Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1([CH3:35])[CH2:34][O:33][CH2:32]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][C:31]2([CH3:35])[CH2:34][O:33][CH2:32]2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(C)COC2)c1OC
Temperature: 80 °C
Yield: 29.3 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.798 mmol) and 3-(bromomethyl)-3-methyloxetane (132 mg, 0.798 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (30 mg, 29%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([O:28]CC)=[O:27])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[CH:31]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCO3)cc1
Reaction time: 8 h
Yield: 32.5 %

Procedure:
Ethyl 8-[4-(2-butoxyethoxy)phenyl]-3,4-dihydro-1-benzoxocin-5-carboxylate (527 mg) was dissolved in THF (40 ml) and methanol (40 ml). Aqueous 1N sodium hydroxide solution (12.4 ml) was added to the solution and the resulting solution was stirred overnight. After neutralization with 1N hydrochloric acid at 0° C., the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from hexane-ethyl acetate to obtain colorless crystals of 8-[4-(2-butoxyethoxy)phenyl]-3,4-dihydro-2H-1-benzoxocin-5-carboxylic acid (160 mg).
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:19]>[OH-].[Na+].O>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:19])[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(-c2nsc(S)n2)c1
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2nsc(SN)n2)c1
Reaction time: 0.25 h

Procedure:
A solution of 2.2 g of 5-mercapto-3-(3-methoxyphenyl)-1,2,4-thiadiazole in 35 ml of 5% sodium hydroxide and a solution prepared by diluting 22 ml of 5.25% NaOCl solution to 35 ml with water were added dropwise simultaneously to 95 ml of ammonium hydroxide solution while maintaining the mixture at 0°. The resulting mixture was stirred for 15 minutes and the precipitated solid was collected, washed with water and dried (P2O5 /high vacuum) to give 1.76 l g of solid, m.p. 157°-160° C.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][C:2]=12.[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:14][CH:9]1[C:2]2=[N:1][CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8]1)(=[O:13])[CH3:12]
Reactant: [O-][n+]1cccc2c1CCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCc2cccnc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide and acetic anhydride was stirred for 30 minutes at 100° C. Concentrated and added DCM (30 mL). The organic layer was washed with Sat. NaHCO3. The organic layer was dried over sodium sulfate and filtered. The organic layer was concentrated in vacuo and purification of the crude material via Isco (3-5% Methanol/DCM) gave rise to the desired 6,7-dihydro-5H-cyclopenta[b]pyridine-7-yl acetate (900 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[F:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1ccccc1CBr
Product: N#Cc1ccc(N(Cc2ccccc2F)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 2-fluorobenzyl bromide
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(CCCn3ccnc3)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 69.1 %

Procedure:
A mixture of 3-(4-benzyloxyphenyl)propyl methanesulfonate (55.0 g), imidazole (17.6 g), potassium carbonate (35.7 g) and N,N-dimethylformamide (500 ml) was stirred for 6 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give 1-[3-(4-benzyloxyphenyl)propyl]imidazole (34.7 g, 69%). Recrystallization from ethyl acetate-hexane gave colorless needles, mp 80-81° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A slurry of 6.00 g(16.8 mmol) of 6-nitro-4-[(3-trifluoromethylphenyl)amino]-3-quinolinecarbonitrile and 18.9 g (83.3 mmol) of SnCl2 dihydrate in 240 mL of ethanol was refluxed under N2 for 1 h. After cooling to 25° C., the reaction was diluted with ice water, neutralized with sodium bicarbonate and stirred for 2 h. The product was extracted with chloroform, treated with Darco, dried(magnesium sulfate) and evaporated. The residue was filtered through silica gel(10% methanol in chloroform), evaporated and dried in vacuo(40° C.) to give 4.87 g of brown solid: mass spectrum (electrospray, m/e): M+H 329.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:38][N:39]([CH3:45])[C@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[C@H:40]1[CH2:44][CH2:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4[NH:16][C:17]([C:19]5[C:27]6[C:22](=[CH:23][C:24]([C:28]7[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=7[CH2:36][CH3:37])=[CH:25][CH:26]=6)[NH:21][N:20]=5)=[N:18][C:12]=4[CH2:11]3)=[O:9])=[N:6][CH:7]=2)[CH2:41]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CC[C@H](N(C)C)C5)cn3)C4)n[nH]c2c1
Yield: 41.4 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80 mg, 154 μmol) and (S)-3-dimethylaminopyrrolidine, (35 mg, 308 μmol) using the method of Example 32. The crude material was purified by HPLC Method C to afford (38 mg, 40%) of the title compound as off-white solid.
Reaction SMILES: CI.[I:3][C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][O:14][C:7]1[CH:6]=[CH:5][C:4]([I:3])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(I)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(I)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl iodide (0.29 ml, 4.68 mmol) was added to a mixture of 1.0 g (3.60 mmol) of methyl 5-iodosalicylate, 0.50 g (3.60 mmol) of potassium carbonate and 4 ml of dimethylformamide, and they were stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite and then after-treated in by an ordinary method to obtain the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:21][NH:20][CH2:19][CH2:18][C:11]=3[N:12]=[C:13]([NH:15][CH2:16][CH3:17])[N:14]=2)=[CH:5][CH:4]=1.I[CH2:23][CH3:24]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18][C:11]=3[N:12]=[C:13]([NH:15][CH2:16][CH3:17])[N:14]=2)=[CH:5][CH:4]=1
Reactant: CCI
Reactant: CCNc1nc2c(c(-c3ccc(Cl)cc3)n1)CNCC2
Agent: Cl
Product: CCNc1nc2c(c(-c3ccc(Cl)cc3)n1)CN(CC)CC2
Yield: 98.4 %

