Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][C:18]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:5])=[O:4]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Trifluoromethanesulfonic anhydride (15.5 mL, 92.0 mmol) was added over approximately 0.1 h, via syringe, to a stirred solution of the product of step B (33.8 g, 84.0 mmol) and N,N-diisopropylethylamine (17.6 mL, 101.0 mmol) in methylene chloride (300 mL) at −78° C. After allowing to warm to ambient temperature overnight, the reaction mixture was quenched with saturated aqueous sodium bicarbonate, poured into water and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution; 0–20% ethyl acetate/hexanes as eluent) gave the title compound as an amber colored oil (23.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[CH:10][N:11]2[CH2:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCn1cc(C)c2ccc(C(=O)OC)cc21
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-methyl-1H-indole-6-carboxylic acid methyl ester (2.5 g, 13.2 mmol) in DMF (25 mL), a solution of NaH (580 mg, 14.5 mmol, 60% dispension in grease) in DMF (25 mL) is slowly added under a N2 atmosphere. The mixture is stirred at 80° C. for 20 min, and cooled to RT before the addition of 1-bromo-3-methoxypropane (4.04 g, 26.4 mmol). The resulting mixture is stirred for 24 h. 1-Bromo-3-methoxypropane (2.02 g, 13.2 mmol) and NaH (580 mg, 14.5 mmol) are added and the mixture further stirred for 24 h to complete the reaction. The solvent is concentrated under reduced pressure and the mixture diluted with AcOEt. An aqueous saturated solution of NaHCO3 is added, the layers are separated, and the aqueous one is back-extracted with AcOEt. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude residue is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 80:20) to give the title compound. MS (LC-MS): 262.0 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mumin): 5.80 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30].[CH3:31][C:32]([CH3:34])=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:29][CH2:28][N:27]([CH:32]([CH3:34])[CH3:31])[CH2:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1)C3
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(C(C)C)CC1)C3
Temperature: 25 °C
Reaction time: 60 h
Yield: 41.8 %

Procedure:
To a solution of Example 3 (100 mg; 0.23 mmol; 1 eq.) in DCM (3 mL) was added acetone (52 μL; 0.70 mmol; 3 eq.) and AcOH (16 μL; 0.28 mmol; 1.2 eq.) and then after few minutes sodium triacetoxyborohydride (149 mg; 0.70 mmol; 3 eq.). The reaction mixture was stirred at room temperature for 60 hours and acetone (104 μL; 1.41 mmol; 6 eq.) and sodium triacetoxyborohydride (50 mg; 0.23 mmol; 1 eq.). The reaction mixture was stirred for 5 hours then diluted with DCM. The organic phase was washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (45 mg, 41%). 1H NMR (CDCl3) δ 7.41-7.33 (m, 2H), 7.08-6.96 (m, 2H), 4.99 (s, 0.8H), 4.98 (s, 1.2H), 4.66-4.49 (m, 3H), 2.98-2.14 (m, 5H), 2.91 (s, 2H), 2.86 (s, 1H), 2.70 (s, 1H), 2.62 (s, 2H), 1.89-1.61 (m, 4H), 1.09 (s, 6H). HPLC (max plot) 93.8%; Rt 2.80 min. UPLC/MS: (MS+) 468.5 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:21])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:28](Br)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:21][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(S)c(C(C)(C)C)cc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Sc2cc3c(cc2C(C)(C)C)N(C(=O)OC(C)(C)C)CC3)cc1

Procedure:
The title compound was prepared according to General Method 15 using 6-tert-Butyl-5-mercapto-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (prepared in Example FF), pyridine, tosyl bromide, carbon tetrachloride, and EtOAc.
Reaction SMILES: [NH2:1][C:2]1([C:7]([N:9]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:10][C:11](=[O:37])[C@@H:12]([C@@H:17]([C:27](=[O:36])[NH:28][O:29]C2CCCCO2)[CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1>CO>[C:42]1([CH3:52])[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:49])=[O:50])=[CH:46][CH:47]=1.[NH2:1][C:2]1([C:7]([N:9]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:10][C:11](=[O:37])[C@@H:12]([C@@H:17]([C:27](=[O:36])[NH:28][OH:29])[CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C1(N)CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C1(N)CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 1.7 h
Yield: 79.2 %

