Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:27])[CH2:12][O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([O:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)C.O>[CH3:10][CH:11]([CH3:27])[CH2:12][O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([O:23][C:24](=[O:25])[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:20]=[CH:21][CH:22]=1)=[O:15]
Reactant: CC(C)COC(=O)Nc1cccc(OC(=O)Cl)c1
Reactant: CNc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)COC(=O)Nc1cccc(OC(=O)N(C)c2ccc(Cl)cc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 14.2 g (0.1 mole) 4-chloro-N-methylaniline in 100 ml acetic acid ethyl ester is mixed with 50 ml water. Then a solution of 27.2 g (0.1 mole) chloroformic acid-3-(2-methylpropoxycarbonylamino)-phenyl ester in 100 ml acetic acid ethyl ester and simultaneously a solution of 13.8 g (0.1 mole) potassium carbonate in 50 ml water is added in drops within 20 minutes while agitating and cooling to 10° to 15° C. Agitation is continued at 15° C. for another 30 minutes. Then the organic phase is separated, washing at 0° C. with dilute soda lye, dilute hydrochloric acid and water. Drying with magnesium sulfate is followed by evaporation under reduced pressure. Recrystallization from acetic acid ethyl ester/pentane.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13]1
Reactant: CC1(C(=O)O)CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)O)CCCN(c2ccncc2[N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
4-chloro-3-nitropyridine (1.1 eq) was added to a solution of 3-methylpiperidine-3-carboxylic acid (1 eq) and DIEA (3 eq) in iPrOH (0.1 M). The reaction mixture was heated in a 60° C. oil bath for 3 h then concentrated in vacuo. The crude residue was diluted with EtOAc and washed with 1.0 N NaOH. The combined aqueous washes were acidified to pH=4 with 1.0 N HCl and extracted with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 3-methyl-(3-nitropyridin-4-yl)piperidine-3-carboxylic acid. LC/MS (m/z): 266.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=O)[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.C([O-])(=O)C.[N+:25]([CH3:28])([O-:27])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=[CH:28][N+:25]([O-:27])=[O:26])[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: COc1ccc2c(n1)c(C=O)c1n2Cc2ccccc2-1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Product: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2Cc2ccccc2-1

Procedure:
600 mg (2.27 mmol) of the compound obtained in Step E dissolved in 25 ml of nitromethane are heated at 120° C. for 3 hours in the presence of 440 mg (5.67 mmol) of animmonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation of the organic phase yields the title compound in the form of a yellow solid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17]O)[CH3:14]>>[C:1]([O:12][CH2:14][CH2:13][N:15]([CH2:19][CH3:20])[CH2:16][CH3:17])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCN(CC)CCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(diethylamino)ethanol as starting materials to give the aimed compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[Br:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=[O:25]>>[Br:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([CH:24]([OH:25])[C:9]#[C:8][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1ccc(C=O)c(OC)c1Br
Product: COc1ccc(C(O)C#Cc2ccccc2)c(OC)c1Br
Yield: 59 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 3-bromo-2,4-dimethoxy-benzaldehyde (0.80 g, 3.26 mmol) [prepared as described in Helv. Chim, Acta, 1990, 73, 48], was reacted to give the title compound (0.67 g, 59%). 1H NMR (400 MHz, DMSO-d6): δ 7.67-7.62 (d, 1H), 7.45-7.35 (m, 5H), 7.01-6.96 (d, 1H), 6.14-6.11 (d, 1H), 5.78-5.74 (d, 1H), 3.88-3.84 (m, 6H).
Reaction SMILES: Cl[C:2](=[CH2:12])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[OH-].[Na+].Cl>CN(C)C=O>[C:6]1([CH:4]([CH2:3][C:2]#[CH:12])[OH:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C(Cl)CC(O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C#CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.3 %

