Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][CH:14]=2)=[CH:6][CH:5]=1.[C:15]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[S:13]1[CH:14]=[CH:10][N:11]=[N:12]1.[C:15]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:11]=[N:12][S:13][CH:14]=4)=[CH:6][CH:5]=3)[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: ClCCc1ccc(-c2csnn2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: c1ccc2c(N3CCN(CCc4ccc(-c5csnn5)cc4)CC3)cccc2c1
Product: c1csnn1

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 0.64 g (2.83 mmol) (4-(4-(2-chloroethyl)phenyl)-1,2,3-thiadiazole, 0.60 g (2.83 mmol) N-(1-naphthyl)piperazine, 0.49 ml (2.83 mmol) diisopropylethylamine, 0.60 g (5.66 mmol) sodium carbonate, 2 mg sodium iodide, and 20 ml methylisobutylketone. The reaction was refluxed 4 days, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent and the product fractions dissolved in ethyl acetate and precipitated with ethyl acetate saturated with HCl. The precipitate was filtered and dried to give a solid, 0.62 g (50%), m.p. 286-289° C. NMR (DMSO-d6 and TFA): 3.6 (m, 2H), 3.9 (m, 2H), 4.4-4.7 (m, 8H), 7.5-8.2 (m, 11H), 9.42 (s, 1H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:27])(=O)=O.C(OCC)C.C([O-])([O-])=O.[K+].[K+]>ClCCl.O>[C:1]1([C:7]2[CH:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]3[N:27]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: C(#Cc1ccccn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(-c2cc3ccccn3n2)cc1
Reaction time: 0.5 h

Procedure:
2-Phenylpyrazolo[1,5-a]pyridine was prepared by the following procedure. A solution of 2-(phenylethynyl)pyridine (3.2 g, 0.018 mol) in dichloromethane (20 mL) was cooled to 0° C. in an ice bath. A solution of O-mesitylenesulfonylhydroxylamine in dichloromethane was added dropwise, keeping the temperature below 5° C. The mixture was stirred for 30 minutes, then ethyl ether was added to precipitate a solid (5–7 g). The solid was filtered off, washed with ethyl ether and dried. The solid was re-dissolved in DMF and solid K2CO3 (4.5 g, 0.033 mol) was added in small portions. After stirring 2 h, water (100 mL) was added to the mixture, followed by extraction with dichloromethane. The organics were dried over magnesium sulfate, filtered, and evaporated to an orange oil (2.3 g). Chromatography on silica with dichloromethane eluent yielded the 2-(phenylethynyl)pyridine in 83% yield, mp 110° C. 1H NMR and mass spectra analysis confirmed the structure.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH:7]([C:9]([OH:11])=[O:10])[NH2:8])[CH2:5][C:4](=[O:12])[NH:3]1.[OH-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>O.O1CCOCC1>[CH2:15]([O:22][C:23]([NH:8][CH:7]([CH:6]1[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:1])[C:9]([OH:11])=[O:10])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(C(=O)O)C1CC(=O)NC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1

Procedure:
In 250 ml of water-dioxane (1:1) was suspended 10 g of 2-(2,5-dioxopyrrolidin-3-yl)glycine and under cooling at 0°-5° C. the above amino acid was dissolved by addition of 70 ml of 1 N sodium hydroxide. To this solution was added 15 ml of benzyloxycarbonyl chloride and, with adjusting pH to 7.1-7.4 with sodium hydrogen carbonate, the mixture was stirred at the same temperature as above for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent and the concentrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 1 with conc. hydrochloric acid and allowed to stand in a refrigerator overnight to give crystals. Yield 15.8 g.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][C:48]=1[F:49])[O:30][C:31]1[CH:43]=[CH:42][C:34]2[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=2[C:32]=1[C:44]#[N:45]>O1CCCC1.C(OCC)(=O)C>[C:39]([NH:38][C:36]1[S:37][C:33]2[C:32]([C:44]#[N:45])=[C:31]([O:30][C:29]3[CH:46]=[CH:47][C:48]([F:49])=[C:27]([NH:26][C:9](=[O:11])[C:8]4[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=4)[CH:28]=3)[CH:43]=[CH:42][C:34]=2[N:35]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)c(C#N)c2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (66 mg, 0.350 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (37 μL, 0.438 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (100 mg, 0.292 mmol) produced in Example 34(ii) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (25 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was successively purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0) and silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (43 mg, 28%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)[C:6]=1[CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CO.ClCCl>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)=[O:33])[C:6]=1[CH3:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3nccc(OCCO)c3C)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(OCCO)c3C)nc2c1
Reaction time: 4.5 h
Yield: 61.6 %

