Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[Na].[CH2:13]([OH:18])[C:14]([F:17])([F:16])[F:15].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[O:18][CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: Fc1nc(F)c(Cl)c(OCC(F)(F)F)c1F
Temperature: -78 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
3-Chloro-2,4,5,6-tetrafluoropyridine (18.0 g, 97.0 mmol) was dissolved in anhydrous THF (100 mL) under an N2 atmosphere and the resulting solution cooled to −78° C. To the cold solution was slowly added a solution of sodium 2,2,2-trifluoroehtoxide (97 mmol), prepared from trifluoroethanol (7.1 mL, 97.0 mmol) and NaH (3.88 g, 97.0 mmol, 60% dispersion in mineral oil), in anhydrous THF (100 mL). The resulting mixture was slowly warmed to ambient temperature. After 18 h at ambient temperature a GC analysis indicates all the starting material was consumed. The volatiles were evaporated and the residue dissolved in CH2Cl2 (200 mL). The organics were washed with H2O (3×100 mL), dried (MgSO4), filtered and concentrated to give the crude product as a yellow oil. The yellow oil was distilled at reduced pressure to afford 3-chloro-2,5,6-trifluoro-4-(2,2,2-trifluoroethoxy)pyridine as a clear oil (16.3 g, 63% yield): bp 48° C. (ca 0.2 mm Hg); 1H NMR (CDCl3) δ 4.81-4.78 (dq, J=1.6, 7.7 Hz); GC-MS (El, 70 eV) m/z (% relative intensity) 267 (33), 265 (100), 248 (5), 246 (16), 198 (22), 196 (60).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13]C.Br.CCOC(C)=O>C(O)(=O)C>[OH:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 39.5 %

Procedure:
To a solution of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (3 g, 15.2 mmol) in acetic acid (3.1 mL) was added 40% hydrobromic acid (9.24 mL). The mixture was heated at 90° C. for 17 h. Reaction mixture was cooled and poured into ice water (100 mL), followed by a standard aqueous/EtOAc workup and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to give 3,4-dihydroxy-5-nitrobenzaldehyde (1.1 g, yield 39.5%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:35][C:36]1[CH:45]=[C:44]2[C:39]([CH:40]=[CH:41][CH:42]=[N:43]2)=[CH:38][CH:37]=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc2cccnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(O)C1
Agent: Br
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cccnc3c2)C1

Procedure:
By alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate [Example 86 (n)] with 7-bromomethyl-quinoline hydrobromide [J.Am.Chem.Soc. 77, 1054(1955)] analogously to Example 1 (g) there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 583 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Cl:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[C:12]([Cl:24])[CH:11]=1)[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CCN(C)CC2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CCN(C)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
80 mg of the t-butyl{(1S)-1-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}carbamate [107-1] was dissolved in 3 mL of chloroform, then 70 mg of N-chlorosuccinimide was added thereto, and stirred at room temperature for 2 hours. The reaction solution was diluted with chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and thus obtained residue was purified by preparative thin-layer chromatography, to obtain 80 mg of t-butyl{(1S)-1-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]ethyl}carbamate [139-1] as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][C:24]([OH:26])=O)[N:21]=1)=[CH:5]2.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][C:24]([NH:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])[N:21]=1)=[CH:5]2
Reactant: O=C(O)CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: NCCN1CCOCC1
Product: O=C(CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)NCCN1CCOCC1
Yield: 26 %