Procedure:
A solution of 0.35 g of (E)-2′-[(1-amino-1-cyclopentyl)carbonyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 3 ml of methanol was treated with 0.14 g of p-toluenesulphonic acid. The mixture was stirred for 1.7 hours at room temperature and evaporated to give a foam. This foam was triturated with diethyl ether, filtered off and dried to give 0.32 g of (E)-2′-[(1-amino-1-cyclopentyl)carbonyl]-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]([CH3:22])[CH3:21])[S:18][CH:19]=1)=O)(=[O:3])[CH3:2].[OH-].[K+]>N1C=CC=CC=1>[CH3:21][N:20]([CH3:22])[C:17]1[S:18][CH:19]=[C:15]([C:13]2[CH:2]=[C:1]([OH:3])[C:4]3[C:5](=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)[N:12]=2)[N:16]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2csc(N(C)C)n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc2c(O)cc(-c3csc(N(C)C)n3)nc2c1
Yield: 74 %

Procedure:
2-Dimethylamino-thiazole-4-carboxylic acid (2-acetyl-5-methoxy-phenyl)-amide (1.29 g, 4.04 mmol) was dissolved in 20 mL pyridine in a microwave vial. Grinded KOH (0.48 g, 8.48 mmol) was added to the solution and the enclosed vial was reacted in the microwave oven at 100° C. for 30 minutes. The mixture was transferred to a round-bottom flask and the solvent was removed by rotary evaporation. The residue was transferred to a beaker with phosphate buffer (pH 7.0, 0.1 M, 300 mL) where the product precipitated while stirring. The precipitate was filtered, rinsed with water and dried with high vacuum. The product was found to be pure by LC-MS and NMR and was obtained in 74% yield (0.90 g). LRMS (M+H) 302.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)=[C:11]3[C:10]([CH3:25])=[N:9]2)=[CH:5][CH:4]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:40](=[O:41])[C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=[N:36]2)=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.C(N(C(C)C)C(C)C)C>O.CN(C=O)C>[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:40](=[O:41])[C:39]([C:42]([NH:24][C:21]3[CH:22]=[N:23][C:18]([O:17][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=6)[N:9]=[C:10]([CH3:25])[C:11]=45)=[CH:19][CH:20]=3)=[O:43])=[CH:38][CH:37]=[N:36]2)=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cn4)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cn4)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 125.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyridin-3-amine (15 mg, 0.0415 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (24.3 mg, 0.104 mmol; prepared as in Example 19, Step C) HOBT-H2O (6.36 mg, 0.0415 mmol), EDCI (7.96 mg, 0.0415 mmol), N-ethyl-N-isopropylpropan-2-amine (5.36 mg, 0.0415 mmol) and DMF (3 mL). The reaction mixture was stirred at room temperature for 18 hours. Diluted with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to obtain product (30 mg, 90%) as a light brown solid. LRMS (esi+) 578 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[C:20]([N:12]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:11])[CH2:9][CH3:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: CCC(=O)c1ccc(F)cc1Nc1ccccc1
Reactant: COC(=O)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(F)cc1N(C(=O)C(=O)OC)c1ccccc1
Temperature: 110 °C

