetrahydropyran-4-carboxylate (1.28 g, 81%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:46])[CH2:25][C@H:26]([C:33]1[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=1)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:54])C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1>[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:46])[C@H:25]([OH:54])[C@H:26]([C:33]1[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=1)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CC(C)(C)OC(=O)c1cccc([C@@H](CC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccccn2)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc([C@H](c2ccccn2)[C@@H](O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 43 %

Procedure:
To a cooled solution (−78° C.) of sodium hexamethyldisilazide (0.38 mL, 0.38 mmol) in THF (0.5 mL) was added tert-butyl 3-{(1R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxo-1-pyridin-2-ylpropyl}benzoate from the previous step (0.153 g, 0.314 mmol) in THF (1 mL) dropwise and stirred for 45 min. 2-(Phenysulfonyl)-3-phenyloxaziridine (0.167 g, 0.629 mmol) dissolved in THF (0.5 mL) was added to cold solution and the mixture was stirred for 10 min. Camphorsulfonic acid, dissolved in THF (2 mL), was quickly added and the bath was removed. The reaction was warmed to room temperature, diluted with saturated aqueous NaHCO3, extracted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed on a 35 g ISCO column using 0-50% EtOAc/hexanes over 40 min and the lowest spot fractions were combined and the solvent removed under reduced pressure to give an oil. This oil was purified by preparative HPLC on a Waters PrepPak using 10% to 100% CH3CN/H2O with 0.1% TFA as eluant over 60 min. The product-containing fractions were combined and the acetonitrile was removed under reduced pressure. The remaining aqueous solution was basicified with saturated aqueous NaHCO3, extracted with 4×20 mL CH2Cl2, dried over Na2SO4 and filtered. The filtrate solvent was removed under reduced pressure to give tert-butyl 3-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-hydroxy-3-oxo-1-pyridin-2-ylpropyl}benzoate as an oil (0.068 g, 43%). TLC Rf=0.3 (1:1 EtOAc:hexanes, UV visualization); HPLC RT=2.61 min, method B; M+H=503.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(OC)=O.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]1[C:32]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][C:34]=2[CH3:41])=[CH:31][C:30]([C:42]([OH:45])([CH3:44])[CH3:43])=[N:29]1>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]1[C:32]([C:33]2[CH:40]=[CH:39][C:36](/[CH:37]=[CH:9]/[C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([O:15][CH3:16])=[O:14])=[CH:35][C:34]=2[CH3:41])=[CH:31][C:30]([C:42]([OH:45])([CH3:43])[CH3:44])=[N:29]1
Reactant: Cc1cc(C=O)ccc1-c1cc(C(C)(C)O)nn1-c1c(Cl)cccc1Cl
Reactant: COC(=O)c1cccc(CP(=O)(OC)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2ccc(-c3cc(C(C)(C)O)nn3-c3c(Cl)cccc3Cl)c(C)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a suspension of NaH (52 mg of a 60% dispersion in mineral oil) in THF (7.5 mL) cooled to 0° C. in an ice bath was added methyl 3-((dimethoxyphosphoryl)methyl)benzoate as a solution in THF (1 mL) followed by a THF (1 mL) rinse of the phosphonate vial and syringe to insure complete transfer. The ice bath was removed and the reaction was allowed to warm to ambient temperature. After 90 minutes at ambient temperature, 4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylbenzaldehyde (0.49 mmol impure from previous step) was added via cannula to the reaction mixture followed by a THF (1 mL) rinse of the flask and cannula after 1 hour-45 minutes at ambient temperature the reaction was quenched by addition of saturated aqueous NH4Cl and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a yellow syrup. The crude product was purified by flash column chromatography eluting with a gradient from 0% to 40% MeCN/CH2Cl2 to afford (E)-methyl 3-(4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoate (180 mg, 70% yield) of slightly impure product. This material was carried on to the ester hydrolysis without further purification. MS(ES): 521 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[S:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:17]=1[NH2:18]>C1(C)C=CC=CC=1>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:18][C:17]2[CH:19]=[C:20]([C:23]([F:25])([F:26])[F:24])[CH:21]=[CH:22][C:16]=2[O:15][CH3:14])=[S:11])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: COc1ccc(C(F)(F)F)cc1N
Solvent: Cc1ccccc1
Product: COc1ccc(C(F)(F)F)cc1NC(=S)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
3-(trifluoromethyl)phenyl isothiocyanate in toluene (0.76 ml, 5.0 mmol) was added to a solution of 2-methoxy-5-(trifluoromethyl)aniline in toluene (10 ml). The resulting reaction mixture was stirred at RT overnight and the product was subsequently filtered off. 1.00 g (51%) of the title compound was isolated.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11]([NH:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O:26]C)=[O:25])[CH:22]=2)[CH2:17][CH2:16]1)(=[O:13])=[O:12]>C(O)C.O>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11]([NH:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([OH:26])=[O:25])[CH:22]=2)[CH2:17][CH2:16]1)(=[O:12])=[O:13]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)c1cccc(Cl)c1Cl)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)[C@H](NS(=O)(=O)c1cccc(Cl)c1Cl)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
KOH (1 mol/l aq) (2 eq.) was added to a suspension of (R)-methyl 3-(2,3-dichlorophenyl-sulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (C-06) (0.85 mmol, 1 eq.) in a mixture of ethanol (4.9 ml) and water (1.1 ml). The reaction mixture was stirred at room temperature overnight. Ethanol was removed in vacuo and the aqueous residue was diluted with diethyl ether and dist. water. The phases were separated and the aqueous phase was acidified to pH 3 with 1N HCl and extracted 4× with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated to obtain the desired product (F-06). Yield: 61%
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.CON(C)[C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[CH3:37]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:30]([C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:38])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)(=[O:10])=[O:11])=[CH:13][C:14]=1[C:19]([F:21])([F:22])[F:20]
Reactant: CON(C)C(=O)c1cccnc1C
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by procedure analogous to that described in Example 29 using N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide and N-methoxy-2,N-dimethyl-nicotinamide. 1H NMR: (400 MHZ, CDCl3) δ 8.61 (m, 1H), 8.26 (m, 1H), 8.20 (m, 1H), 8.17 (m, 1H), 8.04-8.01 (m, 1H), 7.67 (d, 1H), 7.50 (m, 1H), 7.18 (m, 1H), 2.41 (s, 3H). MS: (M+H)/z=490.0.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])=[CH:11][CH:10]=1
Reactant: C#CCCCCO
Reactant: Clc1ccc(I)cc1
Product: OCCCCC#Cc1ccc(Cl)cc1

