Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:8][N:7]([C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=2)[C@H:6]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>O1CCCC1>[NH2:1][CH:4]1[CH2:8][N:7]([C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[CH:16][CH:17]=2)[C@H:6]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:5]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)N2CC(N=[N+]=[N-])C[C@H]2C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)N2CC(N)C[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.2 g of benzyl 4-azido-1-[3-(4-tert-butyloxycarbonylaminomethylphenyl)propionyl]prolinate (starting material B3) are dissolved in 50 ml of tetrahydrofuran, and 3.52 g of triphenylphosphine are then added a little at a time, as a result of which a clear evolution of gas can be observed. After 4 h of stirring at RT, 10 ml of water are added, and the mixture is stirred at RT for 6 days. 12.5 ml of 1N hydrochloric acid solution are added, and the mixture is then extracted twice with ethyl acetate. Using 13 ml of 1N sodium hydroxide solution, the aqueous phase is made slightly alkaline, and the phase is then extracted three times with a mixture of ether/methanol (8:2). The extract is dried over magnesium sulfate and then concentrated, and the residue is dried under high vacuum. This gives 2.22 g of the title compound as a viscous oil. The mass spectrum shows the molecular peaks MH+, MNa+ and M2H+ at 482, 504 and 962 Da, respectively.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]#[C:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]#[C:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCOCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)N(CCOCC#Cc1cncs1)C(=O)C(=O)O
Temperature: 55 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
A solution of 450 mg of 11e in 4 ml of dioxane was mixed with a solution of 250 mg of KOH in 2 ml of water and stirred at 55° C. for 1 h. The reaction mixture was then cooled and diluted with 20 ml of water and made acidic to pH3 by addition of 0.5N HCl. The product was extracted with ethyl acetate. The organic extract was washed once with water, dried and concentrated, to give 430 mg of 11f as a colorless oil, which solidified on standing; Mp: 104-105° C.; Rf 0.20 (CH2Cl2/methanol 8/2). MS-ESI:
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:20])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:3])[CH3:2].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:20])[C@@H:11]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](CCc1ccccc1)CC(=O)OC(C)(C)C