Procedure:
The compound (150 mg, 0.38 mmol) prepared in Example 149 and 4-(2-aminoethyl)morpholine instead of morpholine were reacted according to the same procedure as Example 70 to give the title compound (50 mg, Yield 26%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C1C=CC=CN=1)C.[C:24](O)([CH3:27])([CH3:26])[CH3:25].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([O:13][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A mixture of 2-(4-nitrophenyl)propanoic acid (15.0 g, 76.9 mmol), dimethylaminopyridine (4.70 g, 38.4 mmol) and tert-butanol (8.10 mL, 84.6 mmol) in methylene chloride (300 mL) was stirred at 0° C. for 2 h. After this time, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (17.0 g, 84.6 mmol) was added and the reaction stirred for a further 2 h. The ice bath was then removed and the reaction left to stir at room temperature overnight. After this time, the solvents were concentrated under reduced pressure and the solids redissolved in ethyl acetate (200 mL). The organic layer was then washed with saturated sodium bicarbonate (200 mL), 1 M citric acid (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1:20 ethyl acetate/hexanes) afforded tert-butyl 2-(4-nitrophenyl)propanoate (14.4 g, 75%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=9.2 Hz, 2H), 7.46 (d, J=9.2 Hz, 2H), 3.73 (q, J=7.1 Hz, 1i), 1.49 (d, J=7.1 Hz, 3H), 1.40 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.IN1[C:26](=[O:27])CCC1=O.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([O:27][CH3:26])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
4.8 g of 3-chloro-2-(4-chloro-3-formylphenyl)-5-trifluoromethylpyridine, 8.4 g of N-iodosuccinimide, 5.2 g of potassium carbonate and 120 ml of methanol were stirred at 23° C. for 20 hours. Most of the methanol was removed by distillation and then a solution of 7 g of Na2S2O3 pentahydrate in 200 ml of water was added, after which the mixture was extracted three times with 100 ml of tert-butyl methyl ether each time. The combined organic phases were washed with 50 ml of water, dried over sodium sulfate and concentrated. Yield: 4.9 g (93%) of a colorless oil;
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)O.[CH2:7]([O:9][C:10]([C:12]1[CH:18]=[CH:17][C:15](O)=[CH:14][CH:13]=1)=[O:11])[CH3:8]>O>[CH2:8]([CH:7]1[C:18]2[C:12](=[CH:13][CH:14]=[CH:15][CH:17]=2)[C:10](=[O:11])[O:9]1)[CH2:2][CH2:3][CH3:5]
Reactant: OCC(O)CO
Reactant: CCOC(=O)c1ccc(O)cc1
Solvent: O
Product: CCCCC1OC(=O)c2ccccc21

Procedure:
100 g of gelatin, 40 g of glycerin, 120 g of water and 200 mg of ethylparaben are used. The gelatin solution is prepared by the same protocol as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Cl)[CH:9]=1)[C:5]#[N:6].ClCl.C[O-].[Na+].C[O:17]C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:17])[CH:9]=1)[C:5]#[N:6]
Reactant: COC
Reactant: N#Cc1cc(Cl)cc(Cl)c1
Agent: C[O-]
Agent: ClCl
Agent: [Na+]
Product: N#Cc1cc(O)cc(Cl)c1

Procedure:
The requisite phenols utilized in the condensation with 15 or 18b were prepared as depicted in SCHEME 3. Dibromofluorobenzene (20a) was treated with sodium methoxide resulting in displacement of the fluorine substituent to afford 20b. Monometallation and formylation of the resulting lithium salt with DMF afforded 21. Conversion of the formyl group into a difluoromethyl group was effected with DAST. Demethylation of the methyl ether afforded the requisite phenol 23. 3-Chloro-5-hydroxy-benzonitrile (24c) was prepared form 3,5-dichloro-benzonitrile by displacement of a chlorine substitutent with sodium methoxide and demethylation of the resulting ether to afford 24c.
Reaction SMILES: C[Al](C)C.[NH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:24]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:25][O:26][C:27]=2[CH2:28][OH:29])=[N:17][CH:16]=1.C1(C)C=CC=CC=1>O1CCOCC1>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:24]2[C:23]([CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([C:14]([NH:5][CH:6]4[CH2:11][CH2:10][O:9][CH2:8][CH2:7]4)=[O:13])=[CH:16][N:17]=3)=[C:27]([CH2:28][OH:29])[O:26][N:25]=2)=[CH:31][CH:32]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 418 μL, 0.84 mmol) was added to a solution of 4-aminotetrahydropyran (87.2 mg, 0.84 mmol) in dioxane (3.75 mL). 6-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (75.0 mg, 0.21 mmol) in dioxane (3.75 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution in toluene (2 M in toluene, 418 μL, 0.84 mmol) and 4-aminotetrahydropyran (87.2 mg, 0.84 mmol) were added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (Isolute® SPE flash NH2 column, ethyl acetate:heptane=1:1 to 9:1) to afford the title compound (24 mg, 27%) as white solid. MS: m/e=428.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[K+].Cl[CH2:24][C:25](=[O:27])[CH3:26]>CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:24][C:25](=[O:27])[CH3:26])[CH3:20]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1

