Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8](=[O:23])[CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])[CH2:2]1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([CH2:9][C:8]([NH:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:2]3)=[O:23])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CC(=O)NC1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(NC(=O)Cc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 58.5 %

Procedure:
Using N-(piperidin-3-yl)-2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]acetamide (200 mg, 0.572 mmol) and 3-(methoxycarbonyl)phenylboric acid (205 mg, 1.14 mmol), the same procedure was followed as in Example 2 to give 162 mg (59%) of the desired compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)[C:3]=1[CH:19]=[O:20].[O:21]1CCC[CH2:22]1.CO.[H-].[Na+]>O>[CH:19]([C:3]1[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)=[N:5][N:6]([CH3:7])[C:2]=1[O:21][CH3:22])=[O:20]
Reactant: C1CCOC1
Reactant: Cc1cc(-c2nn(C)c(Cl)c2C=O)ccc1OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C=O)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Reaction time: 3 h

Procedure:
At room temperature, to a mixture of 5-chloro-4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference Preparation example 96) 4.8 g and tetrahydrofuran 100 ml was added methanol 0.6 g and 55% sodium hydride 0.8 g, and the resulting mixture was stirred for three hours. To the reaction mixture was added water 50 ml, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole 4.5 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[CH3:25][O:26][CH2:27]Cl>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:25][O:26][CH3:27])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: O=Cc1cc(O)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a mixture of 2-benzyloxy-5-hydroxybenzaldehyde (16.68 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 3.07 g) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Chloromethyl methyl ether (11.8 g) was dropwise added to the reaction mixture. The reaction mixture was further stirred at room temperature for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-5-methoxymethoxybenzaldehyde as a colorless oil (10.32 g, 52%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[Br-:14].[CH2:15]([N:11]1[CH:12]=[CH:13][N+:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:10]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCBr
Reactant: COc1ccccc1-n1ccnc1
Solvent: C1CCOC1
Product: CCCCCCCn1cc[n+](-c2ccccc2OC)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 5.8 mmol (1.00 g) 1-(2-methoxyphenyl)imidazole and 7.0 mmol (1.25 g, 1.1 ml) 1-bromoheptane are dissolved in 5 ml THF and heated for 17 h to 90° C.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[C:4]([CH3:18])=[C:3]([CH3:19])[C:2]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: C1CNCCN1
Reactant: Cc1c(Cl)nn2cc(-c3ccc(F)cc3)nc2c1C
Solvent: O
Product: Cc1c(N2CCNCC2)nn2cc(-c3ccc(F)cc3)nc2c1C
Temperature: 150 °C
Yield: 69.6 %

Procedure:
A mixture of 1.4 g (5.08 mmol) of 6-chloro-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine and 8.7 g (100 mmol) of piperazine is heated at 150° C. for 3 hours in a reactor. The medium is then poured into water and the precipitate formed is isolated by filtration. The product is then recrystallized from a mixture of diisopropyl ether and isopropanol to give 1.15 g of a white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[N:10][C:9]=2[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1)=O.O.[NH2:27][NH2:28]>CO.O>[CH2:18]([NH:17][C:15]([NH:14][C:11]1[S:12][C:13]2[C:5]([C:3]([NH:27][NH2:28])=[O:2])=[CH:6][C:7]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:8][C:9]=2[N:10]=1)=[O:16])[CH3:19]
Reactant: NN
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OC)c2s1
Solvent: CO
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NN)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A suspension of 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester (319 mg, 0.895 mmol) in methanol (10 ml) was treated with hydrazine hydrate (2 ml) and stirred at ambient temperature for 16 h. HPLC indicated that the reaction mixture still contained a considerable amount of starter so a further 1 ml of hydrazine hydrate was added and the stirring continued for a further 24 h. The resultant mixture was diluted with water (50 ml) and the solid collected by filtration. This was washed with water (25 ml) followed by ethanol (25 ml) and dried in vacuo to give 1-Ethyl-3-(7-hydrazinocarbonyl-5-pyridin-3-yl-benzothiazol-2-yl)-urea as an off-white solid (312 mg, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:34]=1[C:35](Cl)=[O:36]>CC#N>[C:1]([O:5][C:6]([CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:35](=[O:36])[C:34]3[C:33]([Cl:32])=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:42])=[CH:19][CH:20]=2)[CH2:10]1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OC(=O)c3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.6 %