Procedure:
To a solution of 1-(4-fluoro-2-phenylamino-phenyl)-propan-1-one (6.0 g, 24.7 mmol) in toluene (75 mL) was added methyl chlorooxoacetate (14.2 mL, 148 mmol) at room temperature under nitrogen. The reaction mixture was heated at reflux at 110° C. for 16 hr. The reaction mixture was concentrated under vacuum to afford N-(5-fluoro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester. The crude product was used in the next step without further purification.
Reaction SMILES: C(O[C:9](=O)[N:10](C)[CH2:11][C:12]1[C:24]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[C:17](=[O:25])[NH:16][C:15]=2[N:14]([CH3:26])[N:13]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(#N)C>[CH3:26][N:14]1[C:15]2[NH:16][C:17](=[O:25])[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[C:24]=2[C:12]([CH2:11][NH:10][CH3:9])=[N:13]1
Reactant: CN(Cc1nn(C)c2[nH]c(=O)c3c(c12)CCCC3)C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CNCc1nn(C)c2[nH]c(=O)c3c(c12)CCCC3

Procedure:
A solution of EXAMPLE 38A (160 mg) in trifluoroacetic acid (10 mL) was heated at 60° C. for 18 hours. The mixture was cooled, diluted with acetonitrile and concentrated. The residue was purified by HPLC (Zorbax C-8, 0.1% trifluoroacetic acid/acetonitrile/water) and the trifluoroacetate salt dissolved in methanol and treated with a solution of hydrochloric acid in ether to provide the title compound as the hydrochloride salt (82 mg, 79%). 1H NMR (DMSO-d6): 1.67-1.79 (m, 4H), 2.38-2.45 (m, 2H), 2.66 (t, J=4.3 Hz, 3H), 2.84-2.95 (m, 2H), 3.86 (s, 3H), 4.40-4.44 (m, 2H), 9.06 (br s, 1H), 12.17 (br s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23]>>[ClH:23].[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(C2CCN(Cc3ccccc3)C2)nn1
Agent: Cl
Product: O=C(O)c1cn(C2CCN(Cc3ccccc3)C2)nn1
Temperature: 110 °C

Procedure:
A solution of N-benzyl-3-(4-ethoxy carbonyl -1,2,3-triazol-1-yl)-pyrrolidine (5 g) in 5N HCl (200 ml) was heated under reflux at 110° C. for 16 hrs. The solution was evaporated under vacuum to dryness and the residue was crystallized from methanol/ether. Yield 3.6 g, 70.17%). 1H NMR (D2O) δ: 2.11-2.72 (m, 2H), 3.30-3.90 (m, 4H), 4.27 (S, 2H), 5.18-5.48 (m, 1H), 7.30 (S, 5H), 8.30 (S, 1H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.N1C=CC=CC=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>C(Cl)Cl>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a round-bottomed flask equipped with magnetic stir bar was charged 1a (3.0 g, 20 mmol), pyridine (4.7 g, 59 mmol, 3 equiv) and CH2Cl2 (25 mL). The mixture was cooled in a dry ice-acetone bath and Tf2O (6.6 mL, 11.1 g, 39 mmol, 2 equiv) was added dropwise over 30 min Afterwards, the mixture was stirred at room temperature for 2 h. The reaction mixture was washed with H2O (2×25 mL) followed by brine (25 mL). The organic phase was separated, dried over anhydrous MgSO4 and evaporated under reduced pressure leaving a brownish oil (5.12 g, 90%). The crude product could be further purified by short-path distillation at reduced pressure (0.1 ton) to give the product as colorless oil. However, the compound appears to be heat sensitive as there was a significant decomposition residue in the distillation pot. 1H NMR (CDCl3): δ 9.98 (s, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.51 (dd, J=8.2 and 1.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 3.99 (s, 3H); 13C NMR (CDCl3): δ 190.53, 152.49, 142.97, 137.06, 124.27, 123.45, 121.06, 118.92 (q, 1JCF=321.5 Hz), 112.06, 56.75; 19F {13C} NMR (CDCl3): δ −74.2. The product was used in the synthesis of compound 3a without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8](O)[CH3:9].[Cl:28]CCl>S(Cl)(Cl)=O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([Cl:28])[CH3:9]
Reactant: CC(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a solution of 0.96 g of 3-[3-chloro-4-(1-hydroxyethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 20 mL of dichloromethane, 0.2 mL of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into 20 mL of ice water, and the organic phase was collected, washed with water (20 mL×1) and then saturated sodium hydrogen carbonate aqueous solution (20 mL×3), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and then the solvent was distilled off under reduced pressure to obtain 0.88 g of the aimed product as yellow oily substance.
Reaction SMILES: [Na].[CH3:2][OH:3].[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)C=O>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([O:3][CH3:2])[CH:15]=[CH:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: CO
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium (2.49 g, 0.11 mol) was added portionwise to methanol (70 ml) and was stirred at room temperature under a nitrogen atmosphere for 30 minutes. N,N-dimethylformamide (35 ml) was added and the solution was added to 6-benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (2.8 g, 10.9 mmol) (see reference WO98/30560 Example 33b). The mixture was heated at reflux under a nitrogen atmosphere for 5 days and then was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane (gradient from 0:100 to 4:96) and the material obtained was dried under vacuum to give the title compound (2.54 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:13].C1C=C(O[C:22](OC2N=CC=CC=2)=[S:23])N=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[N:1]([C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:13])=[C:22]=[S:23]
Reactant: Cc1cc(N)c(C)c2c(C)ccnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1cc(N=C=S)c(C)c2c(C)ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-amino-4,5,8trimethylquinoline (0.37 g), di-2-pyridyl thionocarbonate (0.494 g) (DPT) (Aldrich), dimethylaminopyridine (0.052 g) and methylene chloride (4 mL) is stirred at room temperature for 2 hours. An additional 100 mg of DPT is added, and stirring is continued for one hour. Another 100 mg portion of DPT is added, and the reaction is stirred at room temperature for one more hour. The mixture is concentrated by evaporation and purified by chromatography through a short column consisting of layers of sand/flash silica gel/sand, using 20% ethyl acetate in hexane as the eluting solvent, providing 6-isothiocyanato-4,5,8-trimethylquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]3([CH2:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:22]=4)[O:17]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[NH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]3([CH2:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21](/[CH:27]=[CH:28]/[C:29]([NH:32][O:33][CH:34]5[CH2:39][CH2:38][CH2:37][CH2:36][O:35]5)=[O:30])[CH:22]=4)[O:17]3)[CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)O)ccc2O3)cc1
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: COc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)cc1

