Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:25][CH2:24][CH2:23][N:15]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[CH:22]=[C:14]4[C:13]=3[CH:26]=2)O1.Br[C:29]1[C:30]([N:49]([CH3:54])[S:50]([CH3:53])(=[O:52])=[O:51])=[CH:31][C:32]2[O:36][C:35]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[C:34]([C:44]([NH:46][CH3:47])=[O:45])[C:33]=2[CH:48]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:26]1[C:13]2[C:14]3[N:15]([CH2:23][CH2:24][O:25][C:12]=2[CH:11]=[CH:10][C:9]=1[C:29]1[C:30]([N:49]([CH3:54])[S:50]([CH3:53])(=[O:52])=[O:51])=[CH:31][C:32]2[O:36][C:35]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)=[C:34]([C:44]([NH:46][CH3:47])=[O:45])[C:33]=2[CH:48]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[CH:22]=3
Reactant: CC1(C)OB(c2ccc3c(c2)-c2cc4ccccc4n2CCO3)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(c3)-c3cc5ccccc5n3CCO4)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
A mixture of compound 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydrobenzo[6,7][1,4]oxazepino[4,5-a]indole (72 mg, 0.2 mmol), 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (91 mg, 0.2 mmol), K3PO4-3H2O (160 mg, 0.6 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol) in 2 mL of DMF was stirred at 90° C. for 8 h under N2, then the mixture was purified using prep-HPLC to provide Compound 42 (30 mg, yield: 24.9%). 1H-NMR (CDCl3, 400 MHz) δ 7.92˜7.97 (m, 3H), 7.81 (s, 1H), 7.63˜7.65 (m, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.12˜7.25 (m, 5H), 6.97 (s, 1H), 6.00 (d, J=4.0 Hz, 1H), 4.62 (t, J=4.2 Hz, 2H), 4.54 (t, J=4.2 Hz, 2H), 3.18 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 610.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 55.1 %

Procedure:
A solution of 4-chloro-3-nitro aniline (2.0 g, 11.16 mmol), 4-benzyloxyphenol (2.55 g, 12.76 mmol), powdered potassium hydroxide (0.94 g, 16.80 mmol) in dimethylformamide (15 ml) was heated at 120° C. for 20 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a dark red solid as the title compound, (2.07 g, 53%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:22]([N:24]1[CH2:43][CH2:42][CH2:41][C@H:25]1[C:26]([NH:28][C@H:29]([C:34]([NH:36][CH2:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])=[O:23])[NH:11]C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.C(Cl)(Cl)(Cl)Cl.CO>[Pd].C(N(CC)CC)C>[CH2:1]([S:8][CH2:9][C@@H:10]([C:22]([N:24]1[CH2:43][CH2:42][CH2:41][C@H:25]1[C:26]([NH:28][C@H:29]([C:34]([NH:36][CH2:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])=[O:23])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CSCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CSCc1ccccc1)C(=O)NCC(N)=O
Reaction time: 0.17 h

