Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCCC1C[NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15](NS(C)(=O)=O)[C:14](C)=[CH:13][C:12]=1OC)C.C(N(CC)CC)C.CN(C)S(Cl)(=O)=O>C(Cl)Cl>[C:10]([NH2:9])(=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN1CCCC1CNC(=O)c1cc(NS(C)(=O)=O)c(C)cc1OC
Agent: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Yield: 214.1 %

Procedure:
A mixture of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide (500 mg), triethylamine (823 mg), dimethylaminosulfonyl chloride (1.17 g), and methylene chloride (20 ml) is refluxed for 39 hours. The reaction mixture is washed with aqueous sodium hydrogencarbonate. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 0.5-1% methanol/methylene chloride. The eluate is evaporated to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-[N-(dimethylaminosulfonyl)-methanesulfonamido[benzamide (351 mg) as an oil. This product is mixed with tetrahydrofuran (3 ml) and 10% sodium hydroxide (3 ml) and warmed at 80° C. for 1 hour. The reaction mixture is evaporated to remove the tetrahydrofuran, acidified with hydrochloric acid, made alkaline with sodium hydrogencarbonate, salted out with sodium chloride, and shaken with methylene chloride. The organic layer is washed with saturated brine, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 3% methanol/methylene chloride. The eluate is evaporated to remove the solvent. The residue is washed with ether/isopropyl ether and filtered to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide (211 mg). The product is recrystallized from acetonitrile/isopropyl ether to give crystals melting at 129° to 129.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:26]4[C:35]5[C:30](=[CH:31]C(Cl)=CC=5)N=CC=4)[CH2:18][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.BrCCCCBr.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][N:25]4[CH2:31][CH2:30][CH2:35][CH2:26]4)[CH2:20][CH2:21]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(NCCCN3CCN(CCCNc4ccnc5cc(Cl)ccc45)CC3)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCCCCBr
Solvent: CN(C)C=O
Product: Clc1ccc2c(NCCCN3CCN(CCCN4CCCC4)CC3)ccnc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,4-bis{3-[N-(7-chloroquinolin-4-yl)amino]propyl}piperazine described in example 1 (0.15 g, 0.41 mmol), 1,4-dibromobutane (0.06 mL, 0.5 mmol) in DMF (5 mL), K2CO3 (287 mg, 2.07 mmol) is added. After stirring the mixture at room temperature for 48 h, the solvent was removed under reduced pressure. The residue was solubilized in CH2Cl2, washed with NaHCO3 1M and dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH/NH4OH: 80/20/2.7).
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([CH:16]=[O:17])[C:3]=1[CH3:18].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O>[CH3:18][C:3]1[C:4]([CH:16]=[O:17])=[CH:5][NH:6][C:2]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C=O)c[nH]c1-c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A suspension of 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.78 g), phenylboronic acid (1.37 g), dichloro[bis(triphenylphosphine)]palladium (0.19 g) and sodium carbonate (1.72 g) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100° C. for 1 hr. 8 mol/L aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at 90° C. for 3 hr. After cooling, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1), and the obtained solid was washed with hexane to give the title compound as a pale-yellow solid (yield 815 mg, 69%).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.CCOCC>[NH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([O:18][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(CC(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1
Reaction time: 16.75 h

Procedure:
To a solution of 2-[4-(tert-butoxycarbonylamino)cyclohexyl]acetic acid (1.0 g, 4 mmol) in DMF (10 mL) was added K2CO3 (600 mg, 4 mmol) followed by benzyl bromide (0.5 mL, 4.2 mmol). The resulting mixture was stirred for 16.75 hours, diluted with ether, washed with water (2×) followed by brine, dried over magnesium sulfate and concentrated. The residue was taken up in dichloromethane (12 mL). To this solution was added TFA (3 mL). The resulting solution was stirred for 2.5 hours then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution followed by brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1B(O)O.C(O)(O)=O>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:20]1[CH:19]=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[Cl:14])[C:3]([CH3:13])=[N:4]2
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: O
Solvent: CC#N