Procedure:
Potassium carbonate (200 mmol, 27.6 g) was added to a solution of ethyl benzoylacetate (100 mmol, 19.2 g) and potassium iodide (20 mmol, 3.3 g) in dry acetone (100 mL). The resulting solution was refluxed, and chloroacetone (110 mmol, 10.7 g) was added dropwise. Analysis of the reaction mixture by GC/MS indicated the presence of Intermediate 2. Solid material was filtered from the reaction mixture, then washed with 200 mL acetone. The resulting filtrate was concentrated under vacuum, redissolved in ether, then washed three times with water (100 mL). The organic layer was separated from the aqueous layer, and dried over MgSO4. The solids were separated, and the organic solvents removed under vacuum to yield a yellow/orange oil. The crude oil was purified by Kugelrohr distillation (b.p. 175-185 at 0.65 Torr.).
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)C.[CH2:16]([Mg]Br)[CH2:17][CH2:18][CH2:19][CH3:20].[NH4+].[Cl-]>C1COCC1>[OH:13][CH:4]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: CCCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 369.2 %

Procedure:
A solution of 4-diethoxymethyl-benzaldehyde (0.300 mL, 1.51 mmol) in THF (3 mL) was cooled to 0° C. Pentylmagnesium bromide (3.0 mL, 2.0 M in THF, 6 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and was warmed to room temperature. Aqueous NH4Cl (satd) was added and the aqueous solution was extracted with EtOAc. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 10% aqueous acetone (50 mL) and wet Amberlyst-15 resin (1.5 g) was added. The mixture was stirred for 24 h and the resin was filtered off through Celite. The solution was concentrated in vacuo. Purification via flash chromatography (4:1 hexanes:EtOAc) provided the title compound (1.15 g). 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 7.86 (d, 2H), 7.51 (d, 2H), 4.77 (m, 1H), 1.89 (m, 1H), 1.74 (m, 2H), 1.48-1.28 (m, 6H), 0.87 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)[CH:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][C:2]1[N:7]=[C:6]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)[N:5]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)[CH:3]=1
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)nc(Cl)n1
Reactant: Oc1ccnc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)nc(Oc2ccnc(C(F)(F)F)c2)n1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A mixture of 0.63 g (2.4 mmol) of 6-methyl-4-(4-trifluoromethyl-1H-1-pyrazolyl)-2-chloropyrimidine, 0.39 g (2.4 mmol) of 4-hydroxy-2-trifluoromethylpyridine and 0.66 g (4.8 mmol) of K2CO3 in 20 ml of acetonitrile stirred under reflux for 8 h and then allowed to stand at RT overnight. The mixture is poured into 40 ml of water and extracted four times with in each case 20 ml of CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated. Chromatographic purification on silica gel using heptane/ethyl acetate (7:3) gives 0.8 g (85%) of 6-methyl-4-(4-trifluoromethyl-1H-1-pyrazolyl)-2-(2-trifluoromethylpyridin-4-yloxy)pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:29])[CH3:9])=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1>>[CH3:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:29])[CH3:9])=[CH:6][CH:7]=2)[CH:34]=[CH:33][N:32]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCNS(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCNS(C)(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from N-(2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)methanesulfonamide and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.12, m/z=494; 1H NMR (CDCl3) 1.48 (d, 3H), 2.10 (m, 2H), 2.20-2.41 (m, 2H), 2.43 (m, 1H), 2.71 (s, 3H), 2.73 (s, 3H), 3.11 (m, 2H), 5.52 (m, 1H), 7.13 (d, 2H), 7.25 (m, 3H), 7.34 (m, 2H), 7.62 (d, 2H), 7.91 (m, 1H), 8.08 (s, 1H), 8.56 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Br:66][C:67]1[CH:68]=[C:69]([CH2:74][NH2:75])[CH:70]=[CH:71][C:72]=1[CH3:73]>ClCCl>[Br:66][C:67]1[CH:68]=[C:69]([CH2:74][NH:75][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:70]=[CH:71][C:72]=1[CH3:73]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reactant: Cc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(Br)c2)n1
Temperature: 25 °C
Yield: 134.4 %