Procedure:
40.00 Grams of the 2-chloroallylphenylcarbinol obtained above were dissolved in 400 g of N,N-dimethylformamide, and 17.52 g of sodium hydroxide in a flake form were added. The mixture was stirred at 25° C. for 7 hours. After the reaction was completed, the reaction mixture was neutralized with concentrated hydrochloric acid, and insolubles were filtered off. The filtrate was concentrated under reduced pressure, and then the concentration residue was subjected to extraction with toluene, washed with a 7% sodium carbonate aqueous solution and dried over sodium sulfate. The desiccant was filtered off, and the toluene was distilled off under reduced pressure. The resultant oily substance was distilled under reduced pressure to give 30.84 g of phenylpropargylcarbinol. The results were as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[C:20](Cl)(=[O:22])[CH3:21]>C1COCC1>[C:20]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
6-Nitroindoline (3.0 g, 18.3 mmol) is dissolved in THF (45 mL) and Et3N (3.4 mL, 24.4 mmol) at 0° C. Acetyl chloride (1.5 mL, 21 mmol) is added dropwise. The mixture is stirred at room temperature for 30 minutes. The mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated to yield 1-acetyl-6-nitroindoline (3.8 g, 100%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][OH:13])=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[OH:13][CH2:12][CH2:11][C:10]1[CH:14]=[CH:15][C:7]([NH:6][C:3](=[O:4])[O:2][CH3:1])=[CH:8][CH:9]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(CCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc(CCO)cc1
Yield: 34.3 %

Procedure:
9.45 g (0.1 mole) methylchloroformate was added to a solution of 13.72 g (0.1 mole) p-aminophenethyl alcohol and 8.4 g (0.1 mole) pyridine in dichloromethane at 0° C. The reaction was stirred between 0° C. and room temperature, and when completed, poured onto ice water and the product was extracted with ethyl acetate, dried and the solvent was evaporated in vacuo to give 6.7 g (yield 34.7%) of methyl N-[4-(2-hydroxyethyl)phenyl]carbamate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([CH2:19]O)=[CH:16][C:15]=2[CH:21]=1.CCN(C(C)C)C(C)C.S(Cl)([Cl:33])=O>C(Cl)Cl>[Cl:33][CH2:19][C:17]1[O:18][C:14]2[CH:13]=[CH:12][C:11]([O:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:21][C:15]=2[CH:16]=1
Reactant: OCc1cc2cc(Oc3nc4ccccc4s3)ccc2o1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: ClCc1cc2cc(Oc3nc4ccccc4s3)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of [5-(benzothiazol-2-yloxy)-benzofuran-2-yl]-methanol (55 mg, 0.19 mmol) and DIEA (0.042 mL, 34 mg, 0.24 mmol) in DCM (0.8 mL) was added thionyl chloride (0.017 mL, 26 mg, 0.22 mmol) and the resulting mixture was stirred (rt, 2 h). The reaction mixture was concentrated under a stream of nitrogen to afford the title compound (50 mg, 100%). MS (ESI): mass calcd for C16H10NO2SCl, 315.0; m/z found 316.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([N+:22]([O-])=O)[CH:7]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:22][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Yield: 92 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate (8.53 g, 24.8 mmol) and Pd/C (10%, 0.85 g) in EtOAc (150 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate as an oil (7.15 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 6.15 (s, 1H), 5.60 (br, 2H), 4.30 (q, 2H), 4.13 (t. 2H), 4.08 (t, 2H), 3.78 (t, 2H), 3.73 (t. 2H), 3.45 (s, 6H), 1.36 (t, 3H); LC-MS (ESI) m/z 314 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1)=[O:3].[CH:12]1([C:15](O)=[O:16])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH:11][C:15]([CH:12]2[CH2:14][CH2:13]2)=[O:16])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: O=C(O)C1CC1
Reactant: CC(=O)c1ccc(F)c(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(F)c(NC(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
To a round, bottom flask was added 3-amino-4-fluoroacetophenone (Method 64, 1 g, 6.54 mmol), cyclopropyl carboxylic acid (0.62 ml, 7.84 mmol), HATu (2.5 g (6.57 mmol), and DIEA (2.3 ml, 13.08 mmol) in DMF (15 ml). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with water and partitioned with EtOAc. The layers were cut, followed by an additional wash of the aqueous with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue obtained was then purified by silica gel chromatography (Biotage Horizon System) using a gradient elution of 5-15% EtOAc in DCM to give 458 mg of the title compound (32% isolated yield). 1H NMR: 10.16 (s, 1H) 8.53 (dd, J=7.91, 2.26 Hz, 1H) 7.67-7.82 (m, 1H) 7.40 (dd, J=10.55, 8.67 Hz, 1H) 2.54 (s, 3H) 1.95-2.09 (m, 1H) 0.78-0.88 (m, 4H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CCN(CC)CC>C(Cl)Cl.[Cu]I>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#CCCCCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC#Cc1cncc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c1
Yield: 93 %

