Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:6])=[O:5])[CH3:2].[CH:13]([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.CI.ClCl>>[CH2:1]([C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([CH3:13])[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(C(=O)O)c1cccnc1
Reactant: CC(C)[N-]C(C)C
Agent: ClCl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CCC(C)(C(=O)O)c1cccnc1
Yield: 30 %

Procedure:
To ethyl 3-pyridylacetic acid (10.86 grams) (65.7 mmoles) was added a 2.0M solution of lithium diisopropylamide in THF/heptane/ethyl benzene (32.87 ml.) (65.8 mmoles) at -30° C. The semi-solid mixture was agitated and sonicated for 1 hour. The mixture was allowed to remain at 25° C. for 1 hour, whereupon methyl iodide (4.09 ml.) (65.7 mmoles) was added. After 1 hour at 25° C. the mixture was taken up in CH2 Cl2 and washed with saturated aqueous sodium bicarbonate and water. The CH2Cl2 was dried (magnesium sulphate), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 10% EtOAc in hexane as the eluant to give the title compound (Yield: 3.48 grams, 30%, MH+ 180).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:19])[N:15]=[C:16]([CH3:18])[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1>>[CH3:27][C:25]1[N:26]=[C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:19])[N:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:23][CH:24]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C)nn1C
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cc(C)nn2C)n1

Procedure:
The title compound, was prepared in accordance with the general method of Example 78, step 2 from 3-(2,5-Dimethyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methylthiazole to yield the final compound as a yellow solid, MS (ISP): m/e=343.1 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH2:8][C:7]([O:9]C)=[CH:6][CH:5]([CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>Cl.O1CCCC1>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][CH:5]1[CH2:6][C:7](=[O:9])[CH2:8][C:3](=[O:2])[CH2:4]1
Reactant: COC1=CC(CC2OCCO2)C=C(OC)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CC(=O)CC(CC2OCCO2)C1
Temperature: 25 °C

Procedure:
A solution of 2-(3,5-dimethoxycyclohexa-2,5-dienylmethyl)-[1,3]-dioxolane (730 mgs, 3.2 mmol) in a mixture of 10% aqueous hydrochloric acid (2.9 ml) and tetrahydrofuran (29 ml) is stirred at room temperature for ¾ hour. The reaction mixture is poured into an aqueous solution of saturated potassium carbonate and extracted with ethyl acetate. The organic extract is discarded. The aqueous extract is acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate, filtered and then filtrate evaporated in vacuo to give 5-([1,3]-dioxolan-2-ylmethyl)-cyclohexane-1,3-dione as a white solid, used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:30]([CH3:32])[CH3:31])[NH:11]1.[NH2:33][N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:33][N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[O:28])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:30]([CH3:32])[CH3:31])[NH:11]1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(C(=O)O)cc3)nc(=O)c1-2
Reactant: CN1CCN(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(C(=O)NN4CCN(C)CC4)cc3)nc(=O)c1-2
Temperature: 45 °C
Reaction time: 16 h
Yield: 57.7 %

Procedure:
Part F: To a stirred solution of 49 mg (0.10 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carboxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.06 mL (0.5 mmol) of 1-amino-4-methylpiperazine in 1 mL of DMF was added 0.052 mL of DIEA followed by 48 mg (0.15 mmol) of TBTU. The solution was stirred 16 h at 45° C., cooled to RT, and poured into water. The mixture was extracted with EtOAc, and the organic extract was concentrated under reduced pressure. Chromatography with 4:1 chloroform-MeOH afforded 34 mg (58%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-on as a white solid. Mass spec: (ESI+) 588 (M +H)+.
Reaction SMILES: C([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])(OC(C)(C)C)=O.[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N[C@H](C(O)=O)CO)(=O)CCCCCCC/C=C\CCCCCCCC.N1C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:8][C@H:9]([C:12]([O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:13])[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](CO)C(=O)O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC(=O)[C@@H](N)CO
Temperature: 25 °C

Procedure:
0.03 moles of N-Boc-serine was constantly stirred under nitrogen in 100 mL of chloroform. 0.03 mole of oleoyl chloride was dissolved with 100 mL of chloroform and added to this heterogeneous mixture of N-Oleoylserine and followed by adding 10 mL of anhydrous pyridine. The reaction for 30 minutes under constantly stirring at room temperature, the mixture turned to homogeneous and the reaction was completed when no detectable oleoyl chloride was in the mixture. The bulk solvent was removed under vacuum and the crude product was used to next step without further purification. The resulting product (% of yields 75-80) is showed in Chemical Structure 4.
Reaction SMILES: [CH2:1]([C:21]([CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:22])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:43](O)[CH:44]([OH:48])[CH2:45][CH2:46][OH:47].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:21]1([CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:48][CH:44]([CH2:45][CH2:46][OH:47])[CH2:43][O:22]1)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(=O)CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC
Reactant: OCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC1(CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC)OCC(CCO)O1
Temperature: 25 °C

