Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[I-].[Li+]>C(OCC)(=O)C>[C:33]([O:32][C:30]([NH:29][CH2:28][CH2:27][CH2:26][C:25]#[C:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:6]2[CH2:7][CH2:8][S:9][C:10]([CH3:12])([CH3:11])[CH:5]2[C:3]([OH:4])=[O:2])(=[O:15])=[O:14])=[CH:17][CH:18]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCCNC(=O)OC(C)(C)C)cc2)CCSC1(C)C
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)O)cc1
Yield: 56.2 %

Procedure:
A solution of 0.764 g (1.41 mmol) of methyl4-{[4-({6-[(tert-butoxycarbonyl)amino]-2-hexynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate and 3.77 g (28.2 mmol) of lithium iodide in 30 mL of ethyl acetate was heated to reflux for 18h. The resulting reaction was acidified, washed with water, an aqueous solution of Na2S2O3 , brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0.5% methanol/dichloromethane to provide 0.417 g (56%) of 4-{[4-({6-[(tert-butoxycarbonyl)amino]-2-hexynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylic acid as a white solid. Electrospray Mass Spec: 527.2(M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])(=[O:17])=[O:16])=[O:13])[N:4]=1.[Cl-].Cl[CH:27]=[N+:28]([CH3:30])[CH3:29]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]=[CH:27][N:28]([CH3:30])[CH3:29])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2N=CN(C)C)n1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
A mixture of 0.80 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-aminobenzenesulfonamide, 0.29 g of [chloromethylene]dimethylammonium chloride and 8 ml of DMF is stirred at room temperature until the reaction has ended. The volatile components are distilled off under reduced pressure and the residue is washed with water and methyl acetate, affording 0.28 g of the desired product. Melting point: 209-210° C. (decomp.)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:9][CH2:8][CH:7]1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([Cl:29])[CH2:27][CH3:28]>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:9][CH2:8][CH:7]1[C:10](=[O:18])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:28][CH2:27][CH2:26][Cl:29])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC1C(=O)c1ccc(O)cc1
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCC1C(=O)c1ccc(OCCCCl)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 2-(4-hydroxy-benzoyl)-cyclobutanecarboxylic acid ethyl ester (0.55 g, 2.20 mmol) in acetone (10 mL) was added potassium carbonate (0.91 g, 6.58 mmol) and 1-bromo-chloropropane (0.26 mL, 2.63 mmol). After overnight stirring at 70° C., the reaction was filtered, partitioned between dichloromethane/water, washed with brine, dried over sodium sulfate, and concentrated. The product was purified using a Single Step column (9:1 hexanes:ethyl acetate) to obtain 0.30 g (42%); MS m/z 325 (M+H).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccc(F)cc12
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-5-fluoro-3-methyl-1-benzofuran (400 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (355 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4), the title object compound (303 mg, 46%) was obtained as a pale-yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: COc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)c(O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a stirred suspension of N-[3-methoxy-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (0.75 g, 1.9 mmol) in dry methylene chloride (22 mL) was added boron tribromide (3.8 mL of a 1.0M solution of boron tribromide in methylene chloride, 3.8 mmol). The resulting solution was stirred at room temperature for 3 hours, diluted with methylene chloride (50 