Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[I:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[I:11][C:12]1[CH:13]=[N:14][N:15]([CH2:2][CH2:3][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)[CH:16]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 1 L 3-neck flask equipped with magnetic stir bar, nitrogen blanket and internal temperature probe dissolve 2-(2-bromoethoxy)tetrahydro-2H-pyran (34 g, 156 mmol) in acetonitrile (ACN, 400 mL). Add 4-iodopyrazole (29.34 g, 149.74 mmol) followed by cesium carbonate (73.4 g, 223.02 mmol). Stir the mixture at RT for 18 hours. Filter the reaction mixture through CELITE®, wash the filter cake with ACN and concentrate the filtrate to a golden oil. Use without further purification. Yield: 47.819 g (99%). MS (ES) m/z 323 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1)[CH3:25]
Reactant: CNC
Reactant: CC(C)(C)c1cc(-c2nc(CCl)no2)cc(C(C)(C)C)c1O
Product: CN(C)Cc1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1

Procedure:
In a manner analogous to Example 70, 0.5 g (0.002 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol is reacted with excess dimethylamine gas to give 0.3 g (59%) of analytically pure 4-[3-[(dimethyamino)methyl]-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol, mp 129°-130° C.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[O:18])=[CH:19][CH:20]=2)=[N:4][CH:3]=1
Reactant: NCc1ccc(O)cc1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(O)cc1)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino) benzoic acid (116 mg, 0.35 mmol), 4-aminomethylphenol (43 mg, 0.35 mmol), and N,N-diisopropylethylamine (0.094 mL, 0.525 mmol) in DMF (1 mL) is cooled to 0° C., and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (160 mg, 0.42 mmol) is added. The cooling bath is removed, and the reaction mixture stirred at 25° C. for 18 hours. After this time the solvent is removed in vacuo, and the residue triturated with MeOH. The resultant solid is collected by filtration and identified as the desired phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:18][CH2:19][CH2:20]CBr>CC(C)=O>[Br:18][CH2:19][CH2:20][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 500 mL flask was charged with 4-amino-3-nitrophenol (15.4 g, 100 mmol, commercially available from Aldrich). Acetone (300 mL), cesium carbonate (39.09 g, 120 mmol) and 1,3-dibromopropane (40.84 mL, 400 mmol) were added to the flask and stirred at refluxed temperature. The reaction was monitored by LCMS. After 6 hours, the reaction mixture was cooled to room temperature, filtered and washed with acetone. The organic layer was removed on a rotary evaporator under reduced pressure and the resulting material was purified by silica column chromatography using 40% hexane in dichloromethane as eluant. 20 g of 4-(2-bromoethoxy)-2-nitroaniline was isolated which was used in the next step without any further purification. MS (EI): 275 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.CO[CH:21]1[CH2:25][CH:24]([CH:26]=O)[CH:23](OC)[O:22]1.O>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:21]=[CH:25][C:24]([CH:23]=[O:22])=[CH:26]2)=[N:2]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: COC1CC(C=O)C(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Yield: 21.6 %

Procedure:
Compound 2 (0.30 g, 1.3 mmol) was dissolved in acetic acid (5.0 mL) and 2,5-dimethoxy-4-tetrahydrofurancarbaldehyde (0.36 mL, 2.6 mmol) was added, followed by heating under reflux for 3 days. The reaction mixture was added with water and filtered through Celite, extracted with ethyl acetate and the organic layer was concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to ethyl acetate) to obtain Compound 167 (88 mg, 22%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:17])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(Cl)Cl.C(O)(=O)C>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=3)[C:7](=[O:17])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(c2ccccc2)c2cc(O)ccc21
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccc(O)cc2N1c1ccccc1
Temperature: 140 °C
Yield: 17 %

Procedure:
A mixture of 6-hydroxy-1-phenyl-1H-indole-2,3-dione (13 mg, 0.054 mmol) and 3-(trifluoromethyl)aniline (160 mg, 1 mmol) in CH2Cl2 (1 mL) and acetic acid (1 drop) was heated at 140° C. The crude product was purified preparative TLC [Eluent: EtOAc/hexane (2:3)], giving the desired product (3.5 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]#[CH:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)Cl>[Br:14][C:3]1[C:4]([NH:10][CH2:11][C:12]#[CH:13])=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[Cl:1]
Reactant: C#CCNc1cc(Cl)nc(SC)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: C#CCNc1nc(SC)nc(Cl)c1Br
Reaction time: 4 h

