Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[C:29]5[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=5)[CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:32]([O:34]C)=[O:33])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:36]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[C:29]5[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=5)[CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:32]([OH:34])=[O:33])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:36]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCc4cc(OC)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of methyl 2-(5-fluoro-1-benzofuran-2-yl)-3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (40 mg, 0.083 mmol) in methanol (20 mL) and water (three drops) was added sodium hydroxide (16.5 mg, 0.41 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 5 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(5-fluoro-1-benzofuran-2-yl)-3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (23 mg, 44%).
Reaction SMILES: [C:1]1(=[CH:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][Mg]Br.Cl>CCOCC>[C:1]1(=[CH:6][CH2:7][CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)CCC=C1CCCC1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CC(C)(O)CCC=C1CCCC1
Temperature: 25 °C
Yield: 76 %

Procedure:
5-Cyclopentylidene-2-pentanone (13.4 g; 88 mmol) in ether (13 ml) was added dropwise during 30 minutes to a 3M solution of methylmagnesium bromide in ether (38 ml; 114 mmol). After addition of more ether (25 ml), the mixture was heated under reflux for 2 hours, then cooled down to room temperature, poured into ice (40 g), acidified with 5N HCl (50 ml) and extracted with MTBE (130 ml). The aqueous phase was separated and extracted with MTBE (2×130 ml). The combined organic phases were washed with saturated NaHCO3 (2×130 ml), water (130 ml), dried over MgSO4 and concentrated in vacuo. Distillation (52° C.-55° C./0.06 torr) yielded 11.24 g (76% yield) of 5-cyclopentylidene-2-methylpentan-2-ol.
Reaction SMILES: O1C2(CC[N:8]([C:11](=[O:31])[CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:30][CH2:29][C:24]5([O:28][CH2:27][CH2:26][O:25]5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=O)CC2)OCC1.[NH2:32]N>C(O)C.O1CCCC1>[O:28]1[C:24]2([CH2:29][CH2:30][N:21]([C:18]3[CH:17]=[CH:16][C:15]([C:13]4[NH:32][NH:8][C:11](=[O:31])[CH:12]=4)=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[O:25][CH2:26][CH2:27]1
Reactant: O=C(CC(=O)N1CCC2(CC1)OCCO2)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: NN
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)[nH][nH]1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-propane-1,3-dione (which was obtained in Example 143) (0.43 g, 1 mmol) was dissolved in a mixture of ethanol (10 mL) and tetrahydrofuran (4 mL). The solution was treated with 0.08 mL (2.4 mmol) of hydrazine and heated at reflux for 4 days. After cooling to room temperature, the resulting suspension was filtered, and the precipitate was washed with ethanol and dried in vacuo to give 0.24 g of light yellow solid; 1H NMR (DMSO-d6) δ 1.67-1.71 (t, 4H), 3.29-3.32 (t, 4H), 3.91 (s, 4H), 5.72 (s, 1H), 6.97 (d, 2H), 7.48 (d, 2H), 9.50 (brs, 1H), 11.80 (brs, 1H); MS (ES) m/z: 302 (MH+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][C:10]([CH3:12])=[CH:9][CH2:8][N:7]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])C.[ClH:20]>>[ClH:20].[CH2:13]([N:7]1[CH2:8][CH:9]=[C:10]([CH3:12])[CH2:11][CH:6]1[C:4]([OH:5])=[O:3])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CC(C)=CCN1Cc1ccccc1
Agent: Cl
Product: CC1=CCN(Cc2ccccc2)C(C(=O)O)C1

Procedure:
A stirred solution of 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine-2(R,S)-carboxylic acid ethyl ester (Preparation 33(a); 20.1 g, 77.5 mmol) in 5M hydrochloric acid (200 ml) was heated at 100° C. for 4.5 hours and then evaporated to dryness under reduced pressure. Residual water was removed azeotropically using dichloromethane followed by toluene to give the required product (24.0 g) as a white foam, Rf 0.40 (SS 13), which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:41])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([O:42][CH2:43][CH2:44][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[O:41])[CH2:38][CH2:39]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: O=C(OCCN1CCOCC1)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(CC(=O)N2CCC(C(=O)OCCN3CCOCC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.26 mmol) in DMF (2 mL) was added 2-(morpholin-4-yl)ethyl piperidine-4-carboxylate hydrochloride (140 mg, 0.50 mmol), DIEA (101 mg, 0.78 mmol), HATU (119 mg, 0.31 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 10% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (31.0% MeCN up to 38.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 31.0% in 2 min); Detector, UV 254/220 nm. This resulted in 35.6 mg (20%) of the formic acid salt of 2-(morpholin-4-yl)ethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as a off-white solid. LCMS (Method 28) [M+H]+=687.2, RT=0.86 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.27-5.22 (m, 2H), 4.20-4.15 (m, 3H), 3.89-3.82 (m, 1H), 3.58-3.55 (m, 4H), 3.26-3.17 (m, 1H), 2.89-2.78 (m, 1H), 2.69-2.59 (m, 1H), 2.53-2.51 (m, 2H), 2.40-2.32 (m, 4H), 1.91-1.80 (m, 2H), 1.69-1.41 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][C:3]1=[O:17].[CH2:18]([CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21]1)[CH3:19]>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]([CH2:18][CH3:19])[CH2:21]2)=[CH:4][C:3]1=[O:17]
Reactant: CCC1CNc2ccccc21
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(=O)n1C
Product: CCC1CN(c2cc(C)n(C)c(=O)c2)c2ccccc21
Temperature: 150 °C
Yield: 62 %

Procedure:
A mixture of 1,6-dimethyl-4-(trifluoromethanesulphonyloxy)-2-pyridone (1.5 g, 5.5 mM) and 3-ethylindoline (1.22 g, 83 mM) was heated at an external temperature of 150° C. under argon for 3 hours. The solution was cooled. The residue was triturated with acetone to afford a solid which was collected by filtration. This solid was washed with acetone to give 1,6-dimethyl-4-(3-ethylindolin-1-yl)-2-pyridone as the hemi-trifluoromethylsulphonate salt; (1.76 g, 62% yield); m.p. 174°-175° C.; microanalysis, found C, 60.2; H, 6.0: N, 8.0%; C18H21N2. 0.5CF3SO3H requires: C, 60.1; H, 5.9; N, 8.0%: NMR (DMSOd6); 0.9-1.0(3H, t, CH2CH3), 1.4-1.6(1H, m, CHEt), 1.70-1.9(1H, m, CHEt), 2.44(3H, s, CH3), 3.25-3.4(1H, m, indoline H), 3.5(3H, s, +NCH3), 3.6-3.7(1H, m, indoline H), 4.05-4.15(1H, m, indoline H), 6.2(1H, d, pyridine CH), 6.6(1H, d, pyridine CH), 6.9-7.05(1H, t, aromatic), 7.15-7.4(3H, m, aromatic).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[F:13][CH:14]([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C)C=O>[F:26][CH:14]([F:13])[O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(OC(F)F)cc1)n1ccc2cc(I)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