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to yield an off-white foam. Purification by flash column chromatography (10% to 30% v/v ethyl acetate in methylene chloride) yielded the title propanamide as a white solid (0.34 g, 46%); mp 155°-156° C. 1H-NMR (250 MHz, d6-DMSO): 1.58 (s, 3H, CH3) 7.30 (dd, 1H, J=8.8,1.8 Hz, aromatic) 7.48 (s, 1H, OH) 7.51-1.66 (m, 4H, aromatic) 7.80-7.86 (m, 3H, aromatic) 10.19 (s, 1H, NH) 10.60 (s, 1H, OH). MS (CI, CH4): 390 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[C:39]([CH3:45])=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH:29]2[CH2:35][CH2:34][CH:33]1[CH2:32][N:31]([C:36]([C:38]1[C:39]([CH3:45])=[N:40][C:41]([NH:44][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:42][CH:43]=1)=[O:37])[CH2:30]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: Cc1nc(N)ccc1C(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Product: Cc1nc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)ccc1C(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Yield: 26.8 %

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (127 mg, 0.433 mmol, 1.0 eq) was combined with 3-(6-Amino-2-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (180 mg, 0.520 mmol, 1.2 eq) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-methyl-pyridine-3-carbonyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70 mg) in 27% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 10H) 1.61 (t, J=8.34 Hz, 1H) 1.68-1.81 (m, 2H) 1.81-1.93 (m, 1H) 1.95-2.18 (m, 7H) 2.48 (br. s., 2H) 2.56 (d, J=8.59 Hz, 3H) 2.62 (br. s., 1H) 3.09 (d, J=7.58 Hz, 1H) 3.18 (s, 7H) 3.26-3.36 (m, 1H) 3.40 (br. s., 1H) 4.17 (br. s., 1H) 4.37 (br. s., 1H) 4.58 (d, J=13.14 Hz, 1H) 4.74-4.89 (m, J=9.09, 8.84, 8.72, 8.72 Hz, 1H) 6.48 (s, 1H) 7.50 (br. s., 1H) 8.11 (br. s., 1H) 8.38 (d, J=8.08 Hz, 1H) 8.76 (s, 1H). HRMS m/z, (M+H)+: 603.3417.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45].N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
To a solution of t-butyl 4-hydroxypiperidine-1-carboxylate (250 mg, 1.242 mmol) was added triphenylphosphine (326 mg, 1.242 mmol) and 2-hydroxyisoindoline-1,3-dione (203 mg, 1.242 mmol). After stirring at rt for 10 min, (E)-diisopropyl diazene-1,2-dicarboxylate (251 mg, 1.242 mmol) was added. After stirring at 30° C. overnight, the reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, washed with NH4Cl (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column with gradient hexanes:EtOAc to give the title compound as a colorless oil (252 mg, 59%). LCMS (method B): [MNa]+=369, tR=2.59 min.
Reaction SMILES: [N:1]1([C:6]2[N:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH:5]=[N:4][CH:3]=[N:2]1>O.N.CO.[Ni]>[N:1]1([C:6]2[C:7]([CH2:8][NH2:9])=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#Cc1cccnc1-n1cncn1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: NCc1cccnc1-n1cncn1
Temperature: 25 °C
Reaction time: 11 h
Yield: 91.6 %

Procedure:
A catalytic amount of Raney 2800 nickel in water (Aldrich; withdrawn as a wet slurry with the tip of a spatula) was added under air to a translucent slurry of 2-[1,2,4]triazol-1-yl-nicotinonitrile (1.053 g, 6.16 mmol), as prepared in the previous step, in 2 M NH3/MeOH (50 mL). The flask was then sealed with a septum, the air was removed from the system, and the flask was flushed with H2 gas under balloon pressure. The reaction was stirred at rt under H2 for 11 h (TLC showed no starting material remained), and the bulk of the Raney nickel was then removed with a magnet. The translucent white reaction mixture was then diluted with DCM (50 mL), filtered, and the translucent filtrate was concentrated under vacuum to provide the title compound as a beige crystalline solid (988 mg, 92%).
