Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.C(O)(=O)C>O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 3-bromo-2-chloro-5-nitropyridine (10.00 g, 42.1 mmol) and acetic acid (12.16 mL, 211 mmol) in water (100 mL) at 0° C. was added iron (11.76 g, 211 mmol, powder −325 mesh). The mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was filtered and washed with water. The filtrate was then extracted with EtOAc. The filter cake was then washed with EtOAc, and the resulting filtrate was combined with the previous organic layer from the aqueous extraction. The two organic mixtures were then washed with water (2×), washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 5-bromo-6-chloropyridin-3-amine. MS (ESI, pos. ion) m/z: 207.9 and 209.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)=[N:15][N:14]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:33](=[O:37])[N:34]([CH3:36])[CH3:35].[N:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:44]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:45])=[C:3]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH:4]=3)[CH:9]=2)[N:14]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[N:15]=1
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1N
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1NC(=O)N1CCOCC1
Reaction time: 48 h
Yield: 49.3 %

Procedure:
2,2-Dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(3-chloro-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (300 mg, 0.577 mmol), chloroform (50 ml), 4-morpholinecarbonyl chloride (1.2 ml, 10.45 mmol), and di-iso-propyl ethyl amine (2.4 ml, 13.78 mmol) were combined and stirred for 48 hours at 50 oC. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 180 mg (49%) of 2,2-dimethyl-propionic acid 3-(3-chloro-benzyl)-5-{3-dimethylcarbamoyl-4-[(morpholine-4-carbonyl)-amino]-phenyl}-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. MS: m/z 633.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:21]4[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=4)[C:19]#[N:20])[CH:16]=3)[N:11]=[C:10]([NH:28][NH2:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C1COCC1.[N:36]([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:21]4[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=4)[C:19]#[N:20])[CH:16]=3)[N:11]3[N:36]=[N:29][N:28]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: N#CC(c1ccc(I)cc1)c1ccc2nc(NN)nc(-c3cccc(Cl)c3)c2c1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 5 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Intermediate (41) (0.0121 mol) was added at 5° C. to a mixture of HCl 1N (60 ml) and THF (60 ml). A solution of sodium nitrite (0.0133 mol) in water (20 ml) was added dropwise at 5° C. The mixture was stirred at 5° C. for 1 hour then brought to room temperature, stirred at room temperature for 5 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc; 70/30; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 3.8 g (60%) which were crystallized from 2-propanone/CH3CN. The precipitate was filtered off and dried till dryness, yielding 3.5 g (55%) of 5-(3-chlorophenyl)-α-(4-iodophenyl)-tetrazolo[1,5-α]quinazoline-7-acetonitrile (intermediate 42).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1.[BrH:23].[OH-].[Na+]>C(O)(=O)C.Br.[NH+]1C=CC=CC=1>[Br:23][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:11]2[NH:12][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:14]([CH3:16])[N:15]=2)[CH:5]=1
Reactant: COc1ccc(-c2nc(C)c(-c3cccnc3)[nH]2)c(OC)c1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: COc1cc(OC)c(-c2nc(C)c(-c3cccnc3)[nH]2)cc1Br
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 2-(2,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.0 g) in acetic acid (10 ml) were added a solution of hydrogen bromide in acetic acid (28%, 0.2 ml) and pyridinium hydrobromide perbromide (1.49 g), and was stirred at ambient temperature for 19 hours. Then the mixture was poured into ice-water (100 ml), adjusted to pH 4.8 with 8N sodium hydroxide, and extracted with chloroform. The organic layer was washed by aqueous sodium bicarbonate and evaporated, and the residue was triturated in diisopropyl ether to give 2-(5-bromo-2,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.92 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[N+:10]([C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:16]([O:18][C:19](=O)[C:14]=12)=[O:17])([O-:12])=[O:11]>C(O)(=O)C>[N+:10]([C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:14]=1[C:19](=[O:18])[N:1]([CH:2]([CH2:3][C:4](=[O:6])[NH2:5])[C:7]([OH:9])=[O:8])[C:16]2=[O:17])([O-:12])=[O:11]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NC(=O)C[C@H](N)C(=O)O
Solvent: CC(=O)O
Product: NC(=O)CC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O

