Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:30][O:31][CH3:32])[C:11]([NH:13][CH:14]2[C:28](=[O:29])[N:16]3[C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O.[OH-].[Na+].C>CO.O>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:30][O:31][CH3:32])[C:11]([NH:13][CH:14]2[C:28](=[O:29])[N:16]3[C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CCCCOC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 4.25 h
Yield: 92.9 %

Procedure:
Conc-Hydrochloric acid (4 ml) was dropwise added to a suspension of n-butyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 7.5 g) in methanol (120 ml) over 5 minutes under ice cooling, and stirred at room temperature for 4.25 hours. The resultant solution was poured into chilled water (75 ml), and adjusted to pH 5.5 with 4N aqueous solution of sodium hydroxide at 5° C. After treating the solution with activated charcoal (0.38 g), the solution was concentrated in vacuo. The aqueous residue was stirred under ice cooling for 30 minutes. The precipitates were collected by filtration, washed with water (10 ml×2), and then dried over phosphorus pentoxide to give yellow powder (6.55 g) of n-butyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:6]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].[H-].[Na+].Cl[C:36]1[N:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][N:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:43][S:42][C:39]1[CH:38]=[N:37][C:36]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:6]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[N:41][CH:40]=1
Reactant: CSc1cnc(Cl)nc1
Reactant: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(SC)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 52.2 %

Procedure:
n-Propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (92 mg) was dissolved in THF (6 ml). Sodium hydride (40 mg) and 2-chloro-5-methylsulfanyl-pyrimidine (71 mg) were added and the mixture was heated to 75° C. for 6 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give n-propanesulfonic acid [6-[2-(5-methylsulfanyl-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (61 mg) as a white powder. LC-MS: tR: 4.37, [M+H]+: 586.19.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15]>>[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=2)=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15]
Reactant: COC(=O)COc1ccc(CCN)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Product: COC(=O)COc1ccc(CCNCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole with 2-(4-carbomethoxymethoxyphenyl)ethanamine, followed by reduction.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)[C:21]([CH2:38][OH:39])=[CH:20][CH:19]=1>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:22]2[C:21]([CH2:38][OH:39])=[CH:20][CH:19]=[C:18]([N:16]3[C:10]4[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[N:23]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2nc(Br)ccc2CO)C1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(CO)c(N3CCC[C@H](N)C3)n2)n1
Yield: 68 %