Reaction SMILES: [C:1]([CH:9]([CH2:13]OC)[CH2:10][O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.O>[C:1]([C:9]([CH2:10][O:11][CH3:12])=[CH2:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(COC)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C=C(COC)C(=O)c1ccccc1
Reaction time: 5 h
Yield: 73 %

Procedure:
An 84 g sample of 91% pure 2-benzoyl-1,3-dimethoxy propane 1 was heated with 4.2 g (5 wt %) of p-toluene sulfonic acid (p-TSA) to 80° with stirring. After 5 hr. a second 4.2 g sample of p-TSA was added. A third p-TSA addition of 2 g was made after another 5 hr. This mixture was left stirring for 6.5 hrs longer and then cooled. The reaction mixture was diluted with ml of Et2O and 100 ml H2O added. This mixture was then neutralized to pH=6-7 with dilute Na2CO3 and the organic layer dried over MgSO4. Filtration and removal of the ether in vacuo left an orange liquid, 2, which was distilled at 0.1 mm and 76° C. Yield: 73%. Purity: 93%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N+:5]([O-:24])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(Cl)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 14 mL of a chloroform solution containing 0.90 g of 4-chloro-7-trifluoromethylquinoline, 1.04 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was added with 15 mL of an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow solid, 4-chloro-7-trifluoromethylquinoline N-oxide.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:31]>CO>[CH2:29]([O:28][CH2:27][C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:31])[C:11]=2[N:12]=1)[CH3:30]
Reactant: N
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2cccnc2)no1
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2cccnc2)no1
Yield: 45 %

Procedure:
A slurry of 4-chloro-2-(ethoxymethyl)-1-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.52 g, 3.62 mmol) in a solution of 7 M ammonia in methanol (15 mL) was heated at 150° C. for 20 hours in a Parr pressure vessel. The volatiles were removed under reduced pressure and the resulting residue was partitioned between dichloromethane and 1 M aqueous sodium hydroxide. The aqueous layer was extracted with several portions of dichloromethane. The organic phases were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution 10% to 30% CMA/chloroform) to yield 2-(ethoxymethyl)-1-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine (653 mg, 45%) as white powder that was dried under vacuum at 70° C., mp 240.0-242.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (d, J=1.7 Hz, 1H), 8.64 (dd, J=3.2, 1.6 Hz, 1H), 8.16-8.20 (m, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.41-7.50 (m, 2H), 7.17 (t, J=7.0 Hz, 1H), 6.97 (s, 1H), 6.17 (s, 2H), 5.75 (s, 2H), 4.88 (s, 2H), 3.50 (q, J=7.0 Hz, 2H), 0.98 (t, J=7.0, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(OC)cc3)CC2)ccc1Cl
Yield: 60 %

Procedure:
The title compound (24 mg, 60%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-methoxybenzoyl chloride. MS: 403.4(MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:8](=[O:10])[N:7]3[CH2:11][CH2:12][CH2:13][CH2:14][C:6]3=[N:5][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:18]([N:1]1[C:9]2[C:8](=[O:10])[N:7]3[CH2:11][CH2:12][CH2:13][CH2:14][C:6]3=[N:5][C:4]=2[N:3]=[CH:2]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCI
Reactant: O=c1c2[nH]cnc2nc2n1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cnc2nc3n(c(=O)c21)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
After 1.20 g (6.32 mmol) of Compound 24 obtained in Example 24 was suspended in 20 ml of dimethylformamide, 0.265 g (6.63 mmol) of 60% sodium hydride was added to the suspension at 0° C. After 30 minutes, 0.755 ml (6.63 mmol) of iodobutane was added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent; chloroform:methanol=40:1) to afford 1.10 g (70.8%) of Compound 26 as white crystals.
Reaction SMILES: Cl[C:2]([CH2:4][C:5]([CH3:50])([CH3:49])[CH2:6][C:7]([O:9][CH:10]([CH2:30][O:31][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:11][O:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:8])=[O:3].[CH:51]1[C:56]([Cl:57])=[CH:55][C:54]([OH:58])=[C:53]([O:59][C:60]2[CH:61]=[CH:62][C:63]([Cl:67])=[CH:64][C:65]=2[Cl:66])[CH:52]=1.N1C=CC=CC=1>C(Cl)Cl>[C:32]([O:31][CH2:30][CH:10]([CH2:11][O:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:9][C:7]([CH2:6][C:5]([CH3:49])([CH3:50])[CH2:4][C:2]([O:58][C:54]1[CH:55]=[C:56]([Cl:57])[CH:51]=[CH:52][C:53]=1[O:59][C:60]1[CH:61]=[CH:62][C:63]([Cl:67])=[CH:64][C:65]=1[Cl:66])=[O:3])=[O:8])(=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CC(C)(C)CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
