Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][O:5][N:4]([CH3:7])[C:3]1=[O:8].[C:9]([C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[CH:16]=[O:17])([CH3:12])([CH3:11])[CH3:10].C(Cl)Cl.Cl>C1C=CC=CC=1.[Zn]>[C:22]([C:19]1[CH:18]=[C:15]([CH:16]([OH:17])[CH:2]2[CH2:6][O:5][N:4]([CH3:7])[C:3]2=[O:8])[CH:14]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:20]=1[OH:21])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CN1OCC(Br)C1=O
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: c1ccccc1
Product: CN1OCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 57 %

Procedure:
A mixture of 6 g (33.3 mmol) of 4-bromo-2-methyl-3-isoxazolidinone, 7 g (30 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 3.25 g (50 mmol) of zinc dust in 125 ml of benzene was refluxed with stirring. One hour later another 3 g of zinc dust was added and, after refluxing for an additional 17 hours, the reaction mixture was stirred for five minutes with 200 ml of methylene chloride and 150 ml of 0.5N hydrochloric acid. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to yield 10 g of crude material. This material was chromatographed on silica gel with 80% ethyl acetatehexane and recrystallized from ether-hexane to afford 5.7 g (17.1 mmol, 57%) of 4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-methyl-3-isoxazolidinone, mp 137°-140° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](I)=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[N:12][CH:13]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Brc1ccc(I)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Clc1ccc(-c2ccc(Br)cn2)cc1
Temperature: 110 °C

Procedure:
Under an N2 atmosphere 11 mL 2 M Na2CO3 solution and 240 mg (0.21 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 3.00 g (10.6 mmol) 5-bromo-2-iodo-pyridine and 3.37 g (21.1 mmol) 4-chlorophenyl-boric acid in 60 mL 1,4-dioxane and 15 mL MeOH and the reaction mixture is heated to 110° C. for 3 h. The mixture is evaporated down i.vac., the residue is combined with 50 mL water, 10 mL 3% NH3 solution and 150 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.F[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[I:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)[CH:24]=1
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Reactant: Fc1cc(I)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cn(-c3cc(I)ccn3)ccc2=O)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one (7.30 g, 31.6 mmol), 2-fluoro-4-iodopyridine (10.56 g, 47.35 mmol), and K2CO3 (10.9 g, 79 mmol) in DMSO (80 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was washed with EtOAc and filtered, and the collected solid dried to give 4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one. 1H-NMR (DMSO, 400 MHz) δ 8.41 (dd, J=8.0, 2.4 Hz, 1H), 8.30 (s, 1H), 8.20 (m, 2H), 7.81 (dd, J=4.0, 0.8 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.28 (d, J=7.6 Hz, 1H), 4.96 (s, 2H), 3.72 (s, 3H). MS (M+H)+ 435.1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[CH3:12]O>Cl>[NH2:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1CC[C@H](CN)CC1

Procedure:
A solution of 15.7 g of trans-4-(aminomethyl)-cyclohexanecarboxylic acid in 150 ml of ethereal hydrochloric acid and 1000 ml of absolute methanol is stirred at room temperature for 20 hours. The solvent is evaporated off under reduced pressure and the residue is triturated with ether and filtered off with suction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1.C1(C)C=CC=CC=1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([O:13][CH:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1OC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1OC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A solution of tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yloxy)piperidine-1-carboxylate (0.019 g, 0.052 mmol) in methanol (2.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.008 g, 0.057 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with toluene, the solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate (2:1→1:4)) to obtain tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yloxy}piperidine-1-carboxylate (0.020 g, 79%).
Reaction SMILES: [Mg].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Cl:11])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]([N:30]([CH3:32])[CH3:31])[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]2=[O:29])[CH:18]=[CH:19][C:20]=1[Cl:21].[Cl-].[NH4+]>CCOCC>[ClH:11].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][C:24]2([OH:29])[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]2[CH:22]([C:17]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=2)[N:30]([CH3:32])[CH3:31])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CN(C)C(c1ccc(Cl)c(Cl)c1)C1CCCCC1=O
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccc(Cl)c(Cl)c1)C1CCCCC1(O)Cc1ccc(C(C)(C)C)cc1
Product: Cl
Temperature: 25 °C
Yield: 38.3 %