Procedure:
To a stirring solution of 1.16 g (5.45 mmol) of 6-chloro-2-(methylthio)-N-(prop-2-ynyl)pyrimidine-4-amine (intermediate 27) in 6 ml of DCM, 1.07 g (6.0 mmol) of N-bromosuccinimide were added, and stirring was continued for 4 hours at room temperature to give 5-bromo-6-chloro-2-(methylthio)-N-(prop-2-ynyl)pyrimidine-4-amine, which was used without further purification in the next step (see intermediate 31). The completion of the reaction is monitored by thin layer chromatography.
Reaction SMILES: [P:1]([O-:32])([O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:13])=[CH:6][C:5]=1[O:21][CH3:22])=[O:2].[Na+:33].[O-]CC.[Na+].Cl[CH2:39][C:40]([OH:42])=[O:41]>C(O)C>[P:1]([O-:32])([O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:39][C:40]([O-:42])=[O:41])[CH:15]=2)=[O:13])=[CH:6][C:5]=1[O:21][CH3:22])=[O:2].[Na+:33].[Na+:33]
Reactant: COc1cc(CCC(=O)c2cccc(O)c2)ccc1OP(=O)([O-])Oc1cc(C)cc(C)c1
Reactant: O=C(O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CCC(=O)c2cccc(OCC(=O)[O-])c2)ccc1OP(=O)([O-])Oc1cc(C)cc(C)c1
Reaction time: 1 h

Procedure:
To a mixture of 22.5 g sodium 4-(3-(3-hydroxyphenyl)-3-oxopropyl)-2-methoxyphenyl 3,5-dimethylphenyl phosphate (see Example 6) and 1000 ml of 0.22 M sodium ethoxide kept under nitrogen, 5.7 g of chloroacetic acid in 50 ml anhydrous ethanol is added dropwise with stirring and the mixture being kept boiling. After all of the acid is added the refluxing is continued for one hour. The reaction mixture is cooled and sodium chloride is removed by filtration. The solvent is evaporated under vacuum, and the residue is dissolved in water, acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated sodium sulphate solution. Water is added and pH adjusted to 7 with 2 M sodium hydroxide. The water layer is freeze-dried giving disodium 4-(3-(3-carboxylatomethoxyphenyl)-3-oxopropyl)-2-methoxyphenyl 3,5-dimethylphenyl phosphate.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O-])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3].N1CCCCC1.C=O>CCO>[CH2:1]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(C(=O)[O-])C(=O)OCC
Agent: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C(CCC)C(=O)OCC
Temperature: 23 °C
Yield: 48.5 %