Product: Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (Prepared in Example 85, 1.0000 g, 4.693 mmol), 2-chloro-5-fluorophenylboronic acid (0.9002 g, 5.163 mmol), tetrakis(triphenylphosphine)palladium (0.2712 g, 0.2347 mmol), and sodium carbonate anhydrous (2.487 g, 23.47 mmol) in acetonitrile-water (3:1) (47.00 mL) was stirred at 100° C. After 3 hs, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-3-(2-chloro-5-fluorophenyl)-2-methylquinoxaline as a red syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1 H, dd, J=8.4, 1.4 Hz), 8.03 (1 H, dd, J=7.6, 1.4 Hz), 7.88 (1 H, dd, J=8.4, 7.6 Hz), 7.75 (1 H, dd, J=9.0, 5.1 Hz), 7.61 (1 H, dd, J=8.6, 3.1 Hz), 7.46-7.53 (1 H, m), 2.54 (3 H, s); LC-MS (ESI) m/z 307.0 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2C=[CH:2]1)C3.[CH3:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15].C1(C=CC(O)=CC=1)O>>[CH3:11][O:12][C:13]([CH:14]1[CH2:4][CH:5]2[CH2:6][CH:15]1[CH:2]=[CH:1]2)=[O:16]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CC(=O)OC
Agent: Oc1ccc(O)cc1
Product: COC(=O)C1CC2C=CC1C2
Temperature: 220 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
Dicyclopentadiene (DCPD, available from Aldrich, 256.5 mL, 1.9 mol), methylacrylate (available from Aldrich, 405 mL, 4.5 mol) and hydroquinone (3.2 g, 0.03 mol) were charged into a 2 L high pressure reactor and heated to 220° C. The mixture was stirred at 300 rpm for 5 hours. After the reaction was completed, the resultant was cooled and transferred to a distiller. Vacuum distillation was carried out at 50° C. using a vacuum pump at 1 torr to obtain the product (yield: 57.6%, exo/endo=58/42).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:17])=[N-].[Si](C=[N+]=[N-])(C)(C)C.N#N>CO>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: CO
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1F
Yield: 99 %

Procedure:
A 1 L flask was charged with 2,6-difluoro-3-nitrobenzoic acid (17.0 g, 83.7 mmol) and MeOH (170 mL, 0.5M). The flask was placed in a cold water bath, and an addition funnel charged with a 2M solution of trimethylsilyl (“TMS”) diazomethane in hexanes (209 mL, 419 mmol) was attached to the flask. The TMS diazomethane solution was added slowly to the reaction flask over the course of 2 hours. A large excess of reagent was required in order for the reaction to reach completion as determined by the ceased evolution of N2 upon further addition of reagent. The volatiles were removed in vacuo to afford methyl 2,6-difluoro-3-nitrobenzoate as a solid (18.2 g, 99%). The material was taken directly onto Step B.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[S:17][C:16]([CH3:18])=[N:15][C:14]=1[CH3:19])(=[O:12])[CH3:11]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([C:13]2[S:17][C:16]([CH3:18])=[N:15][C:14]=2[CH3:19])([OH:12])[CH3:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(=O)c1sc(C)nc1C
Product: COc1ccc(C(C)(O)c2sc(C)nc2C)cc1

Procedure:
Following the general method of Example 3 but starting with 4-bromoanisole and 5-acetyl-2,4-dimethylthiazole, the title compound was prepared. M.p. 114-115.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>C(Cl)Cl>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCOC2)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(C2CCOC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a methylene chloride (5 mL) solution of the obtained tert-butyl 2-(2-hydroxy-5-(tetrahydrofuran-3-yl)benzamido)-4-phenylbenzoate (0.027 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.023 g of 2-(2-hydroxy-5-(tetrahydrofuran-3-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2.C[C@H](N)C1C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C@H:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Agent: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)C1=Cc2cc(Cl)ccc2N[C@@H]1C(F)(F)F
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid (Example 157) (6.75 g, 24.3 mmol) in ethyl acetate (25 mL) was added (S)-(−)-α-methylbenzylamine (1.50 g, 12.2 mmol). To the resulting solution was added hexanes (50 mL) with mixing. Stirring was discontinued and the reaction held static at room temperature for 16 hours during which time yellow crystals formed. The crystals were collected and washed with ethyl acetate-hexanes (100 mL, 1:2). The resulting yellow solid (932 mg) was dissolved in ethyl acetate (20 mL) and extracted with 1 N HCl (3×10 mL). The organic layer was dried over sodium sulfate and solvent removed at reduced pressure. The (s)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid was obtained as a yellow solid (648 mg, 10% yield). mp 173–176° C. 1H NMR (acetone-d6, 300 MHz) 7.80 (s, 1H), 7.35 (d, 1H, J=2.2 Hz), 7.18 (d, 1H, J=8.0, J=2.2 Hz), 6.86 (d, 1H, J=8.0 Hz), 6.60 (brs, 1H), 5.20 (m, 1H). Anal. Calc'd. for C11H7NO2F3Cl C, 47.40 H, 2.54; N, 5.40. Found C, 47.49; H, 2.60; N, 4.98. The compound was determined to have an optical purity greater than 90% ee. Optical purity was determined by HPLC as described in Example 66.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:23][CH3:24])=[O:6]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 10 g of 3-fluoro-2-methylbenzoic acid [J. Org. Chem., 26, 3208 (1961)]in 300 ml of dimethylformamide are added 30 g of potassium carbonate and 30 g of ethyl iodide and the mixture is stirred at room temperature for 8 hours. After adding 500 ml of toluene, washing with water and a saturated saline solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure to give 11 g of ethyl 3-fluoro-2-methylbenzoate (oil). Mass spectrum m/z: 182(M+).