Procedure:
0.9 g of 2-[4-(2-hydroxyethoxy)-3-methylpyridine-2-yl]methylthio-5-methoxy-1H-benzimidazole was dissolved in a mixture comprising 5 ml of methanol and 80 ml of dichloromethane to obtain a solution. 0.51 g of m-chloroperbenzoic acid was added to this solution at -60° C. The obtained mixture was stirred at -50° to -40° C. for 4.5 hours, followed by the addition of 0.38 g of triethylamine. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained mixture and the resulting mixture was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to obtain a crude product. This crude product was crystallized from dichloromethane/isopropyl ether to obtain 0.58 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][N:12]2[CH2:13][CH2:14]3)=[CH:4][CH:3]=1.[CH3:19][S:20]([Cl:23])(=[O:22])=[O:21]>>[ClH:23].[N:12]12[CH2:13][CH2:14][CH:15]([CH2:17][CH2:18]1)[CH2:16][CH:11]2[CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CCCC2CC3CCN2CC3)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(CCCC2CC3CCN2CC3)cc1
Product: Cl

Procedure:
In a manner similar to Example X react 2-[3-(4-aminophenyl)propyl]-1-azabicyclo[2.2.2]octane with methanesulfonyl chloride to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2OC)=[O:7])=[CH:4][CH:3]=1.COC1C=C([N+]([O-])=O)C=CC=1N.[Cl:32]C1C=CC=CC=1N[N+]([O-])=O>>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[Cl:32])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cc(N)ccc1NC(=O)c1ccc(N)cc1
Reactant: O=[N+]([O-])Nc1ccccc1Cl
Agent: COc1cc([N+](=O)[O-])ccc1N
Product: Nc1ccc(C(=O)Nc2ccc(N)cc2Cl)cc1

Procedure:
By operating as described under (a) above, but using, instead of 202 parts of 2-methoxy-4-nitro-aniline, 207 parts of 2-chloro-nitro-aniline, high yields of 4,4'-diamino-2'-chloro-benzanilide were obtained (melting point: 194°-197° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[C:30]([Br:32])[C:29]([OH:33])=[C:28]([Br:34])[CH:27]=1>C(OCCO)C>[Br:32][C:30]1[CH:31]=[C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:27]=[C:28]([Br:34])[C:29]=1[OH:33]
Reactant: Nc1cc(Br)c(O)c(Br)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cc(Br)c(O)c(Br)c3)c2cc1OC
Yield: 89.1 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 320.3 mg (1.2 mmol) of 4-amino-2,6-dibromophenol to give 427.1 mg (89.2%) of the product as a gray solid, m.p.>250° C., mass (electrospray, m/e): M+H 479.7, 481.6.
Reaction SMILES: [NH3:1].Br[CH2:3][CH2:4][N:5]=[C:6]([OH:22])[C:7]1[C:8](=[CH:12][C:13](=[C:17]([CH:21]=1)[C:18](=[NH:20])[OH:19])[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10]>CN(C)C=O>[NH2:1][CH2:3][CH2:4][N:5]=[C:6]([OH:22])[C:7]1[C:8](=[CH:12][C:13](=[C:17]([CH:21]=1)[C:18](=[NH:20])[OH:19])[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10]
Reactant: N=C(O)c1cc(C(O)=NCCBr)c(C(=O)O)cc1C(=O)O
Reactant: N
Solvent: CN(C)C=O
Product: N=C(O)c1cc(C(O)=NCCN)c(C(=O)O)cc1C(=O)O
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a stirred solution of liquid ammonia, 22 ml. (1.0 mole), in 200 ml. of dimethylformamide is added portionwise 3.2 g. (10 mmole) of N-(2-bromoethyl)pyromellitic diimide. The mixture is stirred at room temperature (23° C.) for 48 hours. Excess ammonia is removed by concentration under reduced pressure without heating. Several volumes of dilute aqueous sodium carbonate are added to the concentrate with ice bath cooling. The insolubles are collected, rinsed with water, cold methanol, and ethyl ether furnishing N-(2-aminoethyl)pyromellitic diimide.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[ClH:11].N([O-])=O.[Na+].[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CC(C)=O.O.[Cu]I>[Cl:11][CH:17]([CH2:18][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)[C:16]([O:20][CH3:21])=[O:19]
Reactant: C=CC(=O)OC
Reactant: Nc1ccc(CCO)cc1
Reactant: Cl
Agent: [Cu]I
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(Cl)Cc1ccc(CCO)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(4-Aminophenyl)ethanol (11 g, 81 mmol) and 32 ml conc HCl was dissolved in acetone and cooled to 0° C. Sodium nitrite (5.6 g, 81 mmol) in 20 ml water was added dropwise. The temperature was kept under 0° C. After one hour, methyl acrylate (70 g, 808 mmol) and CuI (1.6 g, 8 mmol) were added (<0° C.). The reaction mixture was stirred at room temperature overnight.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.Cl.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([C:42]2[CH:43]=[C:44]([NH2:47])[NH:45][N:46]=2)[CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:35]([O:34][C:32]1[CH:31]=[C:30]([C:42]2[CH:43]=[C:44]([NH:47][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:45][N:46]=2)[CH:29]=[C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:33]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)n[nH]1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Cl
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)n[nH]1