Procedure:
The title compound was prepared as described in Example 9 starting with 4-(4-chlorophenyl)-2-ethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (3.0 g, 9.3 mmol) and iodoethane (0.74 mL, 18.5 mmol) to produce 2.9 g (100%) of 4-(4-chlorophenyl)-6-ethyl-2- ethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. m.p. 129°-132° C. MS: 317 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:10])[C:8]=1[F:9])[NH2:5].Cl[CH2:12][CH2:13][OH:14]>C(O)C.[OH-].[Na+]>[OH:14][CH2:13][CH2:12][NH:5][C:4]1[CH:6]=[C:7]([CH3:10])[C:8]([F:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: OCCCl
Reactant: Cc1cc(N)cc(C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(NCCO)cc(C)c1F
Yield: 86.5 %

Procedure:
In a mixed solution of 100 ml of ethanol and 60 ml of a 2N-NaOH solution were dissolved 12.3 g of the 3,5-dimethyl-4-fluoroaniline and 81 g of 2-chloroethanol, and the resulting solution was subjected to reaction with refluxing for 3 hours. After completion of the reaction, the ethanol was distilled off and the residue was extracted with ethyl acetate, after which the extract was washed with water, dried and then concentrated to obtain 14 g of crude N-(2-hydroxyethyl)-3,5-dimethyl-4-fluoroaniline. Subsequently, this crude compound was dissolved in 100 ml of isopropanol, followed by adding thereto 15 g of iodoethane and 20 g of potassium carbonate, and the reaction was carried out with refluxing for 5 hours. After completion of the reaction, the solvent was distilled off and the residue was extracted with ethyl acetate, and the extract was washed with water, dried and then concentrated to obtain 16 g of a crude product of the desired compound. The crude product was purified by a column chromatography (packing; Wakogel C-300, a registered trade name, mfd. by Wako Pure Chemical Industries, Ltd., eluent: ethyl acetate : n-hexane =1 : 2) to obtain 9.5 g of oily N-ethyl-N-(2-hydroxyethyl)-3,5-dimethyl-4-fluoroaniline.
Reaction SMILES: [F:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(OCC)C.C([Li:21])(CC)C>CCCCCC>[F:1][C:2]1[C:7]([Li:21])=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: [Li]C(C)CC
Reactant: Fc1cc(F)c(F)c(F)c1F
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Temperature: -65 °C