Procedure:
To a solution of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.39 g; 1.27 mmol) and N-ethyldiisopropylamine (0.65 mL, 3.81 mmol) in CH3CN (5 mL) was added 2,6-dichlorobenzoyl chloride (0.44 ml; 3.0 mmol), at 0° C. Subsequently, the mixture was allowed to warm to RT and was stirred for 2 days at roomtemperature. The resulting mixture was partitioned between Et2O and 5% aqueous NaHCO3 solution. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O to afford 2,6-dichloro-benzoic acid 4-[4-(2-tert-butoxycarbonyl-ethyl)-morpholin-2-yl]-phenyl ester (0.51 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:29](Cl)=[O:30].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:29]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:30]
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4ccc(Cl)c(Cl)c4)C3)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, (60 mg, 0.13 mmol), 3,4-dichloro benzoyl chloride (Aldrich, 27 mg, 0.13 mmol) and Et3N (76 uL, 0.54 mmol) in DCM (4 mL) was stirred at room temperature for 1 hour followed by aqueous workup with sat NaHCO3 and DCM. The organic layer was dried (Na2SO4) and concentrated in vacuo followed by column chromatography purification (5% NH3 in MeOH mixed with EtOAc) resulting in the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][CH2:32]Cl.[NH:34]1[CH2:39][CH2:38][CH:37]([CH:40]([OH:43])[CH2:41][OH:42])[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][CH2:32][N:34]5[CH2:39][CH2:38][CH:37]([CH:40]([OH:43])[CH2:41][OH:42])[CH2:36][CH2:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OCC(O)C1CCNCC1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: ClCCBr
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCC(C(O)CO)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[4-(1,2-dihydroxyethyl)piperidin-1-yl]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1), 1-bromo-2-chloroethane and 1-piperidin-4-ylethane-1,2-diol following General Procedure G.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(N[C@H](C(O)=O)CCC(O)=O)(=O)=O)=CC=1>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][O:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Agent: Cc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(Cc3ccccc3)CCO2)cc1
Yield: 77.3 %

Procedure:
To a solution of 4-benzyl-2-(toluene-p-sulphonyloxy-methyl)morpholine (18.1 g.) in methanol (100 ml.) was added a solution of (+)-toluene-p-sulphonylglutamic acid (16.0 g.) in methanol (50 ml.) and the mixture was allowed to crystallise during twelve hours. The mixture was filtered, the filtrate was put on one side, and the filtered solids (18.3 g.) were recrystallised from methanol (150 ml.) to obtain the (+)-toluene-p-sulphonylglutamic acid salt of (2S)-4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine (14.0 g.), m.p. 184° C. This salt was stirred with a mixture of 2 N sodium hydroxide and ether. The ether layer was separated, dried and the ether was distilled to leave optically pure (2S)-4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine as an oil, from which was prepared the hydrochloride m.p. 150° C., [α]D25 + 19.4° (c, 5 in methanol).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:7]=2[C@H:6]1[CH2:21][N+:22]([O-])=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.C1(C)C=CC=CC=1>C1COCC1>[NH2:22][CH2:21][C@H:6]1[C@H:5]([CH2:3][OH:2])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:7]1=2
Reactant: COC(=O)[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NC[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1CO