Procedure:
Following the procedures as described in EXAMPLE 86 and starting with 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine and tert-butyl N-[(3S)-1-[6-bromo-3-(hydroxymethyl)-2-pyridyl]-3-piperidyl]carbamate, 218 was obtained as an off-white solid (40.8 mg, 68%) over 2 steps. 1H NMR (400 MHz, DMSO) δ 9.77-9.73 (s, 1H), 9.49-9.45 (s, 1H), 9.34-9.31 (s, 1H), 8.69-8.67 (s, 1H), 8.64-8.61 (s, 1H), 8.03-7.98 (d, J=8.1 Hz, 1H), 7.65-7.61 (d, J=8.1 Hz, 1H), 4.59-4.52 (d, J=2.9 Hz, 2H), 3.60-3.52 (d, J=12.4 Hz, 1H), 3.51-3.43 (d, J=9.8 Hz, 1H), 3.21-3.15 (d, J=10.4 Hz, 1H), 3.00-2.92 (s, 1H), 2.74-2.68 (d, J=12.0 Hz, 1H), 2.67-2.64 (s, 3H), 1.98-1.89 (d, J=9.4 Hz, 2H), 1.77-1.66 (m, 1H), 1.37-1.26 (d, J=10.0 Hz, 1H); MS (ESI) m/z: 417.1 [M+H]+
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23]>>[N+:22]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:24])=[O:23]
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
Anthraquinone is nitrated using a mixed acid comprising sulfuric acid and nitric acid, the concentration of sulfuric acid being 70 to 76% by weight and the amount of nitric acid being 33 to 55% by weight based on the total weight of sulfuric acid and nitric acid, whereby 1-nitroanthraquinone is obtained in a high yield and a high purity.
Reaction SMILES: Cl.[CH:2]([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[C:31]([CH3:32])=[C:30](Cl)[N:29]=[CH:28][N:27]=1>ClCCl>[Cl:25][C:26]1[N:27]=[CH:28][N:29]=[C:30]([N:13]2[CH2:14][CH2:15][CH:10]([C:8]3[O:7][N:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:9]=3)[CH2:11][CH2:12]2)[C:31]=1[CH3:32]
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)ncnc1N1CCC(c2nc(C(C)C)no2)CC1
Temperature: 27 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of 4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine hydrochloride (2.0 gm, 0.008369 moles) and diisopropylethylamine (2.78 gm, 0.0215 moles) in dichloromethane (30 ml) was added to an ice-cooled solution of 4,6-dichloro-5-methylpyrimidine (2.1 gm, 0.001295 moles) in dichloromethane (10 ml) and the reaction was stirred at 27° C. for 2 h. The reaction mixture was diluted with dichloromethane and washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The crude was purified by flash column chromatography (silica gel, 15% ethyl acetate in hexane) to afford the title compound as a white solid (43% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCC(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(OCC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from [2-amino-4-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J30) (230 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (298 mg, 75%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[N:43]1[CH2:55][CH2:54][N:46]2[C:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=3[CH:53]=[C:45]2[C:44]1=[O:56])(=[O:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:30][CH:31]=[CH:32][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CC(C)N(C)Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(CN(C)C(C)C)cn3)c(=O)n(C)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 61.7 %

Procedure:
Following Example 179a, 180d (125 mg, 0.39 mmol), 114a (215 mg, 0.47 mmol), 1N Na2CO3 (0.86 mL) and tetrakis(trihenyl-phosphine)palladium(0) (23 mg, 5 mol %) were reacted to give 180e (150 mg, 61% yield).
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:12]([OH:14])=[O:13])=[CH:4][NH:3]2)=[CH:7][CH:8]=1
Reactant: BrBr
Reactant: O=C(O)c1c[nH]c2ccccc12
Solvent: CC(=O)O
Product: O=C(O)c1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Bromine (49.58 g, 3100 mmol) is added slowly to a white suspension of Indole-3-carboxylic acid (50 g, 310 mmol) in 500 mL of acetic acid at room temperature, and the mixture is stirred at room temperature overnight. The solid formed is filtered and dried under vacuum for 3 hours to afford 45 g of the title compound as a grey solid (60%). MS (m/e): 240 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])=[O:4].C(=O)([O-])O.[Na+].[Cl:16][CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27](Cl)=[O:28])[N:25]=1)=[O:19].O>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:27](=[O:28])[C:26]([C:24]1[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][Cl:16])[S:22][CH:23]=1)=[N:30][O:31][CH3:32])=[O:4]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: CON=C(C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C(=O)OC)c1csc(NC(=O)CCl)n1

Procedure:
Under ice-cooling and stirring, 6 ml of an aqueous solution containing 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester and 561 mg of sodium hydrogen carbonate is added to a suspension of 1.18 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride (syn isomer) in 10 ml of tetrahydrofuran. After the mixture is stirred for 2 hours at room temperature, the solvent is distilled off in vacuo to leave a residue, which solidifies. Water is added to the solid, followed by filtration, and the collected crystals are washed successively with water and ethanol to give cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-4-carboylic acid methyl ester (syn isomer), m.p. 270°-275° C. (dec.).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][NH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=[O:29]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:28]([C:27]3[CH:31]=[CH:32][N:33]=[C:25]([NH:24][CH3:23])[CH:26]=3)=[O:29])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: CNc1cc(C(=O)O)ccn1
Agent: Cl
Product: CNc1cc(C(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)ccn1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(methylamino)isonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.41 (m, 1H), 1.52-1.74 (m, 4H), 1.83 (m, 1H), 2.74 (d, 3H, J=4.6 Hz), 3.19 (m, 1H), 3.40 (m, 1H), 4.19 (dd, 1H, J=9.9, 3.6 Hz), 4.65 (t, 1H, J=10.1 Hz), 5.20 (m, 1H), 6.30 (s, 1H), 6.61 (m, 2H), 6.88 (d, 1H, J=8.5 Hz), 7.46 (t, 1H, J=8.6 Hz), 7.83 (br s, 1H), 8.01 (d, 1H, J=5.4 Hz), 8.30 (br s, 1H), 10.93 (s, 1H). MS 445 (MH+).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CN(C)C=O>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CN2CCCCC2)c1
Yield: 88.6 %