Procedure:
S-Benzyl-N-benzyloxycarbonyl-L-cysteinyl-L-prolyl-L-leucyl-glycinamide (300 mg.) was dissolved in 35 ml. of anhydrous liquid ammonia and hydrogenated in the presence of freshly prepared palladium black (ca 0.1g.) and triethylamine (0.28 ml.) at the boiling point of the solvent. The reaction was followed by thin layer chromatography (solvent system CCl4 /CH3OH/CH3COOH8:1:1) which showed incomplete reaction (50-60%) after 6 hours. Evaporation of ammonia under nitrogen was followed by addition of methanol (10 ml.) and stirring for 10 min. The catalyst was then removed by filtration and washed with methanol (10 ml.). The combined filtrate and washings were passed through a column (1.2 × 10 cm) of Dowex 50 × 8 (H+ form) which was washed with methanol. The desired material was then eluted with 2N ammonium hydroxide-methanol (1:1) and the eluate evaporated in vacuo. Crystallization from water gave 95.2 mg. (42.3%); m.p. 130°-134°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][CH:3]=1.[CH:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([OH:25])[CH:17]=1>ClC1C=CC=CC=1>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=[C:6]2[C:11]=1[C:2]([O:25][C:18]1[CH:17]=[CH:16][C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)=[CH:3][CH:4]=[N:5]2
Reactant: COc1cc(OC)c2c(Cl)ccnc2c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Clc1ccccc1
Product: COc1cc(OC)c2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloro-5,7-dimethoxyquinoline (100 mg, 0.40 mmol) and p-nitrophenol (124 mg, 0.89 mmol) in chlorobenzene (2 mL) was heated at reflux for 14 h. Then the reaction mixture was cooled to rt, filtered, and the residue washed with toluene. The solid was suspended in 10% NaOH solution and stirred for 1 h at rt. The yellow solid was collected and washed with EtOAc to give 5,7-dimethoxy-4-(4-nitrophenoxy)quinoline. LCMS m/z=327 (M+1); 1H NMR (CDCl3) δ: 8.60 (d, 1H, J=6.0 Hz), 8.44 (d, 2, J=8.8 Hz), 7.72 (s, 1H), 7.35 (d, 2H, J=8.4 Hz) 6.71 (s, 1H), 6.69 (d, 2H, J=6.4 Hz), 4.08 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: [Na].N.[C:3]1([C:9]2[C:18]3[C:13](=[C:14](Cl)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](#[N:22])[CH3:21]>[Fe](Cl)(Cl)Cl>[C:3]1([C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:21][C:20]#[N:22])[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1cccc2c(-c3ccccc3)nccc12
Reactant: CC#N
Agent: Cl[Fe](Cl)Cl
Agent: N
Agent: [Na]
Product: N#CCc1cccc2c(-c3ccccc3)nccc12
Reaction time: 5 h

Procedure:
Metallic sodium (1.15 g) was added to 100 ml of liquid ammonia, and 1.3 g of acetonitrile and 2.39 g of 1-phenyl-5-chloroisoquinoline were added to the solution. A small amount of iron trichloride was added, and the reaction was performed for 5 hours. After the reaction, ammonia was distilled off, and ice water was carefully added to the residue. The resulting oily product was extracted with ether, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was chromatographed to afford 1-phenylisoquinoline-5-acetonitrile as an oil.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH2:7][C:6](=O)[C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2:12][OH:13].C(O)C>N1C=CC=CC=1>[OH:13][N:12]=[C:6]1[CH2:7][CH:8]=[CH:9][C:10]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]1=2
Reactant: NO
Reactant: O=C1CC=Cc2cnccc21
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CC=Cc2cnccc21
Yield: 61.8 %

Procedure:
Isoquinolin-5-one (21.57g, 0.147M) and hydroxylamine (15.55g, 0.22M) together with approximately 300 ml of dry ethanol and 75 ml of pyridine were stirred at reflux temperature of the mixture for 6 hours. The solvent was then removed by evaporation and the residue was dissolved in a mixture of diethyl ether and water (600 ml, ca. 1:1). The organic phase was separated and extracted with water to remove residual pyridine, washed with saturated, aqueous solution of sodium chloride and dried over magnesium sulfate crystals. The inorganic matter was removed by filtration and the solvent by evaporation leaving 14.7 grams of the desired product (61.7% yield).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19](O)[CH2:18][C@:14]2(O)[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4](OC(C)=O)[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2OC(C2C=CC=CC=2)=O)[C@:11]2(OC(C)=O)[CH2:31]O[C@@H:10]2[CH2:9][C@@H:8]1O)=O.C(=O)=O.C(#N)C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[CH3:31][C@H:11]1[C@H:12]2[CH2:13][C@H:14]3[C:15]([CH3:16])([CH3:17])[C@@H:3]([CH2:4][CH2:5][C@:7]2([CH3:38])[CH2:8][CH2:9][CH2:10]1)[C@H:2]([CH3:1])[CH2:19][CH2:18]3
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H]1CCC[C@@]2(C)CC[C@H]3[C@H](C)CC[C@@H](C[C@H]12)C3(C)C
Reaction time: 0.5 h
Yield: 190.1 %