Procedure:
A solution of trans-2-Chloro-11-nitromethyl-10,11-dihydro-dibenzo[b,f]oxepine-10-carboxylic acid methyl ester (4) (4.6 g, 13.23 mmol) in dry THF (23 ml) is added at—15° C. to a mixture of THF (23 ml) and 3.5 M Lithium aluminum hydride (LAH) suspension in THF/Toluene (15.1 ml, 52.9 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([CH:20]=C)=[CH:15][CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:23].[Na+].O1CCCC1.O>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH:20]([C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]2)=[CH:16][CH:15]=1)=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)CC(CNC(=O)OC(C)(C)C)CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCc2ccc(C=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.5% solution of osmium tetroxide in tertbutanol (2 ml) is added to a mixture of the compound obtained in step b) above (1.4 g, 0.0049 mol), sodium periodate (3.5 g), tetrahydrofuran (40 ml), and water (10 ml). The reaction mixture is stirred at room temperature under nitrogen atmosphere for 1 hour, poured into water and extracted with ethyl acetate. The organic solution is washed with water, dried over sodium sulfate and concentrated under vacuum. The dark oily product which is thus obtained is purified by chromatography eluting with a mixture cyclohexane:ethyl acetate 6:4.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:5][N:4]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:4][N:5]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Reactant: NCc1ccncc1
Agent: Cl
Product: Clc1ccc(Nc2nnc(NCc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
A mixture of 0.5 g (1.5436 mmol) 1-chloro-4-(4-chloroanilino)phthalazine hydrochloride (for preparation see J. Chem. Soc. 1948, 777-782) and 2 g (18.50 mmol) 4-aminomethylpyridine is stirred for 36 h at 90° C. and then purified by means of flash chromatography on silica gel with a particle size of 0.04-0.06 mm using acetate and acetate/methanol (20:1). Evaporation of product-containing fractions, recrystallization of the residue from methanol, and drying of the crystallizate under HV yield the title compound; m.p. 233-236° C.; ESI-MS: (M+H)+=362.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[H][H].[F:20][C:21]1[C:22]([N+:30]([O-:32])=[O:31])=[C:23]([O:28][CH3:29])[CH:24]=[C:25](F)[CH:26]=1>CN(C=O)C.O>[F:20][C:21]1[CH:26]=[C:25]([CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:24]=[C:23]([O:28][CH3:29])[C:22]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(F)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 61.9 %

Procedure:
In DMF (60 ml) was suspended sodium hydride (2.75 g, 68.7 mmol). Under stirring at 0° C., di-tert-butyl malonate (14.9 g, 68.7 mmol) was added dropwise. After vigorous emission of a hydrogen gas stopped, a solution of 3,5-difluoro-2-nitroanisole (5.20 g, 27.5 mmol) in DMF (40 ml) was added. The reaction mixture was stirred at 80° C. for 4 hours. After cooling the reaction mixture to room temperature, water (200 ml) was added to terminate the reaction, followed by extraction with ether (300 ml). The extract was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate and distilled reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby hexane-ethyl acetate (10:1) eluate fractions, the title compound (6.56 g, 62%) was obtained as an yellow oil.
Reaction SMILES: C12(CO)CC3CC(CC(C3)C1)C2.[CH3:13][C:14]1([CH3:23])[C@H:19]2[CH2:20][C@@H:15]1[CH2:16][CH2:17][C@@H:18]2[CH2:21][OH:22].ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:40][C:41]1[C:42](F)=[CH:43][C:44]([F:56])=[C:45]([CH:55]=1)[C:46]([NH:48][S:49](=[O:54])(=[O:53])[N:50]([CH3:52])[CH3:51])=[O:47]>>[Cl:40][C:41]1[C:42]([O:22][CH2:21][C@H:18]2[CH2:17][CH2:16][C@H:15]3[CH2:20][C@@H:19]2[C:14]3([CH3:23])[CH3:13])=[CH:43][C:44]([F:56])=[C:45]([CH:55]=1)[C:46]([NH:48][S:49](=[O:53])(=[O:54])[N:50]([CH3:52])[CH3:51])=[O:47]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC[C@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace adamantan-1-ylmethanol with ((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol and 5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide (as prepared in Example 31), the title compound was obtained as a colorless solid (0.25 g, 45%): 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.24 (d, J=12.3 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.87 (s, 6H), 2.50-2.40 (m, 1H), 2.10-1.65 (m, 6H), 1.48-1.37 (m, 2H), 1.21 (s, 3H), 0.85 (s, 3H); MS (ES−) m/z 431.2, 433.2 (M−1).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4].[O:42]1[CH:47]=[CH:46][CH2:45][CH2:44][CH2:43]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C(OCC)(=O)C>[O:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[O:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:30])=[CH2:4]
Reactant: C1=COCCC1
Reactant: C=C(CO)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(COC1CCCCO1)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1