Procedure:
Inside of a 100 ml volume glass three-neck flask equipped with a 50 mol volume glass dropping funnel, temperature resistor and septum rubber was sufficiently replaced with nitrogen. Into the flask, 5 g (29.8 mmol) of pentafluorobenzene and 30 ml of diethyl ether were charged, of which solution was cooled to -65° C. Thereafter, 14.2 g (34.3 mmol) of 15.5 wt. % hexane solution of sec-butyllithium charged into the dropping funnel were added dropwise while making the inner temperature not to exceed -55° C. After the completion of dropwise addition, the reaction mixture was kept at a temperature of -65°~-55° C. with stirring to give pentafluorophenyllithium. The yield of pentafluorobenzoic acid obtained by blowing of carbon dioxide into the prepared solution of pentafluorophenyllithium was 96.8% by means of gas chromatographic quantitative determination.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([C:15]1[C:16]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:17][C:18]([NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:39][OH:40])=[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[N:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1)#[N:14]>C1COCC1>[CH3:8][S:9]([O:40][CH2:39][C:30]1[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])=[N:32][C:33]2[N:24]([C:22](=[O:23])[NH:21][C:18]3[CH:17]=[C:16]([O:41][CH:42]([CH3:44])[CH3:43])[C:15]([C:13]#[N:14])=[CH:20][N:19]=3)[CH2:25][CH2:26][CH2:27][C:28]=2[CH:29]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COC(OC)c1nc2c(cc1CO)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1COS(C)(=O)=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (80 μL, 0.577 mmol) and methanesulfonyl chloride (38 μL, 0.488 mmol) were added to solution of N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 164, 194 mg, 0.439 mmol) in THF (7 ml) at 0° C. The reaction mixture was stirred for approximately 2.5 h at 0° C. and filtered to remove solid impurities. The solid residue was washed with THF and the filtrate was concentrated to yield the title compound as slight yellow resin which was used directly in the next step.
Reaction SMILES: [CH:1]1([N:4]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5](=[O:8])[CH2:6][CH3:7])[CH2:3][CH2:2]1.[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][NH:22][C:23](=[O:38])[NH:24][CH:25]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:26](O)=[O:27])[N:17]=[CH:16]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:1]1([N:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:26](=[O:27])[CH:25]([NH:24][C:23]([NH:22][CH2:21][CH2:20][C:18]3[N:17]=[CH:16][NH:15][CH:19]=3)=[O:38])[CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[CH2:11][CH2:10]2)[C:5](=[O:8])[CH2:6][CH3:7])[CH2:3][CH2:2]1
Reactant: CCC(=O)N(C1CCNCC1)C1CC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCC(=O)N(C1CC1)C1CCN(C(=O)C(Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
100 mg (0.51 mmol) of N-cyclopropyl-N-piperidin-4-ylpropionamide, 170 mg (0.51 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propanoic acid (cf. preparation 2-3), 108 mg (0.56 mmol) of EDC and 76 mg (0.56 mmol) of HOBT are dissolved in 5 mL of DMF under nitrogen. The mixture is stirred at room temperature overnight, and the solution is then washed with aqueous 5% citric acid solution and extracted with ethyl acetate. The organic phase is washed with aqueous 1N NaOH solution and then dried and evaporated. The crude product obtained is purified by preparative HPLC (conditions cf. page 38). 2 mg of N-cyclopropyl-N-{1-[2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]piperidin-4-yl}-propionamide are obtained in a yield of 8%.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=O)[CH2:4]1)[CH3:2].[CH3:10][Li]>CCOCC>[C:7]([CH:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6]1)(=[O:9])[CH3:10]
Reactant: [Li]C
Reactant: CCC1CC(C(=O)O)C1
Solvent: CCOCC
Product: CCC1CC(C(C)=O)C1
Reaction time: 3 h

Procedure:
A solution of 6.61 g of 3-ethylcyclobutane-1-carboxylic acid, in 52 ml of distilled ether was stirred under argon at 0°. Methyllithium (85.0 ml of a 1.53 M solution in ether) was added dropwise over a 30 minute period. The reaction mixture was stirred for three hours at 25°, then quenched with 7.3 water-methanol. The layers were separated, and the aqueous layer extracted with ether. The combined organic layers were washed with brine, dried, filtered and the solvents evaporated in vacuo. The resultant oil was distilled (aspirator vacuum) to afford 5.5 g of 1-acetyl-3-ethylcyclobutane, as a clear oil (bp 64°-67°). The material had the following spectral characteristics: nmr (CDCl3) δ 0.80 and 0.82 (3H total, pair of t, each J=7.0 Hz), 1.10 and 1.12 (ca. 1.5H total, pair of s, side product 1-[2-hydroxy-prop-2-yl]-3-ethylcyclobutane), 1.0-2.4 (7 H, m), 2.07 and 2.09 (3H total, pair of s) and 2.7-3.5 ppm (1H, m); ir (CHCl3) 935, 1175, 1370, 1460, 1705, 2870, 2930 and 2970 cm-1, also small 3200-3600 broad and 3600 cm-1 for the side product noted above.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22][CH3:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25].ClC1C=C(C=CC=1)C(OO)=[O:31].C(OCC)(=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:23])=[O:31])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: CSCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-methyl-3-{3-[(methylthio)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.740 g, 1.90 mmol) in methylene chloride is treated with 3-chloroperoxybenzoic acid (0.580 g, 60%, 2.00 mmol), stirred at room temperature for five minutes, diluted with additional methylene chloride, washed with 5% sodium carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and a 10% ethyl acetate in methylene chloride solution gives the title product as a white solid which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>CC(C)=O.O.CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:18])[NH:19][S:26]([CH3:25])(=[O:28])=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 2 h