Procedure:
A mixture of 3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-5-bromopyridine (300 mg, 0.84 mmol), 1-octyne (0.2 mL, 1.4 mmol), Pd(PPh)3Cl2 (12 mg), CuI (catalytic amount) and NEt3 (2.45 mL) in CH2Cl2 (7 mL) was heated at reflux for 16 h. The solvent was removed, and the residue was washed with 10% NaOH then extracted with CH2Cl2. The organic extract was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3/MeOH, 10:1) to afford the title compound (302 mg) that contaminated with starting material.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[NH2:23].[N:24](OCCC(C)C)=O>C(Cl)(Cl)Cl.C(O)(=O)C>[NH:23]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]3[N:9]=[C:10]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[C:11]4[S:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:4]=2)[CH:1]=[N:24]1
Reactant: Cc1ccc(-c2nc(N3CCOCC3)c3sccc3n2)cc1N
Reactant: CC(C)CCON=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: c1cc2nc(-c3ccc4cn[nH]c4c3)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-methyl-5-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine (99 mg) in chloroform (10 mL) and acetic acid (2 mL) was added isoamyl nitrite (44 μL). The reaction mixture was stirred for 2 days at room temperature. The mixture was then quenched with sodium bicarbonate solution and extracted in to chloroform and reduced in vacuo. The residue was purified using flash chromatography to yield 229. MS: ESI MH+ 338
Reaction SMILES: C(Cl)(=O)C.[CH:5]1([O:8][C:9]2[CH:10]=[C:11]([C:19]3[NH:36][C:22]4[CH:23]=[N:24][N:25](COCC[Si](C)(C)C)[C:26](=[O:27])[C:21]=4[C:20]=3[CH2:37][O:38][CH3:39])[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH2:7][CH2:6]1.C[O-].[Na+]>CO>[CH:5]1([O:8][C:9]2[CH:10]=[C:11]([C:19]3[NH:36][C:22]4[CH:23]=[N:24][NH:25][C:26](=[O:27])[C:21]=4[C:20]=3[CH2:37][O:38][CH3:39])[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:17])[F:18])[CH2:6][CH2:7]1
Reactant: COCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Product: COCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
To 8 ml of methanol was added 1.3 ml (18.3 mmol) of acetyl chloride, and the mixture was stirred at 50° C. for 15 minutes, and then, cooled to room temperature. To the solution was added 140 mg (0.276 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methoxymethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 11-(b), and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, to the reaction mixture were successively added 18.4 ml of methanol solution containing 1M sodium methoxide and then water, and the mixture was extracted with a mixed solvent (chloroform:methano1=9:1 (UV)). The organic layer after separation of liquids was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Water was added to the obtained concentrate, and precipitated solid was collected by filtration and dried under reduced pressure to obtain 58 mg of the title compound as a white solid.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)[C:10]1[CH:15]=[CH:14]C=[CH:12][CH:11]=1.B(F)(F)F.CCOCC>>[F:1][CH:2]([F:8])[C:3]([O:5][CH2:6][C:7]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C(F)F
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C(F)F
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a dried round bottom flask was added ethyl 2,2-difluoroacetate (25 g, 0.20 mol), benzyl alcohol (62.6 mL, 0.60 mol) and boron trifluoride etherate (2.5 mL, 0.02 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 75° C. overnight. The mixture was quenched with saturated aqueous NaHCO3, and then diluted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give benzyl 2,2-difluoroacetate. 1H-NMR: 400 MHz, (CDCl3) δ 7.39-7.29 (m, 4H), 5.93 (t, J=52.8 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[O:28]=[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCCCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of 25.2 g (0.142 mol) of (S)-(-)-4-benzyl-2-oxazolidinone (Aldrich Chemical Company) in 300 mL of THF cooled to -78° C. was added 97.0 mL (0.155 mol) of 1.6M n-butyllithium. The reaction mixture was stirred at -78° C. for 1 hour and nonanoyl chloride (17.4 g, 0.129 mol), dissolved in 75 mL of THF, was then added. The resulting mixture was stirred at -78° C. for 3 hours and then quenched with 5% HCl solution. The resulting mixture was extracted with ether and the combined organics were washed with water, saturated sodium bicarbonate and brine. The organics were then dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate/hexanes (1:10), to provide 24.75 g (78%) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:34]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CO[C@H]1CC[C@H](CCNS(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CO[C@H]1CC[C@H](CCN(C(=O)c2ccccc2)S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C