A mixture of 2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl 4-chloroformyl-3,3-dimethylbutyrate (F) (1.5 g.), triclosan (0.4 g.) and pyridine (0.17 ml.) in methylene chloride (35 ml.) was stirred at 0°-5° C. for 3 hours and then allowed to attain ambient temperature during 45 hours. The methylene chloride was evaporated and replaced by ether (50 ml.). The mixture obtained was washed successively with water (3×20 ml.), 2M hydrochloric acid (25 ml.), saturated sodium hydrogen carbonate solution (2×20 ml.) and water (2×20 ml.), and then dried (MgSO4) and evaporated. The oil obtained crystallised on treatment with ethanol to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 4-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxycarbonyl]-3,3-dimethylbutyrate as white crystals (0.3 g.), (m.p. just below 20° C.); NMR (CDCl3): 0.7-1.0 (6H, m, CH3CH2), 1.12 (6H, s, CCH3), 1.15-1.7 (52H,m, CH2), 2.17 (4H, m, CH2CH2CO), 2.44 (2H,s, CH2CO2CH), 2.60 (2H, s, aromatic O.CO CH2), 3.9-4.4 (4H, m, CH2O), 5.1-5.4 (1H, m, CH2CO2CH), 6.9-7.5 (6H, m, aromatic H)ppm.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Li]CCCC.[C:19]([Si:23]([O:26][C@@H:27]1[CH2:31][C@@H:30]([CH2:32]I)[CH2:29][C@H:28]1[F:34])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[Si:23]([O:26][C@H:27]1[C@H:28]([F:34])[CH2:29][C@H:30]([CH2:32][C@H:7]2[C:6]([O:12][CH3:13])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]2)[CH2:31]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)C[C@H]1F
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@H]1C[C@@H](F)[C@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.2 g, 1.5 equiv.) in dry THF (30 mL) was cooled to −78° C. n-BuLi (1.6 M in Hexane, 4.08 mL, 1.5 equiv.) was added dropwise. After stirring 1 h at −78° C., a solution of (±)-tert-butyl((1r,2R,4R)-2-fluoro-4-(iodomethyl)cyclopentyloxy)dimethylsilane (1.56 g, 4.36 mmol) in dry THF (8 mL) was added dropwise. The mixture was stirred another 2 h at −78° C. The mixture was warmed up to rt slowly, quenched by sat. NH4Cl solution (30 mL), extracted by diethyl ether (2×150 mL). The combined organic layers were washed by brine (30 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (40 g column, 0˜25% EtOAc in Hexanes) to afford (2S,5R)-2-(((1r*,3R*,4R*)-3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentyl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.81 g, quant. yield) as a clear oil. MS ESI +ve m/z 415 (M+1).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:18])[CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:18][C:11]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH:15]=[C:10]1[CH3:9]
Reactant: CC1=CC(=O)C(C)=CC1=O
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(C)C(=O)C=C1C
Yield: 87 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,5-dimethyl-p-benzoquinone in 3 mL of THF was added 15 dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.65 g of the desired product (yield 87%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:19])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[C:6]=1[Cl:7].[Mg+2].[Cl-].[Cl-].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:19])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([OH:18])([C:27]3[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=3)[CH2:14][CH2:13]2)[C:6]=1[Cl:7]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: Cc1nc(Cl)c(Cl)n1CCCCN1CCC(=O)CC1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCN(CCCCn3c(C)nc(Cl)c3Cl)CC2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 1.0 g (3.3 mmol) of 4,5-dichloro-2-methyl-1-[4-(4-oxo-1-piperidyl)butyl]-1H-imidazole in 10 ml of anhydrous tetrahydrofuran is added to a suspension of 1.08 g (11.4 mmol) of MgCl2 in 15 ml of anhydrous THF at -40° C. and under a nitrogen atmosphere. The mixture is stirred for 5 minutes and then, at -40° C., 6.8 ml of a 1.0M solution of 4-methylphenylmagnesium bromide are added. The resulting suspension is stirred for 15 minutes at -40° C. and for 3 hours at room temperature. An aqueous ammonium chloride solution is then added and the tetrahydrofuran is evaporated. The resulting aqueous phase is extracted with chloroform. The chloroform phase is washed with water, dried with anhydrous sodium sulfate and evaporated to dryness, a crude product being obtained which is purified by chromatography on silica gel, giving 1.02 g (2.6 mmol) of 4,5-dichloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperidyl]butyl}-2-methyl-1H-imidazole.