Procedure:
0.24 g (9.9 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.81 g (9.9 mmole) of 4-tert.-butylbenzyl chloride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.48 g (8.3 mmole) of the 2-[(3,4-dichlorophenyl)dimethylaminomethyl]cyclohexanone prepared according to Example 39 were dissolved in 10 ml of ether, added dropwise while cooling in an ice bath to the Grignard reagent, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.69 g of crude base (99.6% of theory) were obtained, from which 1.54 g of 1-(4-tert.-butylbenzyl)-2-[(3,4-dichlorophenyl)dimethylaminomethyl]cyclohexanol, hydrochloride (38.3% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[C:11](O)=[O:12])[C:7](=[O:24])[CH:6]=1.[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH:41][C:11](=[O:12])[CH:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:24])[CH2:14][CH:15]([C:20]([F:22])([F:23])[F:21])[C:16]([F:19])([F:17])[F:18])=[N:37]2)[CH2:32][O:31]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC(C(F)(F)F)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(C(F)(F)F)C(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid (31 mg, 0.072 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 20 mg, 0.086 mmol) in N,N-dimethylformamide (1 mL). To this mixture was added N,N-diisopropyethylamine (35 μL, 0.22 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (48 mg, 0.11 mmol) and stirred overnight at 25° C. After this time, the mixture was diluted with ethyl acetate (15 mL) and washed with a saturated aqueous solution of ammonium chloride (10 mL), saturated aqueous solution of sodium bicarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), dried over sodium sulfate, and concentrated with silica gel (1.5 g). Purification by Biotage flash chromatography (AnaLogix 12 g column, 40% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (34 mg, 77%) as a cream colored foam: HR-ES-MS m/z calculated for C25H25N4O5ClF6 [M+H]+ 611.1491, observed 611.1487.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O:14][CH:15](O)[CH3:16].CS(C)=[O:20]>O>[CH3:13][O:14][CH2:15][CH2:16][O:20][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CS(C)=O
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: COC(C)O
Solvent: O
Product: COCCOc1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 10 %

Procedure:
4-Fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol), methoxyethanol (0.28 mL, 3.6 mmol) and DMSO (2.0 mL) were added and stirred at 60° C. for 1.5 hours. The reaction mixture was added with water and was washed with hexane/ethyl acetate=4/1 to remove impurities. After removing impurities, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/1) and concentrated to obtain 4-(2-methoxyethoxy)-2-nitrobenzaldehyde (28 mg, 10%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]=O.[C:10]([C:12]1[CH:22]=[CH:21][C:15]2[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=2[CH:13]=1)#[CH:11]>C1(C)C=CC=CC=1.Cl[Cu].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[N:1]1[CH:8]=[C:11]([CH2:10][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=3[CH:13]=2)[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: C=O
Reactant: Nc1ccccn1
Reactant: C#Cc1ccc2nc(SC)sc2c1
Agent: Cl[Cu]
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: CSc1nc2ccc(Cc3cnc4ccccn34)cc2s1
Temperature: 120 °C
Yield: 37.1 %

Procedure:
A stirred mixture of 2-aminopyridine (100 mg, 1.1 mmol), paraformaldehyde (34 mg, 1.1 mmol), CuCl (5 mg, 0.06 mmol), and Cu(OTf)2 (19 mg, 0.06 mmol) in 3 mL of toluene in a pressure tube was flushed with argon. 6-Ethynyl-2-(methylthio)benzo[d]thiazole (327 mg, 1.6 mmol) from Step 3 of this Example was added. The reaction vessel was sealed and the mixture was heated in an oil bath at 120° C. for 6 h. LCMS analysis showed that the reaction was mostly complete. The reaction mixture was partitioned between EtOAc and saturated aq NaHCO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in hexanes to afford 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole (127 mg, 38%) as a brown oil. LCMS (ESI) m/z 312 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][C:19]([OH:21])=[O:20].[Na].[CH2:23](I)[CH3:24]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][C:19]([O:21][CH2:23][CH3:24])=[O:20]
Reactant: Nc1c(CC(=O)O)cc(Cl)cc1C(=O)c1ccc(Br)cc1
Reactant: CCI
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccc(Br)cc2)c1N
Yield: 91.3 %