Procedure:
(E)-3-{1′-[2-(4-Methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (165 mg, 0.360 mmol) was suspended in DCM (5 ml). TEA (0.075 ml, 0.54 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (163 mg) as a yellow solid. The compound was then dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving the desired hydroxamic acid as a light yellow solid (103 mg, hydrochloride salt).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:21][NH:22][C@H:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][OH:32])[CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[Si:35]([O:34][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][C@H:23]([CH3:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][OH:32])[CH:26]=1)([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:37])[CH3:36]
Reactant: C[C@H](Cc1cccc(CO)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H](Cc1cccc(CO)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
A mixture of 8-(benzyloxy)-5-((R)-1-(tert-butyldimethylsilyloxy)-2-((R)-1-(3-(hydroxymethyl)phenyl)propan-2-ylamino)ethyl)quinolin-2(1H)-one (Example 276, step e) (0.52 g) and 10% palladium on carbon catalyst (0.102 g) in ethanol (36 mL) was hydrogenated at room temperature and at 5 bar pressure of hydrogen for 1.5 hours, then hydrogenated at room temperature and at 1 bar pressure of hydrogen overnight. The mixture was filtered through diatomaceous earth, washing the catalyst well with ethanol, and the combined filtrate and washings were concentrated in vacuo to afford the subtitled compound. Yield 0.42 g. Material used immediately in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[O:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[O:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:26]=2)=[CH:19][CH:18]=1
Reactant: ClCc1coc(-c2ccc(Cl)o2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Clc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)o1
Yield: 86 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(5-chloro-2-furyl)-4-chloromethyloxazole to give 2-(5-chloro-2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 86%. Recrystallization from ethyl acetate-isopropyl ether gave colorless prisms, mp 88-89° C.