Procedure:
A mixture of asparagine (10 mmol) and 3-nitrophthalic anhydride (10 mmol) in 15 ml of acetic acid is heated to reflux. The cooled reaction mixture is concentrated and the residue purified to afford 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-3-carbamoylpropanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26](OC)=[O:27])[CH2:15]1>C1COCC1>[F:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26](=[O:27])[NH:1][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:15]1
Reactant: Nc1cnccn1
Reactant: COC(=O)[C@@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To a solution of aminopyrazine (3.85 g, 40.5 mmol) in THF (120 mL) was added isopropylmagnesium chloride (2.0 M THF solution, 19 mL, 38 mmol) dropwise at 0° C. The resulting slurry was stirred at room temperature for 30 min. A solution of commercially available (2S,4R)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate (3.2 g, 12.9 mmol) in THF (10 mL) was added to the slurry. The reaction mixture was stirred at room temperature for 4 h and quenched with methanol (3 mL). After concentration in vacuo, ethyl acetate (120 mL) and 1N HCl (60 mL) were added to the residue. The organic layers were washed with 1N HCl, water, brine, and dried over Na2SO4, and filtered. Concentration gave (2S,4R)-tert-butyl 4-fluoro-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 65A (4.1 g, 100%) as a colorless foam. LC/MS [M+H]+: 311; Ret time (Method F): 1.46 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[CH2:11]>C(O)(=O)C>[N:15]1[CH:16]=[CH:17][C:12]([CH2:10][CH2:11][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:13][CH:14]=1
Reactant: C=Cc1ccncc1
Reactant: c1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: c1ccc2c(CCc3ccncc3)c[nH]c2c1

Procedure:
Indole (5.85 g, 50 mmol) was dissolved in glacial acetic acid (25 ml) together with 4-vinylpyridine (5.80 g, 55 mmol). The reaction mixture was boiled under reflux for 6 h. For working up, the glacial acetic acid was distilled off. Saturated NaHCO3 solution (75 ml) and water (15 ml) were then added to the mixture. The mixture was extracted with ethyl acetate (1×100 ml, 3×15 ml). (The insoluble oil remaining between the phases contained only polar impurities.) The organic phase was dried over Na2SO4 and then evaporated. The residue was recrystallized twice from ethyl acetate (30 ml each time). The product Ind-14 was obtained as a pale yellow solid in a yield of 7.06 g (31.8 mmol, 63%, m.p.: 154-158° C.).
Reaction SMILES: Br[C:2]1[C:3]([CH2:14][P:15]([OH:18])([OH:17])=[O:16])=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[CH:7]=1.[OH-].[Na+]>[Pd].O>[P:15]([CH2:14][C:3]1[CH:2]=[CH:7][N:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=[C:5]2[N:4]=1)([OH:17])([OH:18])=[O:16]
Reactant: O=C(O)c1cn2cc(Br)c(CP(=O)(O)O)nc2n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cn2ccc(CP(=O)(O)O)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid (18) (15 mg) was introduced in a 250 mL Parr bottle with 0.5N NaOH (1 mL), water (15 mL) and Pd on Carbon (5%, 20 mg). The bottle was evacuated, filled with hydrogen and shaken for one hour at room temperature. The product was purified by passing through a strongly basic ion-exchange column. The product 19 was eluted with 1N HCl.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16]O.C(N(CC)CC)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][O:8][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOS(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Toluene-4-sulfonyl chloride (25.4 g, 133.2 mmol) is slowly added to a solution of 3-methoxy-1-propanol (8.49 mL, 88.8 mmol) and triethylamine (14.8 mL, 106.5 mmol) in CH2Cl2 (80 mL) at 0° C. The reaction mixture is then allowed to warm to RT and stirred for another 16 h. The solvent is evaporated, water is added and the mixture is extracted with CH2Cl2. Drying (Na2SO4) of the combined organic extracts, filtering and evaporation of the solvent affords the crude product which is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 5:1) to give the desired product. MS (LC-MS): 262.1 [M+18]+; 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 mL/min): 5.12 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)[NH2:22]>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[C:19]([F:18])[CH:20]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)Cc1cc(N)cc(F)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: COc1cc(F)ccc1-c1nc(Nc2cc(F)cc(CS(C)(=O)=O)c2)ncc1F

Procedure:
Example 12 was prepared under similar conditions as described in the preparation of Example 1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-fluoro-5-[(methylsulfonyl)methyl]aniline. The batch was purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([O:12][CH3:13])[C:4]=1[O:14][CH3:15].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]1[C:4]([O:14][CH3:15])=[C:5]([O:12][CH3:13])[C:6]([O:10][CH3:11])=[C:7]([CH3:9])[C:8]=1[CH:28]=[O:29]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C)c(OC)c(OC)c1OC
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Yield: 90 %