Procedure:
A solution of 40.9 g (0.1 mole) of 2-amino-3-(4-bromobenzoyl)-5-chlorobenzeneacetic acid, sodium salt, monohydrate in 400 ml of dimethylformamide was treated with 32.0 g (0.2 mole) of ethyl iodide and the solution was let stand at ambient temperature overnight. The solution was poured in 3.5 liters of cold water and a solid gradually crystallized. The solid was collected by filtration, washed with water, and recrystallized from absolute ethanol to yield 36.2 g (91%) of title compound, a yellow solid, m.p. 92°-94° C.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:10]=1.CC1(C)C(C)(C)OB([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[N:40][CH:39]=2)O1.C(=O)([O-])O.[Na+]>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.O.C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:11]2[CH:10]=[C:9]([C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=[N:40][CH:39]=3)[CH:21]=[CH:20][C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-c2cncc3ccccc23)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
To a mixed solution of toluene 4.0 mL, ethanol 1.2 mL and water 0.6 mL of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.20 g were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline 0.17 g, sodium hydrogen carbonate 0.12 g and tetrakis(triphenylphosphine)palladium(0) 35 mg, and it was heated and refluxed under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, tetrakis(triphenylphosphine)palladium(0) 35 mg was added to it, and it was heated and refluxed under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, and water was added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to give tert-butyl 2-(4-fluoroanilino)-4-(isoquinolin-4-yl)benzoate 0.11 g of pale red solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[I:10][C:7]1[CH:8]=[CH:9][C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=Cc1cc(I)ccc1F
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc(I)cc2C=O)cc1
Yield: 65.9 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (1.2 g, 4.8 mmol) (Aldrich) was reacted with 4-methoxyphenol (0.71 g, 5.76 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-iodo-2-(4-methoxy-phenoxy)-benzaldehyde as a yellow oil (Yield 1.12 g, 66%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[N:4][OH:5].[CH2:6]=[C:7]([CH3:9])[CH3:8].C(=O)([O-])O.[Na+]>C(OCC)C>[C:7]([O:5][N:4]=[CH:3][CH2:2][Cl:1])([CH3:9])([CH3:8])[CH3:6]
Reactant: C=C(C)C
Reactant: ON=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)ON=CCCl

Procedure:
Then, 0.47 g of chloroacetoaldehyde oxime, 0.1 ml of concentrated sulflic acid, and 10 ml of diethyl ether are placed in a reaction vessel, into which isobutene gas is blown with stirring under ice cooling, and the stirring is further continued at room temperature. After completion of the reaction, the reaction mixture is slowly poured into saturated aqueous sodium hydrogencarbonate solution, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with 10% aqueous sodium hydroxide solution and water in this order, dried over anhydrous magnesium sulfate, and concentrated, which affords chloroacetoaldehyde O-tert-butyloxime.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[N:13][CH:11]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: NC=O
Product: Oc1ncnc2ncccc12
Yield: 69.7 %

Procedure:
2-aminonicotinic acid (7 g) and formamide (22.8 g) were heated at 167 C (internal temperature) for 2.5 hours. After cooling, the solid was recrystallized from 100 mL of hot water to give Pyrido[2,3-d]pyrimidin-4-ol as pale yellow powder (5.2 g, 69.7%). 1H NMR (DMSO, 400 MHz) δ 12.60 (br, 1H), 8.90 (br, 1H), 8.50 (m, 1H), 8.37 (s, 1H), 7.50 (m, 1H). Rt 0.87 min. MS (ESI+) [M+H]+148.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[ClH:19].[N:20]1([CH2:25][CH2:26][CH2:27][NH:28][S:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Reactant: NCCCN1CCCC1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCN3CCCC3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 15 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with (3-pyrrolidin-1-yl)propylamine as described in Step 5, Example 24 to give the title compound as a solid (15% yield). LC/MS: RT 1.98 min; m/e 394 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CI.[C:17](=O)([O-])[O-].[K+].[K+].CN(C)[CH:25]=[O:26]>O>[CH3:17][O:1][C:2]1[C:3]([C:12]([O:26][CH3:25])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc2ccccc2cc1OC

Procedure:
A mixture of 18.8 g. (0.1 mole) of 3-hydroxy-2-naphthoic acid, 20 ml. of methyl iodide, 28 g. of potassium carbonate, and 200 ml. of N,N-dimethylformamide was heated at 70° C. for 16 hours, then poured into 1 liter of water. The mixture was extracted with diethyl ether and the extracts were washed with water, then 5 percent sodium hydroxide solution, then water again, and dried over magnesium sulfate. Evaporation provided a residue of methyl 3-methoxy-2-naphthoate.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:5][CH:4]=1.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: CN(C)C(=O)Nc1ccccc1-c1ccc(CO)cc1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN(C)C(=O)Nc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the intermediate obtained in Step B in 4 mL of methylene chloride was treated with 0.16 mL (1.21 mmol) of trimethylsilylbromide. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with methylene chloride then washed with aqueous saturated sodium chloride (2×). The organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum to yield 133 mg of crude product. 1H NMR (400 Hz, CDCl3): δ 2.78 (s, 6H), 4.5 (s, 2H), 6.4 (br s, 1H), 7.08 (t, 1H), 7.16 (dd, 1H), 7.34 (m, 4H), 7.49 (d, 1H), 8.10 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.Cl>CC#N.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N5CCCC5=O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C1CCCN1[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C

Procedure:
A mixture of partially purified 1-((1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-one, 45d, (0.105 g, 0.180 mmol) in CH3CN (5 mL) was treated with HCl (2 mL of 4 M, 8.00 mmol) in dioxane at 70° C. After 2H, the mixture was cooled to room temperature. Then CH3CN was added and the solid that precipitated was triturated with more CH3CN (3×). Preparative HPLC provided the desired product as the HCl salt (35 mg).