Procedure:
Coupling reaction: the C-7 triethylsilylprotected baccatin III (0.048 g; 0.0685 mmol) and the triethylsily-isopropyl-β-lactam (3) (0.043 g; 0.0978 mmol; 1.4 eq.) were dissolved in 3.6 ml dry tetrahydrofuran. The solution was cooled to a temperature in the range −45° C. to −50° C. (dry ice-acetonitrile bath) under nitrogen. The base sodium bistrimethylsilylamide (NaHMDS) (1.0 M) solution in tetrahydrofuran; 0.175 ml; 175 mmol; 2.6 eq) was added in one portion at a temperature of −45° C. and the reaction was stirred for 30 min at this temperature. The solution became yellow and was quenched at 30 min with an ammonium chloride saturated solution. The work up consisted of quenching the reaction with saturated ammonium chloride, extracting with ethyl acetate, washing the organic phase with brine and drying the organic layer with magnesium sulphate. After filtration the solvent was evaporated and flash chromatography of the residue with 20% ethyl acetate/hexane in a 6″ chromatography column; 36 mg of the coupled protected taxane (5) was obtained with 14 mg of starting material recovered (4, uncoupled protected baccatin III).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19](O)=[O:20].[N:22]1([CH:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C@H:36]([NH:40]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]3)[CH3:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:9])=[O:10])[C@@H:3]1[CH2:18][C:19]([NH:40][C@H:36]1[C:37]2[C:32](=[CH:31][C:30]([CH:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH3:29])=[CH:39][CH:38]=2)[CH2:33][CH2:34][CH2:35]1)=[O:20]
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)O)cc1
Reactant: CC(c1ccc2c(c1)CCC[C@H]2NC(=O)OC(C)(C)C)N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)N[C@@H]2CCCc3cc(C(C)N4CCCCC4)ccc32)cc1
Reaction time: 8 h

Procedure:
(R)-2-(3-Oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetic acid (140 mg) and (1R)-6-(1-(piperidin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (122 mg, prepared in Example 12) are combined in 2 mL of DMF, then EDCI (112 mg) and HOBT (79 mg) are added and the mix is stirred under nitrogen overnight. Next the mix was quenched with sat. sodium bicarb., extracted with ethyl acetate, washed with brine, washed with water, dried with sodium sulfate, and concentrated. The compound was then purified on the varian using 10 to 90% acetonitrile in water to give the product. MS 551 (ESI, pos. ion).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1>C(O)CCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][C:4]([CH3:13])=[C:3]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[C:2]3=[N:32]2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cnc(C)c(-c2ccc(OC)cc2)c1Cl
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCCCO
Product: COc1ccc(-c2c3nn(-c4ccc(OC)cc4)c(=O)c-3c[nH]c2C)cc1
Yield: 20.9 %