Procedure:
Following the procedure described in Referential Example 4, but using 4-(S)-isopropyl-3-(1-oxo-4-phenylbutyl)-2-oxazolidinone (8.83 g), prepared in Referential Example 91, and tert-butyl bromoacetate (25.0 ml), there was obtained the desired compound (7.35 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=[CH:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: C1=CC=CNC=C1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCCC4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and azepine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.86 (s, 1H), 3.3-3.8 (m, 16H), 1.95 (m, 4H), 1.75 (m, 4H); MS (DCI) m/z 434 (M+H)+;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.19 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: C[Si](Cl)(C)C.[CH:6]1([Mg]Cl)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:14][C:15]([CH3:22])=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[Cl-].[NH4+]>O1CCCC1.[Cu]Cl>[CH:6]1([C:15]([CH3:22])([CH3:14])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCOC(=O)C=C(C)C
Agent: Cl[Cu]
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethylsilyl chloride (1.3 ml, 10.2 mmol), copper (I) chloride (30 mg, 0.3 mmol) and cyclohexylmagnesium chloride (4.6 ml, 2N in diethyl ether, 9.2 mmol) were added slowly to an ice-cooled solution of ethyl 3,3-dimethylacrylate (1 g, 8.5 mmol) in tetrahydrofuran (10 ml). The solution was stirred for 10 minutes, then allowed to warm to room temperature and stirred for an hour. Saturated aqueous ammonium chloride solution (10 ml) was added and the mixture was partitioned between water (10 ml) and diethyl ether (20 ml). The layers were separated and the aqueous phase was extracted with diethyl ether (2×10 ml). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane(5:95) as eluant to afford the title compound, 1.2 g. 1H-NMR (CDCl3, 400 MHz) δ: 0.75 (m, 8H), 1.05-1.28 (m, 7H), 1.62 (m, 1H), 1.78 (m, 4H), 2.20 (s, 2H), 4.10 (q, 2H).
Reaction SMILES: C([Li])CCC.[CH:6]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)[CH2:8][CH2:7]1.[B:18](OC)([O:21]C)[O:19]C>O1CCCC1>[CH:6]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([B:18]([OH:21])[OH:19])=[CH:13][CH:12]=2)[CH2:8][CH2:7]1
Reactant: COB(OC)OC
Reactant: Ic1ccc(OCC2CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCC2CC2)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Butyl lithium (2.5 M in hexane, 14.4 mL, 36 mmol) was added dropwise (5 min) to a cooled (−78° C.) and stirred solution of 4-(cyclopropylmethoxy)iodobenzene 1 (9.00 g, 32.8 mmol) in tetrahydrofuran (100 mL). After 20 min, trimethyl borate (11.3 mL, 10.4 g, 100 mmol) was added dropwise (10 mL). The reaction was stirred for an additional 20 min, and was then allowed to warm to rt. The reaction was quenched with 1 M hydrochloric acid (300 mL) and stirring was continued for 30 min. The product was extracted with diethyl ether (4×100 mL) and then the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in toluene and then concentrated. This operation was repeated (5×) until the distillate was colorless and left 5.67 g (90%) of crude product. This material was used without purification or analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25].O>N1C=CC=CC=1>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)=[O:25])[CH:7]=1)=[O:18]
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reactant: O=C(Cl)c1cccs1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1)c1cccs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (240 mg, 0.86 mmol) was dissolved in pyridine (10 mL). The mixture was stirred at 0° C. for 20 min. and then thiophene-2-carbonyl chloride (113 mg, 0.77 mmol) was added dropwise. The mixture was warmed to 23° C. and stirred under nitrogen overnight. The next day, water (1 mL) was added and the mixture was stirred for 5 min. The reaction was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (Gemini, 200 mm×25 mm, gradient: CH3CN/0.05% NH3.H2O, 50-80, 10 min) to afford the desired product (72.6 mg, yield: 22%). 1HNMR: (DMSO-d6, 400 MHz): δ 11.38 (s, 1H), 10.92 (s, 1H), 8.47 (s, 1H), 8.33 (d, J=5.6 Hz, 1H), 8.26 (d, J=2.8 Hz, 1H), 7.90 (d, J=5.2 Hz, 1H), 7.62-7.51 (m, 4H), 7.22 (t, J=4.4 Hz, 1H). LCMS (ESI) (m/z): 414.3 [M+Na+].
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:22][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:20][CH2:19][N:18](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:17][CH2:16][N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:11][CH2:10][N:9]2S(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)C=CC=CC=1.Br.C(O)C>C(O)(=O)C.C(OCC)C>[C:1]1([CH2:7][CH:8]2[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC(Cc3ccccc3)N(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: c1ccc(CC2CNCCNCCNCCNCCN2)cc1
Temperature: 120 °C
Yield: 39 %

Procedure:
A mixture of 2-phenylmethyl-1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 6C (20.0 g, 0.0186 mole), phenol (8.75 g, 0.0929 mole) and 30% HBr in glacial acetic acid (250 ml) were heated in each of 2 sealed tubes in the dark at 120° C. for 16 h. Upon cooling to room temperature, a 1:1 mixture of ethanol and ethyl ether (250 ml) was added to each tube. The contents of the tubes were combined and ethyl ether (3 l) was added. The dark brown solid was filtered and washed thoroughly with ethyl ether. The oily solid was then dissolved in H2O (1l) and the resulting solution was washed with ethyl ether. The solution was concentrated in vacuo to a volume of 250 ml. The pentahydrobromide salt was crystallized by the addition of isopropanol (1l), followed by cooling to 5° C. The pentahydrobromide salt (21.2 g) was dissolved in H2O (50 ml) and the resulting solution was washed with ethyl ether. The pH of the solution was adjusted to 11 with 10N NaOH and the solvent was removed in vacuo. Ethanol (2×500 ml) was then added and removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and filtered at room temperature. The filtrates were combined, the solvent was removed in vacuo and the oil was redissolved in THF. After filtration, the solvent was removed in vacuo. The residue was redissolved in a 1:1 mixture of CH3CN-THF and the solution was filtered. The solvent was removed in vacuo and the crude product was purified by recrystallization from cold CH3CN (-20° C.) to give 4.47 g (39% yield) of an off-white crystalline solid: mp 98°-100° C.; 1H NMR (CDCl3) δ1.75 (br s, 5 H), 2.35 (m, 1 H), 2.73 (m, 20 H), 7.22 (m, 5 H); Anal. calcd. for C17H31N5 : C, 66.84; H, 10.23; N, 22.93. Found: C, 66.86; H, 10.26; N, 23.32.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].Br[CH2:24][C:25]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[C:20]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:7][C:2]=1[O:1][CH2:24][C:25]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1O
Reactant: CCOC(=O)COc1c(C)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)COc1c(C)cccc1COc1cc(OCc2ccc3ccccc3n2)ccc1C(C)=O
Temperature: 50 °C