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH:14]=[C:13]2[O:32]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC(COC(C2N3C(=O)[C@@H](NC(=O)COC4C=CC=CC=4)[C@H]3SCC=2OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)=CC=1)([O-])=O>FC(F)(F)C(O)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[OH:32])=[O:11])=[CH:46][CH:47]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(OC(c3ccccc3)c3ccccc3)=CS[C@H]12
Agent: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OC(c3ccccc3)c3ccccc3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 340 mg of the resulting isomer mixture, consisting of 7β-phenoxyacetamido-3-diphenylmethoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester and 7β-phenoxyacetamido-3-diphenylmethoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester, in a mixture of 0.5 ml of trifluoroacetic acid and 9.5 ml of methylene chloride is stirred for 40 minutes at room temperature. The mixture is concentrated by evaporation in vacuo, toluene is added to the residue, and the mixture is again concentrated by evaporation. The resulting residue (which still contains trifluoroacetic acid) is chromatographed on 15 g of acid-washed silica gel, using toluene/ethyl acetate (3:1), whereby 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester is obtained; IR spectrum (methylene chloride): characteristic bands at 2.95, 3.3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15 and 8.3μ; NMR spectrum (deuterochloroform): characteristic bands at 3.4 (2H, AB q, J=17 Hz), 4.57 (2H, s), 5.06 (1H, d, J=5 Hz), 5.35 (2H, AB q, J=14 Hz), 5.7 (1H, dd, J=5, 10 Hz), 6.8-8.4 (10 H, c), 11.4 (1H, br. s.) ppm.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=CN=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:38]3[CH:37]=[CH:29][N:36]=[CH:40][CH:39]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: BrCCc1ccncc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccncc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(2-bromoethyl)pyridine hydrobromide and isolated as brown solid. MS (m/e): 388.3 (MH+).
Reaction SMILES: C1([Mg]Br)CCCCC1.C(C1C=CC=C(C(C)C)C=1N=CC(C)C)(C)C.ClC(P)Cl.[Li:30]CCCC.Br[C:36]1[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][C:39]([CH:45]([CH3:47])[CH3:46])=[CH:38][C:37]=1[CH:48]([CH3:50])[CH3:49]>C(OCC)C.C1COCC1>[CH:48]([C:37]1[CH:38]=[C:39]([CH:45]([CH3:47])[CH3:46])[CH:40]=[C:41]([CH:42]([CH3:44])[CH3:43])[C:36]=1[Li:30])([CH3:50])[CH3:49]
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Reactant: [Li]CCCC
Agent: Br[Mg]C1CCCCC1
Agent: CC(C)C=Nc1c(C(C)C)cccc1C(C)C
Agent: PC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: [Li]c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexylmagnesium bromide (1.05 mL of a 2.0 M solution in ethyl ether, 2.1 mmol, Aldrich) was added to a solution of isobutyraldehyde 2,6-diisopropylphenylimine (0.462 g, 2.0 mmol) in THF (5 mL) at −78° C. The yellowish solution was warmed to RT, stirred for 1 h and then added to a solution of dichloromethylphosphine (0.19 mL, 2.1 mmol, Strem) in THF (5 mL) at −78° C. The solution was stirred for 10 min at −78° C., warmed to RT and stirred for 30 min. Assay by 31P-NMR (crude reaction mixture) showed the presence of a single major product (+110.4 ppm). The solution of 2,4,6-triisopropylphenyllithium was prepared by addition of BuLi (1.6 mL of a 1.6 M solution in hexanes, 2.6 mmol, Aldrich) to a solution of 1-bromo-2,4,6-triisopropylbenzene (0.63 mL, 2.5 mmol, Lancaster) in THF (8 mL) at −78° C. followed