5-Iodo-1H-indole (2.0 g, 8.23 mmol) was dissolved in dimethylformamide (DMF) (10 ml) and cooled to 0° C. Sodium hydride (494 mg, 12.34 mmol) was added in small portions. The reaction mixture was stirred for 1 hour at 0° C. 4-(Difluoro-methoxy)-benzenesulfonyl chloride (2.196 g, 9.05 mmol) was dissolved in DMF (5 ml), and added slowly to the reaction mixture. Stirring was continued for 45 minutes. Cold water (150 ml) was added to the reaction mixture. The reaction mixture was extracted twice with ethyl acetate (100 ml). The organic layer was dried over magnesium sulphate, filtered, and the solvent evaporated under reduced pressure to give a crystalline solid (3.0 g, 81%). ESI-MS [m/z]: 449.95 [M+H]+. 1H-NMR (500 MHz, d6-DMSO): δ=8.05 (d, 2H), 8.0 (s, 1H), 7.85 (d, 1H), 7.8 (d, 1H), 7.65 (d, 1H), 7.4 (t, J=70 Hz, 1H), 7.35 (d, 2H), 6.8 ppm (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O>C(O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A mixture of 2-(benzyloxy)-4-bromo-1-nitrobenzene (14.1 g, 45.8 mmol), iron powder (12.8 g, 229.12 mmol) and ammonium chloride (2.9 g, 55.0 mmol) was taken up in ethanol (60 mL) and water (30 mL) and heated at 90° C. for 3 h. After cooling to ambient temperature, the reaction mixture was filtered through a celite bed and the filtrate concentrated in vacuo. The aqueous residue was extracted with dichloromethane and the organic layer washed with brine, dried over sodium sulfate and concentrated in vacuo to give 2-(benzyloxy)-4-bromoaniline (12.6 g, 99%) as a purple oil: 1H NMR (CDCl3, 300 MHz) δ 7.31-7.46 (m, 5H), 6.98 (d, J=2.1 Hz, 1H), 6.92 (dd, J=8.4, 2.1 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 5.05 (s, 2H), 3.81 (br s, 2H).
Reaction SMILES: CN(C[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[CH3:15][C:16]([C:19]1[C:24]([OH:25])=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:22]=[C:21]([C:30](N(OC)C)=[O:31])[N:20]=1)([CH3:18])[CH3:17]>O1CCCC1>[CH3:18][C:16]([C:19]1[C:24]([OH:25])=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:22]=[C:21]([C:30]([C:6]2[NH:5][CH:9]=[CH:8][N:7]=2)=[O:31])[N:20]=1)([CH3:15])[CH3:17]
Reactant: CN(C)Cn1ccnc1
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C(=O)c2ncc[nH]2)nc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 1-[(dimethylamino)methyl]-imidazole (0.70 g, 5.6 mmol) (See Katritzky, A. R.; Rewcastle, G. W.; Fan, W-Q; J. Org. Chem. 1988, 53, 5688) in tetrahydrofuran (10 mL) at -78° C. under nitrogen atmosphere is added a 1.58M solution of n-butyllithium (3.60 mL, 5.69 mmol) in hexanes dropwise. The resulting mixture is stirred 1 hour at -78° C., warmed to ~0° C., and stirred 0.5 hours. After cooling to -78° C., 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide (0.50 g, 1.7 mmol) in tetrahydrofuran (5 mL) is added. This mixture is warmed to room temperature, stirred for 16 hours, and quenched by addition of aqueous 2N hydrochloric acid solution. After extraction with ethyl acetate, the combined extracts are washed with water and brine solution. Concentration of the organic phase under vacuum followed by recrystallization of the organic residue from methanol and water gives 0.43 g (84%) of the title compound, mp 217°-220° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:7][CH2:6][C:5]2C=CC=C[C:4]=2O1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH:2]([NH:7][C:6]1[CH:5]=[CH:4][CH:21]=[CH:20][C:19]=1[CH2:23][OH:22])([CH3:12])[CH3:1]
Reactant: C1CCOC1
Reactant: CC1(C)NCc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)Nc1ccccc1CO
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 2,2,-dimethyl-1,4-dihydro-2H-benzo[1,3]oxazine (125 g, 0.77 mol) in THF (1 L) was filtered through a scintillation funnel and then added dropwise via an addition funnel, over a period of 2.5 h, to a stirred solution of 1.0 M LiAlH4 in THF (800 mL) at 0° C. The reaction was quenched by slow portionwise addition of Na2SO4.10H2O (110 g), over a period of 1.5 h, at 0° C. The reaction mixture was stirred overnight, filtered and the solid salts were washed thoroughly with THF. The filtrate was concentrated under reduced pressure to yield 2-isopropylaminophenylmethanol (120 g, 95%) as a yellow oil. 1H NMR (CDCl3; 300 MHz): 1.24 (d, 6H, CH(CH3)2), 3.15 (bs, 1H, OH), 3.61 (sept, 1H, CH(CH3)2), 4.57 (s, 2H, CH2), 6.59 (t, 1H, ArH), 6.65 (d, 1H, ArH), 6.99 (d, 1H, ArH), 7.15 (t, 1H, ArH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:32]([CH3:34])=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