Procedure:
1-[2-Hydroxy-4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (185 mg, 0.63 mmol, example 58) is dissolved in 2:1 DMF/acetonitrile (6 mL). Ethyl (2-bromomethyl-6-methyl-phenoxy)-acetate (272 mg, 0.95 mmol, example 43b) and K2CO3 (177 mg, 1.26 mmol) are added and the contents are heated to 50° C. for 2 days. The reaction is cooled to r.t. and the volume reduced under a nitrogen stream at 40° C. The contents are partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer is further extracted with ethyl acetate (2×50 mL). The organic fractions are combined and washed with brine (3×75 mL), dried over MgSO4 and concentrated. The crude material is dissolved in 1:1 dichloromethane/methanol, preadsorbed onto silica gel, and purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ion spray) 500 (M+H)+.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+].C(=O)(O)[O-].[Na+]>COCCOC.O>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([OH:22])=[CH:24][CH:25]=3)[S:10][C:9]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)c(F)c1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
To a solution of 2-bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (42, scheme 8) (650 mg, 1.76 mmol) in ethylene glycol dimethyl ether (18 mL) were added 4-hydroxyphenylboronic acid (486 mg, 3.52 mmol), tetrakis-triphenylphosphine palladium(0) (203 mg, 0.18 mmol), cesium fluoride (802 mg, 5.28 mmol) and a solution of sodium bicarbonate (444 mg, 5.28 mmol) in water (1 mL). The reaction mixture was purged with nitrogen, heated at 80° C. for 4 hours, quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by trituration with methanol and ether to afford title compound 153 (418 mg, 62% yield) as a yellow solid. LRMS (M+1) 383.1 (100%).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17](=[N:18][OH:19])[C:16]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:32])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C.O>[Cl:31][C:26]1[CH:25]=[C:24]([C:16]2([C:20]([F:22])([F:21])[F:23])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:33])=[O:5])=[C:8]([CH3:32])[CH:9]=3)[C:17]2=[N:18][OH:19])[CH:29]=[C:28]([Cl:30])[CH:27]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2=NO)ccc1C(=O)OC(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2=NO)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-4-hydroxyimino-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example 13.2) (634 mg) in dichloromethane (4 ml) was added trifluoroacetic acid (“TFA”) (0.2 ml) and the reaction mixture was stirred at ambient temperature for 8 hours. Further trifluoroacetic acid (0.2 ml) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and water and the phases were separated. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated to give 4-[5-(3,5-dichloro-phenyl)-4-hydroxyimino-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (554 mg) as a yellow foam. 1H-NMR (CDCl3, 400 MHz): 8.94 (s, 1H), 8.10 (d, 1H), 7.90 (m, 2H), 7.59 (m, 2H), 7.44 (m, 1H), 2.69 (s, 3H).
Reaction SMILES: C1C=NC=C(C(O)=O)C=1.Br[C:11]1[O:15][C:14]([C:16]([NH:18][C@@H:19]([CH2:24][N+:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([O-:23])=[O:22])=[O:17])=[CH:13][CH:12]=1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:32]=1)#[CH:30]>>[CH2:38]([O:37][C:33]1[CH:32]=[C:31]([C:29]#[C:30][C:11]2[O:15][C:14]([C:16]([NH:18][C@@H:19]([CH2:24][N+:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([O-:23])=[O:22])=[O:17])=[CH:13][CH:12]=2)[CH:36]=[CH:35][CH:34]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1ccc(Br)o1
Reactant: C#Cc1cccc(OCCCCCC)c1
Agent: O=C(O)c1cccnc1
Product: CCCCCCOc1cccc(C#Cc2ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)o2)c1
Yield: 20 %