Procedure:
A mixture of ethyl 4-chloro-3-(4-methoxyphenyl)-2-methyl-5-pyridinecarboxylate (0.1842 g, 0.602 mmol) and 4-methoxyphenylhydrazine hydrochloride (0.1000 g, 0.724 mmol) in anhydrous 1-butanol (7 ml) was degassed by evaporating the flask under vacuum and refilling with nitrogen several times. The mixture was then stirred at reflux under nitrogen for 32 h, during which time more 4-methoxyphenylhydrazine hydrochloride (0.1001 g, 0.724 mmol) was added. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 3-7% MeOH/CH2Cl2) to give 45.5 mg (21%) of the title compound as a yellow solid; mp 274-282° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.40 (3H, s), 3.88 (3H, s), 3.96 (3H, s), 7.08 (2H, d, J 9.2 Hz), 7.19 (2H, d, J 8.7 Hz), 7.59 (2H, d, J 8.7 Hz), 8.11 (2H, d, J 9.1 Hz), 8.61 (1H, s), 12.43 (1H, br s); MS (ES+) m/z 362 MH]+. Anal. found: C, 69.95; H, 5.02; N, 11.60. C21H19N3O3 requires: C, 69.79; H, 5.30; N, 11.63%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].O1CCCC1.S([O-])([O-])(=O)=S.[Na+:30].[Na+]>ClCCl.C(=O)(O)[O-].[Na+]>[Na+:30].[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=CCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
To a cooled solution (0° C.) of 16-hydroxyhexadecanoic acid (800 mg, 2.9 mmol) in dichloromethane (10 ml) and tetrahydrofurane (20 ml) Dess-Martin periodinane (1636 mg, 3.7 mmol) was added at 0° C. The mixture was stirred for 3.5 hrs at 0° C. and 2.5 hrs at room temperature under Ar-atmosphere. Then a 15%-solution of sodium thiosulfate in saturated sodium bicarbonate solution was added, the mixture was stirred at room temperature for 1.5 hrs. Intermediate 1 was extracted with diethylether, after drying over sodium sulfate the organic layer was evaporated to dryness and purified by column chromatography using silica gel as separating agent and a solvent mixture of toluene/ethylacetate. Yield: 34% (white solid).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[O:22][CH2:23][CH:24]([OH:26])[CH3:25].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[O:22][CH2:23][CH:24]([O:26][S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)O)C(=O)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OCC
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 747 mg of the compound obtained in Example 3 in 2 ml of pyridine was added 710 mg of p-toluenesulfonyl chloride and the mixture was stirred under cooling with ice for 24 hours, and then at room temperature for 4 hours. To the mixture were added ethyl acetate and 1 N hydrochloric acid. The mixture was shaken, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 1.0 g of the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 1.16 g, 26.5 mmol) in THF (30 mL) was added a solution of [3-(4-chloro-phenyl)-isoxazol-4-yl]-methanol (24.1 mmol) in THF (60 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (4.65 g, 26.5 mmol) in THF (60 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1 to 2:1) afforded 6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72%) which was obtained as a light yellow solid. To a suspension of 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.0 mmol) in THF (3 mL) and methanol (3 mL) was added a solution of lithium hydroxide monohydrate (85.1 mg, 2.0 mmol) in water (3 mL) and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (1 N, 30 mL) and the resulting mixture was filtered. The solid was dried to afford the title compound (100%) which was obtained as a light yellow solid. MS: m/e=331.1 [M−H]−.
Reaction SMILES: [CH:1]1([C:4]2(N3CCCC3)[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.C(O)C.Cl(O)(=O)(=O)=O.[OH-].[Na+]>O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: c1cc(C2=NOC(C3CC3)(N3CCCC3)C2)ccn1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1cc(-c2cc(C3CC3)on2)ccn1

Procedure:
To a solution of 2.6 g. of 4-[5-cyclopropyl-5-(1-pyrrolidinyl)-2-isoxazolin-3-yl]pyridine in 25 ml. of ethanol is added 1.4 g. of 70% perchloric acid dissolved in 5 ml. of ethanol. This solution is diluted wth 25 ml. of water and heated on a steam bath for 1.0 hour. The solution is poured onto cracked ice, made basic with 10 N sodium hydroxide and filtered to collect straw-colored crystals, melting point 76°-80°C., nmr spectrum δ6.84 (DMSO-d6, s, 4-isoxazolyl H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:41]=[CH:40][C:32]3[N:33]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[S:35][C:31]=3[CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.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>[OH:20][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:4]2[CH:3]=[C:2]([C:29]3[CH:41]=[CH:40][C:32]4[N:33]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[S:35][C:31]=4[CH:30]=3)[CH:7]=[N:6][CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)[CH3:19]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: CC(O)c1ccc(S(=O)(=O)Nc2cncc(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cncc(NS(=O)(=O)c4ccc(C(C)O)cc4)c3)cc2s1
Temperature: 100 °C
Yield: 15.7 %