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: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c(C)n1
Temperature: 80 °C
Yield: 76.1 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 6-Methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (69 mg, 76%). ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention time 1.98 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:9][O:8][C:6](=[O:7])/[CH:5]=[CH:4]/[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[O:1][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: BrCCCCCBr
Reactant: COC(=O)C=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)/C=C/c1ccccc1OCCCCCBr

Procedure:
A mixture of 0.64 g (3.59 mmol) of methyl 2-hydroxycinnamate, 6.6. g (28.7 mmol) of 1,5-dibromopentane, 2 g (14.5 mmol) of anhydrous, granular potassium carbonate, and 25 mL of acetonitrile was stirred and refluxed for 24 hr. The resulting slurry was cooled, diluted with ether, and filtered with suction. The solids were washed well with ether. The filtrate and washes were combined and concentrated under reduced pressure. The oily residue was flash chromatographed on silica gel, eluting with 5:1 hexane-ether giving 1 g (85%) of (E)-3-[2-[(5-bromopentyl)oxy]phenyl]-2-propenoic acid methyl ester as a solid.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17](=[O:18])/[CH:22]=[CH:9]\[CH:8]=[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C=C\C=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
A solution of 3,3-diphenyl-2-propenal (18.73 g) and (carbethoxymethylene)triphenylphosphorane (33.1 g) in ethanol (100 mL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residual solid was refluxed in a mixture of ether (125 mL) and hexane (250 mL) for 10 minutes. The mixture was cooled to room temperature and the precipitated triphenylphosphine oxide (25 g) was removed by filtration and was washed with ether-hexane (1:2; 2×50 mL). The filtrates were evaporated and the residue was passed through a short column of silica gel (200 g) made up in dichloromethane to remove residual triphenylphosphine oxide and starting ylid. After evaporation of the appropriate eluates, the resulting mixture of esters was separated by using HPLC (dichloromethane-hexane; 1:1). The fractions containing the less polar material were combined and evaporated to yield 4.2 g of (Z)-5,5-diphenyl-2,4-pentadienoic acid ethyl ester as an oil which crystallized on standing, mp 36°-37° C.
Reaction SMILES: BrC1C=C(N2C3=NC=CC(C4C=C5C=CN(C[O:29]C)C5=NC=4)=C3C(C(C)C)=N2)C=CC=1C#N.[OH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42]2[CH:49]=[C:48]([N:50]3[C:54]4=[N:55][CH:56]=[CH:57][C:58]([C:59]5[CH:60]=[C:61]6[CH:67]=[CH:66][N:65]([CH2:68][O:69][CH3:70])[C:62]6=[N:63][CH:64]=5)=[C:53]4[C:52]([CH:71]([CH3:73])[CH3:72])=[N:51]3)[CH:47]=[CH:46][C:43]=2[C:44]#[N:45])[CH2:37][CH2:36]1>>[OH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42]2[CH:49]=[C:48]([N:50]3[C:54]4=[N:55][CH:56]=[CH:57][C:58]([C:59]5[CH:60]=[C:61]6[CH:67]=[CH:66][N:65]([CH2:68][O:69][CH3:70])[C:62]6=[N:63][CH:64]=5)=[C:53]4[C:52]([CH:71]([CH3:73])[CH3:72])=[N:51]3)[CH:47]=[CH:46][C:43]=2[C:44]([NH2:45])=[O:29])[CH2:37][CH2:36]1