by stirring for 2 h. The solution of arylLi thus formed was added to the solution of chlorophosphine keeping both flasks at −78° C. The solution was stirred for 20 min at −78° C., warmed to RT and stirred for 30 min. Assay by 31P-NMR (crude reaction mixture) showed the presence of a single major product (−37.9 ppm). The solution was evaporated and CH2Cl2 (10 mL) was added to the residue. Filtration through a 2.2×2 cm plug of silica gel using CH2Cl2 (20 mL) and then ethyl ether (10 mL) as an eluent followed by evaporation of the solvent afforded crude product as a yellowish oil. To the crude ligand was added NiBr2(DME) (0.124 g, 0.40 mmol) and CH2Cl2 (10 mL). The red-brown solution was stirred for 1 h at RT, solution was evaporated and the residue washed with diethyl ether (3×20 mL) and hexanes (20 mL). A brown, insoluble solid (0.310 g, 107% based on Ni) was obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2C)=NC=1.[CH:53]1([NH2:56])[CH2:55][CH2:54]1>>[CH:53]1([NH:56][C:3](=[O:2])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:14][O:15][C:16]=3[C:17]([F:19])([F:18])[F:20])=[N:6][CH:5]=2)[CH2:55][CH2:54]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Reactant: NC1CC1
Agent: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Product: O=C(NC1CC1)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Yield: 94 %

Procedure:
As described for example 89, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol), instead of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, using cylopropylamine instead of morpholine, to the title compound (100 mg, 94%) which was obtained as a white solid. MS: m/e=404.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:39][OH:40]>O1CCCC1>[OH:40][NH:39][C:13](=[O:14])[CH2:12][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:25]
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2Cc3ccccc3C2=O)cc1OC
Yield: 78.3 %

Procedure:
N-Hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (5.00 g, 14.7 mmol), carbonyldiimidazole (2.49 g, 15.4 mmol) and hydroxylamine hydrochloride (1.30 g, 19.1 mmol) in tetrahydrofuran (15 mL) to afford N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide as a white solid (4.1 g, 79% yield): mp, 188.5-189.5° C.; 1H NMR (DMSO-d6) δ2.82-2.87 (m, 2H, CH2), 3.71 (s, 3H, CH3), 3.74 (s, 3H, CH3), 4.15 (d, J=17.5 Hz, NCHH), 4.63 (d, J=17.5 Hz, 1H, NCHH), 5.74 (t, J=7.7 Hz, 1H, NCH), 6.85-6.93 (m, 3H, Ar), 7.45-7.69 (m, 4H, Ar), 8.83 (br s, 1H, OH), 10.60 (1H, NH); 13C NMR (DMSO-d6) δ35.11, 46.26, 51.25, 55.50, 111.09, 111.76, 119.19, 122.79, 123.43, 127.84, 131.29, 131.91, 132.27, 141.68, 148.27, 148.69, 166.03, 166.84; Anal Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 64.08; H, 5.55; N, 7.86.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:4]([N+:17]([O-:19])=[O:18])=[CH:5][C:6]([C:12]([CH3:16])([CH3:15])[CH2:13][O:14][C:20](=[O:22])[CH3:21])=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)CO)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])cc(C(C)(C)COC(C)=O)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-(4-Methoxy-3,5-dinitro-phenyl)-2-methyl-propan-1-ol was dissolved in 5 mL of CH2Cl2. Acetic anhydride was added followed by DMAP. The mixture was stirred overnight, then diluted in 15 mL of CH2Cl2 and washed with 1 M NaSO4, saturated NaHCO3, and brine. The CH2Cl2 solution was then dried with Na2SO4, filtered, and concentrated to provide acetic acid 2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propyl ester (628 mg) as a brown oil.