Procedure:
A mixture of N-(5-bromopyridin-3-yl)-4-(1-hydroxyethyl)benzenesulfonamide (0.120 g, 0.34 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.11 g, 0.34 mmol), tetrakis(triphenylphosphine)palladium (0.019 g, 0.017 mmol) in 1 ml of dioxane and 1 ml of aq. 2M sodium carbonate was heated under microwave (CEM) at 120 W, 100° C. for 20 min. Then, the resultant was diluted with DCM and water. The organic layer was separated, dried and concentrated. The residue was purified by HPLC (5-60% CH3CN in water gradient) to give a light yellow solid (25 mg, 16%). MS (ESI pos. ion) Found m/z: 469, (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]([Cl:37])[CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>C1COCC1.C(Cl)Cl>[Cl:37][C:22]1[CH:21]=[C:20]([S:17]([N:14]2[CH2:13][CH2:12][CH:11]([NH:10][C:38](=[O:41])[CH:39]=[CH2:40])[CH2:16][CH2:15]2)(=[O:18])=[O:19])[CH:25]=[CH:24][C:23]=1[NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1CCN(S(=O)(=O)c2ccc(NC(=O)CCc3ccccc3)c(Cl)c2)CC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(NC(=O)CCc3ccccc3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.2 %

Procedure:
Diisopropylethylamine (0.09 ml, 0.56 mmol) was added in one portion to a stirred solution of N-[4-(4-Amino-piperidine-1-sulfonyl)-2-chloro-phenyl]-3-phenyl-propionamide (0.05 g, 0.1 mmol) in THF (5 ml), followed by the drop wise addition of acryloyl chloride (0.01 ml, 0.12 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 2% Methanol, 98% DCM) to give the title compound (0.002 g, 4% yield) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([OH:10])=[C:5]([Cl:11])[CH:4]=1.[OH-].[K+].[Cl:14][C:15]([F:19])=[C:16]([F:18])[F:17].O>CN(C)C=O>[Cl:14][CH:15]([F:19])[C:16]([F:18])([F:17])[O:10][C:6]1[C:5]([Cl:11])=[CH:4][C:3]([NH2:2])=[C:8]([Cl:9])[CH:7]=1
Reactant: FC(F)=C(F)Cl
Reactant: Nc1cc(Cl)c(O)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(OC(F)(F)C(F)Cl)cc1Cl
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
A solution of 25 g (0.12 mole) of 4-amino-2,5-dichlorophenol hydrochloride in 200 ml dimethylformamide was placed in a 500 ml 3-necked round bottom flask, fitted with a mechanical stirrer, thermometer, reflux condenser and sparger, and 13.4 g (0.24 mole) of potassium hydroxide pellets ground to powder were added. The mixture was heated to 90° C. with stirring under a nitrogen blanket. Then 21 g (0.18 mole) chlorotrifluoroethylene was bubbled in, while stirring and heating at 90° to 100° C., in about 1/2 hour. Stirring was continued for 5 minutes, the mixture cooled in an ice water bath, 500 ml of water were added and the resulting mixture extracted with 250 ml methylene dichloride and then 100 ml methylene dichloride. The extracts were combined, washed with 250 ml water and the methylene dichloride removed in a rotary evaporator. The residue was distilled through a 1"×10" Vigreaux. The cut from 110° to 120° C. at 2 mm pressure was a light tan liquid. Weight 21 grams. Yield was 59 percent. NMR analysis verified structure.