Procedure:
A solution of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (106 mg) and dihydropyran (25 mg) in dry dichloromethane (1 ml) was treated with p-toluenesulfonic acid (1 mg) at room temperature for 50 minutes. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by thin-layer chromatography (SiO2) to yield (3S,4S)-4-(1-tetrahydropyranyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[C:12]([O:16][C:17](=[O:23])[NH:18][CH2:19][CH:20](O)[CH3:21])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[F:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:6]=1)[O:11][CH:20]([CH3:21])[CH2:19][NH:18][C:17](=[O:23])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CNC(=O)OC(C)(C)C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Nitro-5-fluorophenol (3.0 g) and tert-butyl-N-(2-hydroxypropyl)carbamate were dissolved in THF (20 ml) and triphenylphosphine (7.5 g) and di-tert-butyl-azodicarboxylate were added. The exothermic reaction was cooled in an ice bath. Then the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was purified by chromatography (silica gel/dichloromethane: petroleum ether 1:2). The fractions were combined and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 1M NaOH. The organic layer was separated, dried, filtered and concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1OCCOCCOCCOCCOCC[O:16]C1.C(O)(C)(C)C.[OH2:37]>>[Br:1][C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]([Cl:13])=[C:10]([CH:11]=1)[C:12]([OH:16])=[O:37]
Reactant: O
Reactant: COC(=O)c1cc(Cl)c(C)cc1Br
Reactant: C1COCCOCCOCCOCCOCCO1
Solvent: CC(C)(C)O
Product: COC(=O)c1cc(Cl)c(C(=O)O)cc1Br
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 2-bromo-5-chloro-4-methylbenzoate (39.53 g, 0.15 mol), 18-Crown-6 (3.95 g), tert-butyl alcohol (350 mL), and water (750 mL) was combined together with mechanical stirring. The reaction mixture was heated to reflux and monitored by TLC. After refluxing overnight, the reaction was cooled to 55° C. and filtered. The filter cake was washed with hot water (2×100 mL, 50° C.). The filtrate was neutralized with 18% hydrochloric acid to pH 1 and stored in a refrigerator (0˜5° C.) for 3 h. It was filtered, and then washed with ice water (2×50 mL) and petroleum ether (2×50 mL). The filter cake was dried under vacuum to give the title compound as a white crystalline solid. Yield: 32.1 g (73%). 1H-NMR (DMSO-d6, 300 MHz): δ 8.10 (s, 1H), 7.89 (s, 1H), 3.86 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:4]=1[Cl:10].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[Cl:10][C:4]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:3]=1[CH2:2][N:15]1[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1ccc(I)cc1CBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(I)ccc1Cl
Temperature: 80 °C
Yield: 95.4 %

Procedure:
Bromomethyl-2-chloro-5-iodo-benzene (60) (400 mg, 1.2 mmol) and potassium phthalimide (693 mg, 1.5 mmol) were stirred in dry DMF (20 mL) and heated to 80° C. for 3 hours. After cooling, the suspension was filtered and concentrated in vacuo, and the residue was partitioned between water (30 mL) and Et2O (30 mL). The aqueous phase was extracted with ether (20 mL×3). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 63 (455 mg, 95%). 1H NMR (CDCl3, 300 MHz) δ 7.92-7.86 (m, 2H), 7.78-7.75 (m, 2H), 7.54-7:50 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 4.93 (s, 2H). MS (m/e) (API-ES) 397.9 (M)+, m.p. 134-136° C.