Procedure:
A mixture of diarachidonyl ketone (V, 0.30 g, 0.52 mmol), 1,2,4-butanetriol (0.25 g, 2.4 mmol) and pyridinium p-toluenesulfonate (20 mg) in 60 mL of toluene was refluxed under argon overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×30 mL), brine (30 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in a yellowish oily residual. The crude product was purified by column chromatography on silica gel (230-400 mesh, 40 mL) with 0-2% methanol in dichloromethane as eluent. This afforded 0.29 g (84%) of pure VI as pale oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([O:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=2)=[N:7][CH:6]=1)[NH2:4].[C:21]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N=C=NCCCN(C)C)C>ClCCl>[NH2:4]/[C:3](=[N:2]\[O:1][C:31](=[O:32])[CH:29]([NH:28][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH3:30])/[C:5]1[S:9][C:8]([O:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=2)=[N:7][CH:6]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)Oc1ccc(Oc2ncc(C(N)=NO)s2)cn1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ncc(/C(N)=N/OC(=O)C(C)NC(=O)OC(C)(C)C)s2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0 %

Procedure:
A solution of Example 81B (370 mg, 1.25 mmol) and N-Boc-alanine (286 mg, 1.51 mmol) in dichloromethane (10 mL) was treated with 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide (361 mg, 1.88 mmol). The reaction was stirred for 15 minutes at 25° C. Dichloromethane (50 mL) was added and the resulting mixture was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layers were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 30% ethyl acetate in hexanes to provide 482 ng of the title compound (83%) as white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26-1.35 (m, J=5.70, 5.70 Hz, 9H) 1.39 (s, 9H) 4.12-426 (m, 1H) 5.14-5.31 (m, 1 H) 6.86 (d, J=8.82 Hz, 1H) 7.05 (s, 2H) 7.37 (d, J=7.72 Hz, 1H) 7.83 (dd, J=9.19, 2.94 Hz, 1H) 7.87 (s, 1H) 8.26 (d, J=2.94 Hz, 1H); MS (ESI) m/z 466.0 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12]CC)=[O:11])[C:5]([O:7]CC)=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[CH3:17][O:18][CH2:19]Cl.[OH-].[K+]>C1COCC1.C(Cl)Cl.CO>[CH2:1]([C:4]([CH2:19][O:18][CH3:17])([C:10]([OH:12])=[O:11])[C:5]([OH:7])=[O:6])[CH:2]=[CH2:3]
Reactant: COCCl
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCC(COC)(C(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
A solution of 1.0 mL (1.0 equiv, 0.005 mol) of diethyl allylmalonate in 15 mL of dry THF is cooled to 0° C. with an ice/water bath. 210 mg (1.05 equiv, 0.0052 mol) of solid NaH (60% in oil) is added and the mixture stirred for 20 min at 0° C. To the resulting solution is added dropwise 0.305 mL (1.05 equiv, 0.0052 mols) of methoxymethyl chloride at 0° C. The reaction is stirred at 0° C. for 20 min., allowed to warm to RT and stirred 16 h. the reaction mixture is filtered to remove solids and the solvent from the filtrate in vacuo. 50 mL of H2O is added and the mixture extracted with ethyl acetate (2×80 mL). The organic layer is dried over MgSO4 and concentrated in vacuo. The crude product is dissolved in 20 mL of ethanol/water 9/1 and cooled to 0° C. with an ice/water bath. To this solution is added dropwise 695 mg (6.0 equiv, 0.024 mol) of potassium hydroxide dissolved in 10 mL of ethanol/water 9/1. The solution is stirred at RT for 3 days, and then the solvent is removed in vacuo 10 mL of H2O is added and the mixture was extracted with ethyl acetate (2×80 mL). The organic layer is dried over MgSO4 and concentrated in vacuo to yield 500 mg of 2-allyl-2-methoxymethyl malonic acid. 350 mg (1.0 equiv, 0.0019 mol) of 2-allyl-2-methoxymethyl malonic acid is dissolved in 30 mL of CH2Cl2 and cooled in a salt/ice/water bath to -5° C. 0.65 mL (4.0 equiv, 0.0075 mols) of oxalyl chloride is added dropwise at -5° C. The reaction mixture is allowed to stir at RT for 2 h, and then the solvent is removed in vacuo. The crude product is dissolved in 20 mL of dry THF and added dropwise to a solution of 592 mg (0.8 equiv, 0.0015 mol) of N-isopropyl-N-phenyl-2-(2-phenylamino-phenylamino)-acetamide in dry 20 mL of dry THF cooled to 0° C. The reaction mixture is heated at reflux for 22 h, cooled to RT and the solvent is removed in vacuo. 60 mL of brine/ethyl acetate 1/1 are added and the mixture is extracted with ethyl acetate (2×30 mL). The organic extract is dried over MgSO4 and the solvent removed in vacuo. Purification by silica gel flash chromatography with hexane/ethyl acetate 2/1 as eluent gave 550 mg of the title compound as a brown gum: 1H NMR (CDCl3, 300 MHz) δ7.39-6.78 (m, 13H), 6.20-5.65 (m, 1H), 5.04-5.00 (m, 2H), 4.73 (d, J=17.1, 1H), 3.98-3.84 (2s, 3H), 3.43 (s, 3H), 2.80 (s, 2H), 2.33-2.27 (m, 2H), 1.10-1.03 (m, 6H); Rf =0.30 in hexane/EtOAc 2/1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]1[S:13][C:14]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1)=[O:28]
Reactant: COc1ccc(Nc2nc3ccc([N+](=O)[O-])cc3s2)cc1OC
Reactant: O=C(Cl)c1ccccc1Cl
Product: COc1ccc(N(C(=O)c2ccccc2Cl)c2nc3ccc([N+](=O)[O-])cc3s2)cc1OC