Procedure:
To a suspension of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (50.8 g, 112 mmol) in a 2 L 3-neck flask was added dichloromethane (DCM) (600 mL) followed by DIPEA (98 ml, 561 mmol), giving a solution. To it was added TBTU (39.7 g, 123 mmol) and the mixture was then stirred at room temperature for 2 min whereupon 1-(3-bromo-4-methylphenyl)methanamine hydrochloride (29.2 g, 123 mmol) was added. The mixture was stirred under nitrogen at room temperature. After 2.5 h the mixture was partitioned between dichloromethane and water and the aqueous layer extracted well with dichloromethane. The combined organics were washed with water, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated to give 95.5 g of a pale golden foam that was purified on a 750 g Companion XL silica cartridge, eluting with 0-100% ethyl acetate in dichloromethane over 8 column volumes. However, halfway through loading, the material started to crystallise on the column, blocking the loading so this material already on the column was eluted as above to give 30.01 gm, (26%) of a white solid (combined theoretical yield of the two preparations was 116.6 g). The lab HPLC showed 99.4% purity (retention time 2.22 min). LC-MS m/z 634, 636 (M+H)+, 1.06 min (ret time).
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24]
Reactant: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate (214 mg, 0.48 mmol) in a mixture of THF (10 ml) and H2O (5 ml) was added a solution of LiOH (57.5 mg, 2.40 mmol) in H2O (2.4 ml). After stirring at room temperature for 4 h, the reaction was concentrated, acidified with 1 M HCl solution, and extracted with EtOAc (2×20 ml). The organic solution was dried over MgSO4 and concentrated to give 184 mg (100%) of 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylic acid as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:25]#[N:26])=[CH:12][N:13]=[C:14]([NH:15][C:16]4[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=4[F:24])[C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=[O:28].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:25]([NH2:26])=[O:28])=[CH:12][N:13]=[C:14]([NH:15][C:16]4[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=4[F:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: N#Cc1cnc(Nc2c(F)cc(F)cc2F)c2c1[nH]c1ccc(F)cc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cnc(Nc2c(F)cc(F)cc2F)c2c1[nH]c1ccc(F)cc12
Temperature: 70 °C

Procedure:
8-Fluoro-1-[(2,4,6-trifluorophenyl)amino]-5H-pyrido[4,3-b]indole-4-carbonitrile (46.5 mg, 0.13 mmol) and K2CO3 (108 mg, 0.78 mmol) was dissolved in DMSO (2.6 ml). Hydrogen peroxide (30%, 0.100 ml, 1.04 mmol) was added and the solution was heated at 70° C. for three hours. HPLC/MS then showed complete conversion. The solution was cooled to ambient temperature and directly purified by reverse phase HPLC. Desired fractions were combined, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution: The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, CD30OD) δ 8.37 (s, 1H); 8.16 (dd, 1H); 7.64 (dd, 1H); 7.21 (dt, 1H); 6.98 (dd, 2H). LRMS (APCI) calc'd for (C18H10F4N4O) [M+H]+, 375.1. found 375.0.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24]C)[CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19].B(Br)(Br)Br.C(Cl)Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19]
Reactant: COc1ccc(CC2CCN(C3CCc4n[nH]cc4C3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C1C(Cc2ccc(O)cc2Cl)CCN1C1CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Cool a solution of 3-(2-Chloro-4-methoxy-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (3.0 g, 8.3 mmol) in dichloroethane (100 mL) to −78° C. Treat the solution with 1.0M Boron tribromide in CH2Cl2 (46 mL, 46 mmol) and allow the reaction to warm to room temp and stir for 4 hr. Then, cool the reaction to 0° C. and quench with water. Extract the organic with CHCl3, wash with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using 10% EtOH in CHCl3 to elute the pure product. Remove the solvent to afford 2.24 g (78%) of product. MS (m/e): 364 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[O:12][CH2:13][C:14](=[O:21])[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCCCC1>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:13]2[O:12][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[O:21])=[CH:23]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(C(C)C)cc2)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(C(C)C)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 34.6 %

Procedure:
To a solution of ethyl 2-[(4-isopropylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.26 g, 0.90 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.90 mmol) in ethanol (6.0 mL), piperidine (0.045 mL, 0.45 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.13 g, y. 35%).