Procedure:
According to the method described in example S115, (R)-3-(5-bromofuran-2-carboxamido)-4-(trimethylammonio)butanoate was reacted with 1-ethynyl-3-(hexyloxy)benzene. The crude product was purified by silica gel chromatography (CH2Cl2/MeOH 3:2) to give the title compound as a white powder (11.1 mg, 20%). 1H NMR (400 MHz, D2O) δ 6.94-6.89 (m, 2H), 6.81-6.79 (m, 1H), 6.57 (s, 1H), 6.46-6.44 (m, 1H), 6.30 (s, 1H), 4.80-4.76 (m, 1H), 3.67-3.45 (m, 4H), 3.01 (s, 9H), 2.44-2.35 (m, 2H), 1.38-1.32 (m, 2H), 1.10-0.95 (m, 6H), 0.61 (t, 3H, J=6.4 Hz); MS ESI [M+H]+, calcd for [C26H34N2O5+H]+ 455.25; found m/z 455.3.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[C:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:30])[CH3:29].COCCOC.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=3[N:7]=2)=[CH:34][CH:33]=1)(=[O:30])[CH3:29]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)Nc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)nn(C(C)C)c3n2)cc1

Procedure:
The title compound was prepared in the same manner as described in example 93 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol), [4-(acetylamino)phenyl]boronic acid (55.4 mg, 0.31 mmol), bis(triphenylphosphine)palladium(II) chloride (8.4 mg, 0.01 mmol), DME/water (4 mL, 3:1) and sodium bicarbonate (52 mg, 0.62 mmol). The crude product was dissolved in DCM/MeOH (1:1) and preabsorbed onto silica gel. The product was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH. gradient of 0 to 80:20:2). The collected solid was suspended in EtOH/EtOAc (1:1), sonicated, and filtered. After further washing with hexanes, the solid was then air-dried for 15 min, and then in vacuum oven overnight. The final product was collected as 70 mg (69%). LCMS E-S (M+H)=487.3 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br. s., 1H) 10.16 (s, 1H) 8.73 (t, J=5.05 Hz, 1H) 8.17 (m, J=8.84 Hz, 2H) 7.74 (m, J=8.84 Hz, 2H) 7.64 (s, 1H) 5.89 (s, 1H) 5.25 (quin, J=6.69 Hz, 1H) 4.39 (d, J=4.80 Hz, 2H) 2.43 (s, 3H) 2.25 (s, 3H) 2.12 (s, 3H) 2.09 (s, 3H) 1.51 (s, 3H) 1.49 (s, 3H).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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][CH2:17][CH3:18].[O-2].[Zn+2:22].CCCCC(CCC(OS([O-])(=O)=O)CC(C)C)CC.[Na+]>O>[C:1]([O-:20])(=[O:19])[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][CH2:17][CH3:18].[Zn+2:22].[C:1]([O-:20])(=[O:19])[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][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-2]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 67.5 °C
Reaction time: 1 h

Procedure:
A molten stearic acid (22 grams, Industrene 7018) was added gradually to a stirred slurry comprising zinc oxide (3.6 grams), Methocel F50 (0.2 gram), Tergitol 15-S-7 (0.2 gram), and water (70 grams) at 55° C. The mixture was stirred at 65-70° C. for 1 hour to produce a yield of zinc stearate of about 50% by its infrared spectrum.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Product: Clc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, off-white solid (41 mg, 31%), MS (ISP) m/z=405.3 [(M+H)+], mp 172.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-chloro-phenyl)-imidazo[1,2-a]pyridine (intermediate F) (0.1 g, 0.325 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.12 g, 0.39 mmol).
Reaction SMILES: [F:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([NH2:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[C:14](=O)[C:15](=[O:20])[C:16]=1[O:17]CC)[CH3:11]>C(O)C>[Br:8][C:7]1[CH:6]=[C:5]([NH:9][C:14]2[C:15](=[O:20])[C:16](=[O:17])[C:13]=2[O:12][CH2:10][CH3:11])[CH:4]=[N:3][C:2]=1[F:1]
Reactant: Nc1cnc(F)c(Br)c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cnc(F)c(Br)c2)c(=O)c1=O

Procedure:
A solution of 2-fluoro-3-bromo-5-aminopyridine and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example 1A to provide the title compound.