Procedure:
The title compound was synthesised from (3,4-Dimethoxy-phenyl)-(6-nitro-benzothiazol-2-yl)-amine and 2-chlorobenzoyl chloride (commercially available) according to the procedure described for Example 2. MS (m/e): 469.7 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[Br:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[C:23](=O)[CH2:22][CH2:21]2.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl.C(O)(=O)C.O>[Br:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH:23]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH2:21]2
Reactant: O=C1CCc2cccc(Br)c21
Reactant: Nc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc2c1C(Nc1ccccc1)CC2
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.4 g (112 mmol) of aniline in 60 ml of toluene 5.31 g (28.0 mmol) of TiCl4 was added for 30 min at room temperature in argon atmosphere. The resulting mixture was stirred at 90° C. for 30 min followed by an addition of 6.00 g (28.0 mmol) of 7-bromoindan-1-one. The resulting mixture was stirred for 10 min at 90° C., poured into 500 ml of water, and crude product was extracted with 3×100 ml of ethyl acetate. The organic layer was separated, dried over Na2SO4, and then evaporated to dryness. The residue was crystallized from 10 ml of ethyl acetate at −30° C. The resulting solid was separated and dried in vacuum. After that it was dissolved in 100 ml of methanol, 2.70 g (42.9 mmol) of NaBH3CN and 0.5 ml of glacial acetic acid was added. The resulting mixture was refluxed for 3 h in argon atmosphere. The resulting mixture was cooled to room temperature and then evaporated to dryness. The residue was diluted with 200 ml of water, and crude product was extracted with 3×50 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate-triethylamine=100:10:1, vol.). Yield 5.50 g (68%) of a yellow oil. Anal. calc. for C15H14BrN: C, 62.52; H, 4.90; N, 4.86. Found: C, 62.37; H, 5.05; N, 4.62. 1H NMR (CDCl3): δ 7.38 (m, 1H, 6-H in indane); 7.22 (m, 3H, 3,5-H in phenyl and 4-H in indane); 7.15 (m, 1H, 5-H in indane); 6.75 (m, 1H, 4-H in indane); 6.69 (m, 2H, 2,6-H in phenyl); 4.94 (m, 1H, 1-H in indane); 3.82 (br.s, 1H, NH); 3.17-3.26 (m, 1H, 3- or 3′-H in indane); 2.92-2.99 (m, 2H, 3′- or 3-H in indane); 2.22-2.37 (m, 2H, 2,2′-H in indane).
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:20]=[CH:21][C:14]=12>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:19]1[C:15]2=[N:16][CH:17]=[N:18][C:13]([O:1][C@@H:2]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4])=[C:14]2[CH:21]=[N:20]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)COC(C)C
Product: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ccccc1Cl