Procedure:
The named compound is prepared by substituting 5-(3,5-bis-benzyloxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.030 gms.) is reacted with 0.114 gms. of 5-(3,5-bis-benzyloxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride by refluxing in tetrahydrofuran (2.0 mL).
Reaction SMILES: N1C2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=C1.[H-].[Na+].[CH3:16]I.O.[CH3:19][N:20]([CH:22]=O)[CH3:21]>>[CH2:22]([N:20]1[C:19]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:21]1)[CH3:16]
Reactant: CN(C)C=O
Reactant: CI
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCn1ccc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 1H-indole-5-carboxylate (1.5 g) in DMF (30 mL) was added NaH (410 mg) at 0° C. The reaction mixture was warmed to 25° C., followed by stirring for 0.5 hours. Then, the reaction mixture was cooled to 0° C. again, and then methyliodide (1.38 mL) was added thereto. The reaction mixture was warmed to 25° C., followed by stirring for 3 hours. To the reaction liquid was added water (50 mL), followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, CHCl3:MeOH=100:0 to 98:2) to obtain methyl 1-ethyl-1H-indole-5-carboxylate (1465 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](O)[CH2:9]O>>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=[CH:8]1
Reactant: Nc1ccccc1
Reactant: OCCO
Product: c1ccc2[nH]ccc2c1
Temperature: 350 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
93.1 g (1 mole) of aniline and 6.2 g (0.1 mole) of ethylene glycol as well as 3.0 g of the above catalyst were introduced into a stainless steel autoclave having an inner volume of 200 ml. The inside of the autoclave was purged with nitrogen gas and then hydrogen gas was fed to a gauge pressure of 10 kg/cm2. The reaction was conducted under stirring, at 350° C. for one hour. The resulting reaction mixture was analyzed by gas chromatography. Thus, indole was obtained in a yield of 62.3% based on ethylene glycol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:21])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:42]1[C:46](=[O:47])[C:45]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:44]2[C:43]1=[O:52].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][CH2:9][C@@H:10]([O:21][N:42]1[C:43](=[O:52])[C:44]2=[CH:51][CH:50]=[CH:49][CH:48]=[C:45]2[C:46]1=[O:47])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H](CCOCc1ccccc1)COCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1O[C@@H](CCOCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1,4-dibenzyloxy-2-hydroxybutane (8 g, 28 mmol) in dry tetrahydrofuran (150 ml) was added triphenylphosphine (11 g, 42 mmol) and N-hydroxyphthalimide (6.8 g, 42 mmol). The solution was treated dropwise with diethyl azodicarboxylate (6.6 ml, 42 mmol). A dark red colouration appeared, gradually fading and the solution became warm. The solution was stirred at room temperature for 16 hours, then treated with additional triphenyl phosphine (2.25 g, 8.5 mmol) N-hydroxyphthalimide (1.35 g, 8.5 mmol) and diethyl azodicarboxylate (1.35 ml, 8.5 mmol). After stirring for an additional 24 hours at room temperature, the solvent was removed under reduced pressure and the residue dissolved in ethyl acetate-hexane 1:1 (100 ml) and refrigerated. A white solid crystallised out and was filtered off. The solution was evaporated to dryness and the residue dissolved in ethyl acetate-hexane 1:1 (50 ml) and refrigerated. After filtration, the filtrate was evaporated to dryness and the residue chromatographed on silica, eluting with ethyl acetate-hexane 1:2 to give (S)-N-(1,4-dibenzyloxybut-2-oxy)phthalimide (11 g, (91%), [α]25 -17.4° (c 0.8 in ethanol); IR: υmax
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1C=CC=CC=1.[CH:40](OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)(C)C.C(OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C=C.C(OC1C=C(CC(NC(C2C=C(OC)C=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C>>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:25]=[C:26]([CH3:40])[CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OC(C)C)c1)c1ccccc1N1CCCCC1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCc2ccccc2)c1)c1ccccc1N1CCCCC1
Agent: C=CCOc1cc(CC(=O)NC(CCC)c2ccccc2N2CCCCC2)ccc1C(=O)O
Agent: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1cc(OC)ccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(C=C(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
The mixing ratio of 75/25 is obtained from the corresponding ratio of intensities of the particularly characteristic signals in the 400 MHz-1H-NMR spectrum (CDCl3). The position of the signals is: 3-methyl-2-buten-1-yl compound: olefinic H: 5.25 (d), CH3 : 1.64 (s) and 1.77 (s). benzylic ##STR18## 6.00 (t), benzylic CH2 --; 3.52 ppm (s) 3-methyl-1-butyl compound: CH3 : 0.90 (d), benzylic ##STR19## 5.35 (m), benzylic --CH2 --: 3.54 ppm (s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[NH:18][C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.P(Cl)(Cl)([Cl:22])=O.CN(C)C1C=CC=CC=1>>[ClH:22].[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1Nc1nc2ccccc2c(=O)[nH]1
Solvent: CN(C)c1ccccc1
Product: Cc1ccccc1Nc1nc(Cl)c2ccccc2n1
Product: Cl
Yield: 95.5 %