Procedure:
In a manner described in Example 18 above, 5-hexyn-1-ol was reacted with 1-chloro-4-iodobenzene to give the title compound, MS m/Z exact mass 209.724 (M+H)(calcd. For C12H13OCl 209.70).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:3].[C:17]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:17]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:2][CH3:3])[CH2:16][CH2:15]2)[CH:18]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: CCOc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCOc1ccccc1N1CCN(Cc2cccc(-c3ccccc3)c2)CC1

Procedure:
48 mg of the target compound (0.13 mmol, 23.4%) was obtained using 1-(2-ethoxyphenyl)piperazine monohydrogen chloride (266 mg, 1.09 mmol), biphenyl-3-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Cc1ccnc(Cl)n1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-methyl-pyrimidine. MS (ESI) mass calcd. for C24H24N4O, 384.49; m/z found, 385.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CC1(C)[NH:58][CH2:57][CH2:56][O:55]1>C1COCC1.C(OCC)(=O)C>[OH:55][CH2:56][CH2:57][NH:58][C:14]([C:10]1[CH:9]=[C:8]([O:7][C:6]2[CH:17]=[CH:18][C:3]([NH:2][CH3:1])=[C:4]([N+:19]([O-:21])=[O:20])[CH:5]=2)[CH:13]=[CH:12][N:11]=1)=[O:16]
Reactant: CNc1ccc(Oc2ccnc(C(=O)O)c2)cc1[N+](=O)[O-]
Reactant: CC1(C)NCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1ccc(Oc2ccnc(C(=O)NCCO)c2)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a suspension of the 4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid (1 eq) in dry THF, EDC-HCl (1.2 eq), HOAT (1.2 eq), and diisopropylethylamine (3 eq) were added. The suspension was stirred for 10 minutes whereupon 2,2-dimethyl-oxazolidine (1.1 eq) was added and the solution is allowed to stir overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was washed with ethyl acetate, the organic layers combined, dried over MgSO4, filtered, and concentrated. LCMS m/z 333.2 (MH+), tR=2.1 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=1.CC1N(CCCN2C(=O)C3C(=CC=CC=3)C2=O)C=NC=1>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=1
Reactant: Cc1cn(CCCN2C(=O)c3ccccc3C2=O)cn1
Agent: Cc1cncn1CCCN1C(=O)c2ccccc2C1=O
Product: Cc1cn(CCCN)cn1