Procedure:
To 10 mmol of (S)-N2-(benzyloxycarbonyl)-arginine suspended in a mixture of acetone/water 80/20 there is added, at 0° C., a sufficient amount of 4N sodium hydroxide solution to bring the pH of the reaction mixture to between 11 and 11.5. After stirring for 2 hours, there is then added a solution of methanesulphonyl chloride in acetone and then, after stirring for a further 3 hours, the mixture is neutralised using 1N hydrochloric acid solution; the acetone is then evaporated off, and the residue obtained is extracted with ether and then washed, dried, filtered and evaporated. The pale yellow oil thereby obtained is purified by chromatography over silica (eluant: dichloromethane/methanol 7/3) to yield the expected product in the form of a whitish meringue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C1COCC1.O.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reaction time: 1.5 h
Yield: 23.4 %

Procedure:
A solution of [1-(3,4-dichloro-phenyl)-1H-imidazol-4-yl]-methanol (10.8 g, 44.3 mmol) in a mixture of THF (270 ml) and H2O (30 ml) was treated with manganese(IV) oxide (5 g, 57.5 mmol) and the mixture was refluxed for 4 h. A second portion of manganese(IV) oxide (1.5 g) was added and reflux continued for 1.5 h. The mixture was filtered over Celite, and the residue was washed with MeOH. Toluene was added to the filtrate, and the H2O was removed azeotropically. The brown residue was taken up in CH2Cl2 and upon standing white crystals formed. Filtration afforded 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carbaldehyde (2.5 g, 25%). MS: m/e=240.0 (M+).
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>C(#N)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[O:10][CH:2]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6]
Reactant: c1nc[nH]n1
Reactant: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Solvent: CC#N
Product: CC(C)(CF)C(=O)C(Oc1ccc(Cl)cc1Cl)n1cncn1
Yield: 88.8 %

Procedure:
96.3 g (0.27 mol) of 1-bromo-1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 200 ml of acetonitrile and the solution was added dropwise to a boiling solution of 46 g (0.56 mol) of 1,2,4-triazole in 200 ml of acetonitrile. After heating the mixture under reflux for 20 hours, the solvent was removed in vacuo, the residue was taken up in methylene chloride, the methylene chloride mixture was washed several times with water and the organic phase was dried over sodium sulphate. After removing the solvent in vacuo, 83 g (89% of theory) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-2-butanone were obtained as an oil, which was further reacted directly. ##STR84##
Reaction SMILES: [Cl:1][C:2]12[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[CH:9][CH:3]1[C:4]([O:6][C:7]2=[O:8])=O.[NH2:16][CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:18][C:19]([OH:21])=[O:20]>C(O)(=O)C>[Cl:1][C:2]12[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[CH:9][CH:3]1[C:4]([N:16]([CH:17]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:18][C:19]([OH:21])=[O:20])[C:7]2=[O:8])=[O:6]
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Reactant: O=C1OC(=O)C2(Cl)C(Cl)=C(Cl)C(Cl)=CC12
Solvent: CC(=O)O
Product: COc1ccc(C(CC(=O)O)N2C(=O)C3C=C(Cl)C(Cl)=C(Cl)C3(Cl)C2=O)cc1
Yield: 91.2 %

Procedure:
A stirred mixture of 2,3,4,5-tetrachlorophthalic acid anhydride (2.85 g, 10.0 mmol) and 3-amino-3-(4'-methoxyphenyl)propionic acid (1.95 g, 10.0 mmol) in 25 mL of acetic acid under nitrogen was heated to reflux for 4.5 hours. Solid formed as the reaction mixture cooled. The resulting slurry was filtered and the solid dried in vacuo (60° C., <2 mm) to afford 4.24 g (92%) of 3-(2,3,4,5-tetrachlorophthalimido)-3-(4'-methoxyphenyl)propionic acid as an off-white solid contaminated with ~ 1% acetic acid: mp 235.6°-238° C.; 1H NMR (DMSO-d6) δ 12.44 (br s, 1H, COOH), 7.36 (d, J=8.7 Hz, 2 H), 6.90 (d, 1 H, J=8.7 Hz), 5.64 (m, 1 H), 3.72 (s, 3 H), 3.35 (m, 2 H); 13C NMR (DMSO-d6) δ 171.5, 163.0, 158.8, 138.4, 129.9, 128.6, 128.2, 127.6, 113.8, 55.0, 50.2, 35.6. Anal. Calcd for C18H11NO5Cl4. Theory: C, 46.68; H, 2.39; N, 3.02. Found: C, 46.58; H, 2.31; N, 2.91.