Procedure:
In 150 ml of N,N-dimethylformamide was suspended 4.8 g of sodium hydride (52% purity), and 20.0 g of 3-piperidinomethylphenol was added in small portions with stirring under ice-cooling. After the addition, the resulting mixture was subjected to reaction at room temperature for 1 hour. To the reaction mixture thus obtained was added 28.0 g of N-(3-bromopropyl)phthalimide, and the resulting mixture was subjected to reaction for 24 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 300 ml of water and 300 ml of chloroform were added to the resulting residue to dissolve the same. The organic layer was separated and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 35.0 g (yield 88.5%) of oily N-[3-(3-piperidinomethylphenoxy)propyl]phthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:13]=1.[H-].[Na+].Br[CH2:27]/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[NH:10][C:11]([CH2:27]/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[C:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:13]=1
Reactant: O=C(OCc1ccccc1)c1c[nH]c(Cc2ccccc2Br)n1
Reactant: COC(=O)/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/Cc1[nH]c(Cc2ccccc2Br)nc1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a stirring solution of phenylmethyl 2-[(2-bromophenyl)methyl]imidazole-4-carboxylate in dimethyl foramide (0.1M) was added sodium hydride (1.2 eq) The reaction was allowed to stir for 10 mins. followed by addition of methyl 4-bromocrotonate continued stirring for 18 hr. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was extracted with 10% hydrochloric acid and the aqueous layer was neutralized with saturated sodium carbonate. The aqueous layer eas extracted with ethyl acetate and dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (50% EtOAc/Hexane). EI-MS m/z 406/408 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:35][C@H:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:37]([O:39]C(C)(C)C)=[O:38].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:35][C@H:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]([OH:39])=[O:38])=[O:32])=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@@H](C(=O)O)c1ccccc1
Reaction time: 0.17 h

Procedure:
[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (0.40 g, 0.827 mmol) was dissolved in CH2Cl2 (40 ml) and tert-butyl (2R)-amino(phenyl)acetate (0.206 g, 0.993 mmol) and N-methylmorpholine (0.251 g, 2.48 mmol) were added. After 10 minutes, TBTU (0.345 g, 1.076 mmol) was added. The reaction was stirred overnight. The resulting tert-butyl ester was concentrated and purified on silica gel (eluted with EtOAc/CH2Cl2 25/75). The pure fractions were collected and concentrated. CH2Cl2 (25 ml) and TFA (3 ml) were added. The mixture was stirred for 5 days and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-70% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions gave the title compound as a colourless solid. M/z: 615.50 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 4.35 (d, 1H), 4.36 (d, 1H), 4.40 (d, 1H), 4.53 (d, 1H), 4.58 (d, 1H), 4.94 (d, 1H), 5.19 (d, 1H), 6.97-7.40 (m, 15H), 8.02-8.06 (m, 2H), 8.26-8.32 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:10]([OH:12])[CH3:11]>>[CH2:10]([O:12][CH2:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)[CH3:11]
Reactant: O=Cc1ccc(CCl)o1
Reactant: CCO
Product: CCOCc1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
5-(Chloromethyl)furfural (CMF, 1) (1.24 g, 8.58 mmol) was dissolved in absolute ethanol (60 mL) and the solution was stirred at room temperature for 8 h. The excess ethanol was recovered by distillation and the residue was chromatographed (silica gel, CH2Cl2:Et2O, 2:1) to give EMF (5) (1.26 g, 95%) as a pale yellow liquid, 1H NMR (CDCl3); 1.04 (t, 3H), 3.39 (q, 2H), 4.32 (s, 2H), 6.34 (d, 1H), 7.06 (d, 1H), 9.40 (s, 1H), 13C NMR (CDCl3); 14.1, 63.6, 65.3, 110.3, 121.8, 151.8, 157.9, 176.7.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH:13]=[N:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[N:11]2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 90 °C
Yield: 77.9 %