Procedure:
Yield: 6.1 g (62.0%) of a mixture of 2-(3-(4-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione and 2-(3-(5-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23]N)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.N(OC(C)(C)C)=O.C(N(C(C)C)C(C)C)C.N[C@@H:50]([C:61]([NH:63][C@H:64]([C:69]([NH:71][C@H:72]([C:80]([N:82]1[CH2:93][CH2:92][CH2:91][C@H:83]1[C:84]([NH:86][CH2:87][C:88]([NH2:90])=[O:89])=[O:85])=[O:81])[CH2:73][CH2:74][CH2:75][NH:76][C:77](=[NH:79])[NH2:78])=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])=[O:62])[CH2:51][C:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[NH:54][CH:53]=1.FC(C(O)=O)(F)F>CN(C)C=O.C(OCC)(=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@@H:50]([C:61]([NH:63][C@H:64]([C:69]([NH:71][C@H:72]([C:80]([N:82]1[CH2:93][CH2:92][CH2:91][C@H:83]1[C:84]([NH:86][CH2:87][C:88]([NH2:90])=[O:89])=[O:85])=[O:81])[CH2:73][CH2:74][CH2:75][NH:76][C:77](=[NH:78])[NH2:79])=[O:70])[CH2:65][CH:66]([CH3:67])[CH3:68])=[O:62])[CH2:51][C:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[NH:54][CH:53]=1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NN
Reactant: CC(C)C[C@H](NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a solution of Boc-Ser(But)-Tyr-NHNH2 (3.68 g) in dimethylformamide (84 ml) at -15° C., was added a solution of hydrogen chloride in ethyl acetate (1.7 N, 12.35 ml), followed by t-butyl nitrite (1.17 ml). After stirring at -15° C. for 15 min, the reaction mixture was cooled to -25° C. and adjusted to pH 7 with N-ethyldiisopropylamine (3.95 ml). To this solution at -20° C. was added a solution of the above H-D-Trp-Leu-Arg-Pro-Gly-NH2 trifluoroacetate and N-ethyldiisopropylamine (1.46 ml) in dimethylformamide (27 ml). The reaction mixture was stirred at -15° C. for 60 min, at ice-bath temperature for 60 min and a room temperature for 18 hr. The solvent was evaporated and the residue was dissolved in methanol. Diethyl ether was added and the precipitate was chromatographed on silica gel using chloroform-methanol-32% aqueous acetic acid (15:4:1 v/v). The pure fractions were combined, evaporated and dried to give 5.4 g of Boc-Ser(But)-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2 ; nmr (DMSO-D6)δ 0.75 (m, 6H), 1.05 (s, 9H) and 1.25 (s, 9H); uv max (methanol) 289 (ε=4546) and 279 nm (ε=5992); amino acid analysis: Gly (1.00), Arg (0.99), Trp (0.44), Ser (0.70), Pro (0.96), Leu (1.39) and Tyr (1.02); and [α]D25 -7.89° (c=1,1% acetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18].[CH3:25][O:26][C:27]([CH2:29]P(OC)(OC)=O)=[O:28]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:29][C:27]([O:26][CH3:25])=[O:28])=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: COc1ccc(C=O)cc1OCc1nc(-c2ccccc2)oc1C
Product: COC(=O)C=Cc1ccc(OC)c(OCc2nc(-c3ccccc3)oc2C)c1

Procedure:
In substantially the same manner as in Reference Example 16, 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolyl methoxy)benzaldehyde was allowed to react with trimethyl phosphonoacetate to yield methyl 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate, which was recrystallized from ethyl acetate-ether to give colorless needles, m.p.135-136° C.