Procedure:
D2a was prepared in an analogous fashion to D1b from (S)-methyl 2-hydroxy-3-isopropoxypropanoate C7a and B1.
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH:14]=[O:15])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([S:9]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][OH:15])(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccccc1CO
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Sodium borohydride (690 mg, 18.2 mmol) was added to a solution of 2-(benzenesulfonyl)-benzaldehyde (1.98 g, 8.04 mmol) and methanol (50 mL). The reaction mixture was stirred at room temperature. When vigorous bubbling subsided, the reaction mixture was cooled in an ice-water bath, then carefully quenched with a 1.0 N aqueous solution of HCl (20 mL). The mixture was concentrated to remove methanol, then the residue was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, filtered, and concentrated to afford 1.94 g (97%) of (2-benzenesulfonyl-phenyl)-methanol as an oil. This product was used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[N+:20]([O-:22])=[O:21].[BH4-].[Na+].C(OCC)(=O)C>CO.CCCCCCC>[CH3:1][O:2][C:3](=[O:24])[CH:4]([OH:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[N+:20]([O-:22])=[O:21]
Reactant: COC(=O)C(=O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 60.9 %

Procedure:
3-(4-Benzyloxy-2-nitrophenyl)-2-oxopropanoic acid methyl ester (4.1 g; 12.4 mmole) was dissolved in methanol (60 ml). Sodium borohydride (0.5 g; 13.12 mmole) was added in portions under stirring. TLC (silica gel, ethyl acetate:heptane, 1:1) after one hour showed remaining starting material and the formation of a by product. The reaction mixture was then cooled in an ice-bath and more sodium borohydride (0.2 g; 5.26 mmole) was added. After addition, the mixture was stirred at 0° C. until the starting material was consumed. The reaction mixture was evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was washed with brine and dried with magnesium sulfate and evaporated. Chromatography of the crude product on silica gel using a gradient of ethyl acetate in heptane as eluant gave 2.5 g (61% yield) of 3-(4-benzyloxy-2-nitrophenyl)-2-hydroxypropanoic acid methyl ester as an oil product.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)=[O:4].[H][H]>C(O)(=O)C.[Pd]>[OH:1][NH:2][C:3]([C:5]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:6][CH2:7][N:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCC(C(=O)NO)(S(=O)(=O)c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)CC2)cc1

Procedure:
A solution of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(4-nitrophenylcarbonyl)-4-piperidinecarboxamide, the product of Example 113, (56.0 mg) dissolved in acetic acid (2.5 mL) was added to 4% palladium on carbon (20 mg) and placed under 43 psi hydrogen gas for 2.5 h. The reaction mixture was filtered through a pad of celite. The solvent was evaporated to afford N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide (50.2 mg) as a pale yellow solid. MS (ES) m/z 580 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][O:48][C:49]([C:51]1[N:52]([CH2:69][C:70]2[CH:75]=[CH:74][C:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])=[CH:72][CH:71]=2)[C:53](=[O:68])[C:54]2[C:59]([C:60]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[CH:58][C:57](Br)=[CH:56][CH:55]=2)=[O:50].[CH3:83][C:84]1[O:88][N:87]=[C:86]([C:89]2[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=2)[C:85]=1[C:95]1[CH:100]=[CH:99][N:98]=[C:97]([NH2:101])[N:96]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:47][O:48][C:49]([C:51]1[N:52]([CH2:69][C:70]2[CH:75]=[CH:74][C:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])=[CH:72][CH:71]=2)[C:53](=[O:68])[C:54]2[C:59]([C:60]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[CH:58][C:57]([NH:101][C:97]1[N:96]=[C:95]([C:85]3[C:86]([C:89]4[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=4)=[N:87][O:88][C:84]=3[CH3:83])[CH:100]=[CH:99][N:98]=1)=[CH:56][CH:55]=2)=[O:50]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1ccnc(N)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Nc3nccc(-c4c(-c5ccccc5)noc4C)n3)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To toluene (6 ml) were added palladium(II) acetate (4.1 mg) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (34 mg) at room temperature and the mixture was stirred for 5 min. under a nitrogen stream. To the reaction mixture were added 6-bromo-2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) and 4-(5-methyl-3-phenylisoxazol-4-yl)pyrimidin-2-ylamine (200 mg) at room temperature and the mixture was stirred for 10 min. under a nitrogen stream. Further, sodium tert-butoxide (70 mg) was added to the reaction mixture at room temperature, and the mixture was heated under reflux under a nitrogen atmosphere for 12 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=1:1), followed by recrystallization (ethyl acetate-hexane) to give the title compound (240 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1N

Procedure:
Prepared from (2-nitro-4-pyridin-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example C5) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a light brown solid (339 mg).