Procedure:
To an ice-cold mixture of 4.0 g. (10 mMol) ethyl trans-4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-cyclohexyloxyacetate, 50 ml. methylene chloride and 1.5 g. (15 mMol) triethylamine is added dropwise a mixture of 1.4 g. (10 mMol) benzoyl chloride and 30 ml. methylene chloride. The reaction mixture is maintained for 4 hours at reflux temperature, cooled, filtered and the filtrate washed with dilute hydrochloric acid and water. It is then dried with anhydrous sodium sulphate and evaporated After purification over silica gel/ cyclohexane/diethyl ether (2:1 v/v), there is obtained a yield of 1.7 g (67% of theory); m.p. 81°-82° C.
Reaction SMILES: [CH2:1]1[CH2:22][O:21][CH:3]([CH2:4][C@H:5]2[C@H:12]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH2:11][C@H:10]3[C@@H:6]2[CH2:7][C:8](=[O:20])[O:9]3)[O:2]1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]1[CH2:22][O:21][CH:3]([CH2:4][CH:5]2[CH:12]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH2:11][CH:10]3[CH:6]2[CH2:7][CH:8]([OH:20])[O:9]3)[O:2]1
Reactant: O=C1C[C@@H]2[C@@H](CC3OCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC1CC2C(CC(OC3CCCCO3)C2CC2OCCO2)O1

Procedure:
The ether (57) (4.700 g) was reduced in toluene (80 ml) at -78° C. with diisobutylaluminum hydride (1.5-M, 12 ml) to give the lactol (58).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:41]3[CH:42]=[CH:43][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (100 mg, 0.17 mmol) was treated as described in general procedure G using 4-trifluoromethylphenylboronic acid to provide 5-{4-[4-(2,4-dichloro-phenyl)-2-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)CO>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Yield: 58.9 %

Procedure:
To a solution of p-nitrobenzyl chloride (5.2 g, 10mM) and 3.2 g of triethylamine in 30 ml of ethylene glycol is added a solution of N-methylpiperazine (3 g, 30 mM) in 20 ml of ethylene glycol. After complete addition, the resulting solution is heated to 80° C. under nitrogen for 30 minutes. The reaction mixture is quenched into aqueous 10% sodium carbonate solution and extracted with methylene chloride. The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 4.15 g (59%) of 1-methyl-4-[(4-nitrophenyl)methyl]piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH2:35][C@@H:36]([C:44]([OH:46])=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:35][C@@H:36]([C:44]([OH:46])=[O:45])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:24])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N[C@H](Cc2ccccc2)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.2 %

Procedure:
To a solution of p-nitrophenyl 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoate (4.73 g, 10 mmol) and D-phenylalanine (1.65 g, 10 mmol) in N,N-dimethylformamide (30 ml), was added triethylamine (1.4 ml, 10 mmol). The mixture was stirred at room temperature for 2 days, whereupon the insoluble matter almost disappeared. The solvent was distilled off under reduced pressure and the residue was chromatographed on a column of silica gel (100 g). The column was washed well with chloroform and elution with chloroform-methanol-acetic acid (18:2:1, v/v) gave 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-D-phenylalanine (2.56 g), melting at 96°-98° C., after washing up in the usual way.