Procedure:
To 3-(4-nitrophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (22.0 g, 65.8 mmol) in acetic acid (132 mL) and water (110 mL) was added iron powder. The reaction was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and filtered through Celite® followed by an ethyl acetate wash. The organic layer was separated and concentrated. Purification by flash column chromatography using 0-50% ethyl acetate/petroleum ether as eluent provided the title compound as a light yellow solid (15.6 g, 74%): 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=1.0 Hz, 1H), 7.68-6.92 (m, 6H), 6.29-5.93 (m, 2H), 3.27 (bs, 2H); ESIMS m/z 305 ([M+H]+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]2=[O:23])=[C:11]([CH3:24])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH3:24])[C:12]([CH:16]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]2=[O:23])=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)CCCC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C)c1C1C(=O)CCCC1=O

Procedure:
To a solution of 2-(4-benzyloxy-2,6-dimethylphenyl)cyclohexane-1,3-dione (0.57 g, 0.0018 mol) in ethyl acetate (30 ml) and methanol (530 ml) is added 5% palladium on carbon (0.100 g), and the suspension is then stirred under 4 bar hydrogen pressure for 5 hours. The suspension is filtered through diatomaceous earth and the filtrate evaporated under reduced pressure to afford 2-(4-hydroxy-2,6-dimethylphenyl)cyclohexane-1,3-dione as a grey solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CN(C)C=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)c2ccccc12
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCCN2CCCCC2)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of 4-bromonaphthalen-1-ol (1.1 g) in N,N-dimethylformamide (30 ml) were sequentially added potassium carbonate (1.0 g) and 1-(2-chloroethyl)piperidine (1.1 g), and the solution was stirred for 1 hour at 60° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was then evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to obtain 1-[2-(4-bromonaphthalen-1-yloxy)ethyl]piperidine (1.59 g). This compound (800 mg) was used according to an analogous synthetic method to Preparation Example 51 to provide the title compound (518 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.Cl.[CH3:20][NH:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>>[CH3:20][N:21]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[OH:22]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: CN(O)C(=O)CCCCCCCCCCBr

Procedure:
According to the procedure shown in Example 11, 2.65 g (10 mmol) of 11-bromoundecanoic acid (IV5) was treated with 1 ml of thionyl chloride and the resulting product was treated with 850 mg (10.2 mmol) of methylhydroxylamine hydrochloride and 1.5 g (10.9 mmol) of potassium carbonate to give N-methyl-11-bromoundecanohydroxamic acid (V6), which was recrystallized from a mixture of ether-n-hexane to give 2.46 g of the compound (V6) as colorless prismatic crystals in 83.6% yield. mp. 49° C. to 51° C. To a solution of 2.11 g (7.2 mmol) of the compound (V6) was allowed to react with 1.71 g (7.2 mmol) of 3,5-di-tert-butyl-4-hydroxythiophenol under the condition shown in Example 11. The prepared product was chromatographed and eluted with a mixture of ether-ethyl acetate (2:1) to give 3.12 g of the aimed compound (I13) as a pale yellow in 96.3% yield.