Procedure:
2-(2-Methylphenylamino)-4-quinazolone (5.0 g, 0.0198 mol) was dissolved in phosphoryl chloride (20 ml, 0.216 mol) and N,N-dimethylaniline (3.5 ml, 0.025 mol) and refluxed for 3/4 hours. The reaction mixture was poured onto ice/N NaoH (100 ml) and the precipitate washed and dried to give 4-chloro-2-(2-methylphenylamino)quinazoline hydrochloride (5.79 g, 95%), used without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=1)=[O:7].[CH3:19][NH:20][CH2:21][CH2:22][OH:23].C=O.[C:26](O)(=O)C>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[C:12]([CH2:19][N:20]([CH2:21][CH2:22][OH:23])[CH3:26])[C:11]([OH:14])=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=1)=[O:7]
Reactant: CNCCO
Reactant: CC(C)(C)c1cc(C(=O)c2cccs2)ccc1O
Reactant: CC(=O)O
Agent: C=O
Solvent: CCO
Product: CN(CCO)Cc1cc(C(=O)c2cccs2)cc(C(C)(C)C)c1O
Yield: 79.5 %

Procedure:
3-(1,1-Dimethylethyl)-4-hydroxyphenyl 2-thienyl ketone (22.0 g) was dissolved in 440 ml of ethanol and heated to reflux for 6 hours with 12.7 g of N-methylethanolamine, 14.5 g of a 35% aqueous solution of formaldehyde and 50.8 g of acetic acid. After the reaction, the solvent was evaporated. A saturated aqueous solution of sodium bicarbonate was added to the residue and the mixture was extracted with chloroform three times. The extract was dried with magnesium sulfate, the solvent evaporated, and the resulting yellow oil subjected to a column chromatography (500 g of silica gel being used; eluates were (1) ethylacetate/n-hexane in 3:1 proportions and (2) the same in 1:1 proportion). The isolated and purified product was recrystallized from methanol/water to give 23.33 g of pale yellow crystals, m.p. 98°-100° C. (methanol/water).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:33](=[O:41])([O:37][CH:38]([CH3:40])[CH3:39])[O:34][CH2:35]Cl.[Na+].[I-].N1C=CC=CC=1>CN(C=O)C.O>[CH:38]([O:37][C:33]([O:34][CH2:35][O:29][C:28](=[O:30])[C@H:27]([OH:31])[CH2:26][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:32])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=1)=[O:18])=[O:41])([CH3:40])[CH3:39]
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Reactant: CC(C)OC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCOC(=O)OC(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 430 mmol), chloromethyl isopropyl carbonate (132 mg, 860 mmol), NaI (129 mg, 860 μmol) and pyridine (136 mg, 1.7 mmol) in DMF (5.0 mL) was stirred at 25° C. overnight. The mixture was then poured into water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=1:1) to yield the title compound as a colorless liquid (10 mg). LC-MS: 580 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.28 (d, J=6 Hz, 6H), 3.37-3.39 (m, 2H), 3.98 (s, 3H), 4.22-4.24 (m, 2H), 4.38-4.40 (m, 1H), 5.78-5.91 (m, 2H), 6.54 (s, 1H), 7.22-7.18 (t, J=9 Hz, 1H), 7.34-7.36 (m, 1H), 7.46-7.55 (m, 5H).