Procedure:
To a solution of 1,2,3,4-tetramethoxy-5-methylbenzene (34.3 g, 162 mmol) in trifluoroacetic acid (200 ml) was added hexamethylenetetramine (25.0 g, 178 mmol), and the solution was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure. Water (200 ml) was added to the residue which was then heated under reflux for one hour, neutralized with 3N sodium hydroxide and extracted with ethyl acetate (200 ml×3), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography to give 34.9 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([O:14][C@H:11]1[CH2:12][CH2:13][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:19]
Reactant: O[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reactant: O=C(O)c1ccccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](c2ccc(Br)cc2)CC1)c1ccccc1F
Reaction time: 12 h

Procedure:
(trans)-4-(4-Bromophenyl)cyclohexanol (100 mg), 2-fluorobenzoic acid (130 mg) and triphenylphosphine (225 mg) are dissolved in tetrahydrofurane (2 mL), treated dropwise with diisopropylazodicarboxylate (170 μL) and the mixture is stirred for 12 hours. Then the mixture is partitioned between ethylacetate and saturated aqueous NaHCO3 solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 1): tR=1.29 min; Mass spectrum (ESI+): m/z=399 [M+Na]+.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]=1.[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:20][CH:9]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of tert-butyl 4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (64.4 g, 237 mmol) in anhydrous ACN (1.5 L) at ambient temperature was added Selectfluor (92.5 g, 261 mmol) portion wise over 10 minutes, during which a slight exotherm (to 40° C.) was observed. The mixture was stirred for 2 hours, then concentrated to dryness and partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to afford 51 g (99%) of desired product as a solid.
Reaction SMILES: O.[OH-].[Li+].O.[OH:5][CH2:6][C:7]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>CO>[OH:5][CH2:6][C:7]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C1(CO)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(CO)CCOCC1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
To a solution of lithium hydroxide monohydrate (4.46 Kg) in methanol (44 liters) and water (11 Kg) was added ethyl 4-hydroxymethyl-tetrahydropyran-4-carboxylate (8.0 Kg) The mixture was refluxed for 30 minutes, then solvent removed under reduced pressure. The mixture was cooled to 20° C., methyl tert-butyl ether (14.8 Kg) added, stirred for 10 minutes, and allowed to settle. The top organic layer was separated. This was repeated twice more, then the remaining mixture cooled to -10° C., and a solution of 31% hydrochloric acid (13 Kg) in water (3 Kg) added, maintaining the temperature below 5° C. The mixture was extracted several times with tetrahydrofuran, and the combined organic phases dried over magnesium sulfate. Approximately 90% of the tetrahydrofuran was removed, and the remaining solution added to a mixture of hexane (64.5 Kg) and methyl tert-butylether (23.7 Kg) with stirring. The precipitated solid material was filtered off and dried under reduced pressure at 60° C., to give 4-hydroxymethyl-tetrahydropyran-4-carboxylic acid (3.7 Kg), the compound of Formula (9a).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:20])=[N:16][C:17]=1[CH2:18][CH3:19].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=2[C:10]#[C:11][C:12]2[C:17]([CH2:18][CH3:19])=[N:16][C:15]([NH2:20])=[CH:14][CH:13]=2)=[CH:23][C:22]=1[F:21]
Reactant: CCc1nc(N)ccc1C#Cc1c(Cl)ccnc1CC
Reactant: COC(=O)c1ccc(B(O)O)cc1F
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CCc1nc(N)ccc1C#Cc1c(-c2ccc(C(=O)OC)c(F)c2)ccnc1CC
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 1.29 g (4.5 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-6-ethyl-pyridin-2-ylamine (A-30) using 1.34 mg (6.8 mmol) 3-Fluoro-4-methoxycarbonylphenyl boronic acid, 1.4 g (0.9 mmol) Pd(PPh3)4 and 1.19 g (8.6 mmol) K2CO3 in a mixture of 9 mL 1,2-dimethoxyethane and 2.25 mL water. The reaction mixture is stirred twice for 30 min at 130° C. under microwave irradiation. The product is precipitated by the addition of water, filtered off and purified by chromatography on silica gel using a cyclohexane/ethyl acetate gradient. Yield: 944 mg (52%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]([O:19][CH3:20])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][C:10]([O:12]C)=[O:11])[CH:7]=1.[CH2:22]([O:24][CH2:25][CH2:26]Br)[CH3:23]>CCOCC>[Cl:1][C:2]1[C:3]([O:21][CH2:23][CH2:22][O:24][CH2:25][CH3:26])=[CH:4][C:5]([O:19][CH3:20])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: CCOCCBr
Reactant: CCCCCC(CC(=O)OC)c1cc(Cl)c(O)cc1OC
Solvent: CCOCC
Product: CCCCCC(CC(=O)O)c1cc(Cl)c(OCCOCC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45a-(i), but using methyl 3-(5-chloro-4-hydroxy-2-methoxyphenyl)octanoate (prepared as described in Preparation 56A) and 2-ethoxyethyl bromide, the corresponding ether derivative was obtained. Hydrolysis of this derivative and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Preparation 7 to give the title compound as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@H:20]([C:23]4[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[N:26]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:24]=4)[CH2:21][CH3:22])=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN.C1COCC1.C[CH2:49][N:50](C(C)C)C(C)C>CN(C=O)C.[Cl-].[NH4+]>[CH3:32][S:29]([C:27]1[CH:28]=[C:23]([C@@H:20]([NH:19][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:18])[CH2:21][CH3:22])[CH:24]=[C:25]([NH:50][CH3:49])[N:26]=1)(=[O:30])=[O:31]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc(OS(=O)(=O)C(F)(F)F)nc(S(C)(=O)=O)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc(NC)nc(S(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
To a stirred solution of trifluoromethanesulfonic acid 4-((S)-1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-6-methanesulfonyl-pyridin-2-yl ester (0.08 g, 0.13 mmol) in DMF (2 mL) was added a 2.0 M solution of methylamine in THF (0.150 mL, 0.30 mmol) followed by DIPEA (0.05 mL, 0.3 mmol). After 16 hours, the mixture was diluted with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate and concentrated onto silica gel. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OC(F)(F)O2
Yield: 56.8 %