Reactant: COCn1ccc2cc(-c3ccnc4c3c(C(C)C)nn4-c3ccc(C#N)c(N[C@H]4CC[C@H](O)CC4)c3)cnc21
Reactant: COCn1ccc2cc(-c3ccnc4c3c(C(C)C)nn4-c3ccc(C#N)c(Br)c3)cnc21
Product: COCn1ccc2cc(-c3ccnc4c3c(C(C)C)nn4-c3ccc(C(N)=O)c(N[C@H]4CC[C@H](O)CC4)c3)cnc21

Procedure:
According to Example 1(6), a crude product of 2-(trans-4-hydroxycyclohexylamino)-4-{(3-isopropyl-4-(1-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was prepared using compound (15a) instead of compound (1e) and was used in the subsequent reaction without being purified. According to Example 1(7), compound (15) (the second stage yield: 45%) was prepared as a white solid using 2-(trans-4-hydroxycyclohexylamino)-4-{3-isopropyl-4-(1-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[CH3:26])[CH:18]=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].[Cs+]>CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[CH3:26])[CH:18]=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CN1CCCC1c1cncc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: CN1CCCC1c1cncc(-c2ccc(O)cc2)c1
Yield: 92.5 %

Procedure:
The above-described pyridine derivative (750 mg, 2.04 mmol) was dissolved in methanol (40 mL) and cesium fluoride (620 mg, 4.08 mmol) was added. The stirred mixture was heated at reflux for 18 h under inert atmosphere. After cooling the solvent was removed in vacuo and the resulting oil was dissolved in ethyl acetate (50 mL). This was washed with water (20 mL), brine (20 mL), dried (MgSO4) and concentrated. The crude material was chromatographed on "flash" silica gel with ethyl acetate:hexane (1:2) to 10% methanol:ethyl acetate as eluant to afford 5-(4-hydroxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine 480 mg, 93% as a colorless foam, 1H NMR (CDCl3, 300 MHz): δ8.66 (d, J=2 Hz, 1H), 8.43 (d, J=2 Hz, 1H), 7.90 (s, 1H), 7.32 (d, J=9 Hz, 2H), 6.81 (d, J=9 Hz, 2H), 3.33 (t, J=8 Hz, 1H), 3.22 (t, J=8 Hz, 1H), 2.41 (m, 1H), 2.28 (s, 3H), 2.10 (m, 2H), 1.93 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:4]([CH:9]=[C:10]([C:13]#[C:14][Si](C)(C)C)[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[OH:27]S(O)(=O)=O>CC(C)=O>[C:13]([C:10]1[C:11]([F:12])=[C:2]([F:1])[C:3]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:27])[CH3:14]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1F
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a suspension of methyl 3,4-difluoro-2-(2-fluorophenylamino)-5-((trimethylsilyl)ethynyl)benzoate (1.20 g, 3.18 mmol) in 85% aqueous acetone (40 ml) were added HgSO4 (943 mg, 3.18 mmol) and H2SO4 (0.33 ml, 6.36 mmol). The reaction was heated at reflux for 24 h. The mixture was cooled to room temperature, concentrated, and diluted with EtOAc (100 ml). The organic solution was washed with H2O (50 ml), dried over Na2SO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=10:90) yielded 832 mg (81%) of methyl 5-acetyl-3,4-difluoro-2-(2-fluorophenylamino)benzoate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]C(=O)N(C)C)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28][CH2:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Sc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3ccc(SCC(=O)C(C)(C)C)cc3)c2CC1
Yield: 30 %

Procedure:
Dissolve 3-(tert-butoxycarbonyl)-7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (57 mg, 0.1 mmol) in methanol (5 mL). Add potassium hydroxide (65 mg, 1.1 mmol) and heat the mixture for 3 h at 65° C. Then add 1-bromo-3,3-dimethyl-2-butanone and heat at 65° C. for 2 h. Cool the mixture and dilute with EtOAc. Wash the organic phase with water, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/diethyl ether (7:3) to obtain the desired intermediate as an oil (18 mg, 30%).