Procedure:
To a solution of 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde [5.48 g, 29.44 mmol, Intermediate (60)] and nitromethane (4.78 mL, 88.32 mmol) in acetic acid (90 mL) is added ammonium acetate (5.67 g, 73.6 mmol). The reaction mixture is heated to reflux for 5.5 hours. Acetic acid is removed in vacuo and the residue is added water (20 mL) and extracted with DCM (3×50 mL), organic layers are combined and washed with 2 N sodium hydroxide, water and brine, dried over sodium sulfate and concentrated. The solid obtained is crystallized in methanol/DCM (1:1) to yield intermediate 2,2-difluoro-5-(2-nitro-vinyl)-benzo[1,3]dioxole [3.83 g, Intermediate (61)] as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3](C)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Br[C:11]1C=C(C)C(N)=NC=1>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:11])[C:5]([Cl:8])=[N:4][CH:3]=1
Reactant: Cc1nc(Cl)ccc1Br
Reactant: Cc1cc(Br)cnc1N
Product: Cc1cc(Br)cnc1Cl
Yield: 67 %

Procedure:
Compound 76A (1.8 g, 67%) was prepared using a procedure similar to the synthesis of 55A from 5-bromo-3-methyl-pyridin-2-ylamine.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]1=O.B#B.Cl>O1CCCC1.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]([CH3:12])[CH2:3]1
Reactant: Cc1nc2ccccc2n(C)c1=O
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1CN(C)c2ccccc2N1

Procedure:
To a stirred solution of 0.2 mole (34.8 g) of 1,3-dimethyl-2-oxoquinoxaline in 300 ml of dry tetrahydrofuran was added dropwise 0.24 mole (240 ml of 1 M) diborane in tetrahydrofuran. The solution was stirred one additional hour, then heated at its reflux temperature for one day. After cooling, about 40 ml of water was added, followed by 2 equivalents of 4 N hydrochloric acid. The solution was heated at reflux for one hour, then evaporated to provide a solid residue. The residue was dissolved in water. The solution was basified and then extracted with diethyl ether. The ether was dried, then evaporated to provide an oil. Distillation provides 1,3-dimethyl-1,2,3,4-tetrahydroquinoxaline, b.p. 85° C./0.1 mm of Hg. Analysis: Calculated for C10H14N2 :%C, 74.0; %H, 8.7; %N, 17.4; Found : %C, 74.2; %H, 8.9; %N, 17.3.