Procedure:
To a solution of ethyl n-propylmalonate (41.3 g, 237 mmol, 1 equiv) in EtOH (500 mL) at 23° C. was added piperidine (28.1 mL, 284 mmol, 1.2 equiv) followed by aqueous formaldehyde (37%, 88 mL). Following the addition, the reaction was refluxed for 29 h. After cooling to 23° C., the mixture was partitioned between diethyl ether (500 mL) and 1.0 N HCl (800 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (500 mL). The combined organic layers were washed with H2O (500 mL), brine (300 mL), dried (MgSO4), filtered and concentrated (rotovap only, product is potentially volatile). The product was vacuum distilled (bp 70° C. at 15 mmHg) to give 16.4 g 21c (R9=n-propyl) (115 mmol, 49%) of the desired product: 1H NMR shows contamination with unidentified material; the product was used in the subsequent step without further purification: 1H NMR (300 MHz, CDCl3) 6.12 (s, 1H), 5.50 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 2.23 (t, J=7.5 Hz, 2H), 1.55–1.42 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.5 Hz, 3H).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[C:7]2[CH:33]=[CH:34][S:35][C:6]=2[C:5](=[O:36])[N:4]1[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[ClH:1].[O:2]=[C:3]1[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][CH2:14]2)[C:7]2[CH:33]=[CH:34][S:35][C:6]=2[C:5](=[O:36])[N:4]1[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42]
Reactant: CCOC(=O)CCCCn1c(=O)c2sccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCCn1c(=O)c2sccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
A mixture of ethyl 5-[2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidin-3-yl]valerate (2.54 g, 4.11 mmol) obtained in Example 135, 2N sodium hydroxide (4.0 ml), tetrahydrofuran (6 ml) and ethanol (6.0 ml) was stirred at room temperature for 6 hours, neutralized with 2N hydrochloric acid, and then extracted with chloroform. The extract was washed with water, dried (MgSO4) and then concentrated. The residue was treated with ethyl ether to give the title compound (2.27 g, 86%) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH3:18][C:19]1([CH3:27])[O:23][C@:22]([CH2:25]O)([CH3:24])[CH2:21][O:20]1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:24][C@@:22]1([CH3:25])[CH2:21][O:20][C:19]([CH3:27])([CH3:18])[O:23]1)=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC1(C)OC[C@](C)(CO)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@@]3(C)COC(C)(C)O3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 32.2 g, 0.14 mol) and ((4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)methan-l-ol (15 g, 0.113 mol) in anhydrous dichloromethane (750 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC) (23 g, 0.12 mol) and N,N-dimethylaminopyridine (DMAP, 7.5 g, 61 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and solvent was evaporated under reduced pressure. The product was purified by column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give the title compound (37.5 g, 96.5% yield) as a white solid, mp 65-66° C. 1H NMR (CDCl3) δ7.75 (d, J=8.7 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.46 (dd, J=8.4 and 1.7 Hz, 1H), 7.15 (m, 2H), 4.27 (m, 1H), 4.19 (m, 2H), 4.03-3.92 (m, 2H), 3.96 (s, H), 3.69 (dd, J=8.4 and 6.0 Hz, 1H), 1.64 (d, J=7.1 Hz, 3H), 1.40 (s, 3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 135.3, 133.7, 129.2, 128.8, 127.1, 126.1, 125.9, 119.0, 109.7, 105.5, 73.4, 66.2, 64.8, 55.2, 45.2, 26.5, 25.3, 18.4; LRMS (APIMS) m/z 362 (M+NH4)+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[C:10][C:11]1[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[N:14]=[C:13]([C:22]([O:24]CC)=[O:23])[CH:12]=1.[OH-].[K+].[CH2:29]([OH:31])C>>[CH3:29][O:31][C:7]1[CH:8]=[CH:3][C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([C:22]([OH:24])=[O:23])[N:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(C#Cc2ccccc2OC)cc(C(=O)OCC)n1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C#Cc2cc(C(=O)O)nc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Methoxyphenyltrimethylsilylacetylene (8.2 g, 39 mmol) was dissolved in 100 mL of methanol with K2CO3 powder (0.5 g, 3.6 mmol). The mixture was stirred at room temperature for 4 hr. After the solvent was removed, 50 mL of water was introduced and the mixture was neutralized with dilute hydrochloric acid. The crude product, 4-methoxyphenylacetylene, was extracted with chloroform (2×50 ml) and purified by column chromatography (silica gel) using 3% chloroform/hexane (96%). 1HNMR (CDCl3), d 7.39 (d, 2H), 6.81 (d, 2H), 3.77 (s, 3H), 2.96 (s, 1H). Diethyl 4-bromo-2,6-pyridinedicarboxylate (2.0 g, 10 mmol) was dissolved in 70 mL of dry THF and 50 ml of anhydrous triethylamine with PdCl2 (75 mg), PPh3 (200 mg) and CuI (120 mg). The mixture was deaerated with argon for 5 min and 2.0 g of methoxyphenylacetylene (15 mmol) was introduced. The mixture was stirred under an atmosphere of argon at 55° for 6 hr. The solvent was removed, and the residue was treated with water and extracted with chloroform (2×75 ml). The crude product from the dried organic extract was purified by column chromatography (silica gel—10% ethyl acetate/hexane). The purified product was recrystallized from 50% chloroform/hexane to yield 1.8 g of white crystals (77%). 1HNMR (acetone-d6): 8.23 (s, 2H), 7.61 (d, 2H), 7.01 (d, 2H), 4.41 (t, 4H), 3.85 (s, 3H), 1.38 (q, 6H). Diethyl 4-(methoxyphenylethynyl)-2,6-pyridinedicarboxylate (1.8 g, 5.5 mmol) was dissolved in 100 ml of ethanol with 2.0 g of KOH. The mixture was stirred at room temperature for 4 hr. After solvent was removed in vacuo, 80 ml of water was added to the residue, and the solution filtered. The filtrate was acidified with dilute hydrochloric acid. The precipitate that resulted was filtered and dried in air, yielding 1.3 g of a white solid, 4-(4-methoxyphenylethynyl)-2,6-pyridinedicarboxylic acid: mp>300° C. 1HNMR (D2ONaOD), δ 8.16 (s, 2H), 7.58 (d, 2H), 7.00 (d, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-methylsulfonylbenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CC[O:26][C:27](/[CH:29]=[C:30](/[CH2:32]P(OCC)(OCC)=O)\[CH3:31])=[O:28]>>[CH3:31][C:30]([CH:32]=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)[CH:17]=1)=[CH:29][C:27]([OH:26])=[O:28]
Reactant: Cc1cc2c(cc1-c1cccc(C=O)c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Product: CC(C=Cc1cccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1)=CC(=O)O
Yield: 70.9 %

Procedure:
In a manner similar to that of Example 2(c), by reaction of 2.0 g (6.53 mmol) of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)benzaldehyde obtained in the preceding example and 1.90 g (7.20 mmol) of triethyl 3-methyl-4-phosphonocrotonate, 1.80 g (66%) of the expected compound was obtained in the form of a white powder having a melting point of 83°-85° C.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[C:12]1([C:10]2[N:2]=[C:3]3[CH2:7][CH2:6][CH2:5][N:4]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N=C1CCCN1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2cn3c(n2)CCC3)cc1
Temperature: 80 °C
Yield: 89 %

Procedure:
Prepare 2-iminopyrrolidine hydrochloride (6.98 g, 57.8 mmol) according to Callahan, et al., J. Med. Chem. 2002, 45, 999-1001) and combine 2-bromoacetophenone (3.8 g, 19.3 mmol) with Na2CO3 (8.2 g, 77.2 mmol) in dry DMF (25 mL) and heat at 80° C. for 18 hours. Then, cool the mixture to room temperature, add water (60 mL), and extract with EtOAc (3×100 mL). Concentrate the combined organic layers in vacuo, dilute the residue with ether (100 mL), and wash with cooled water (3×80 mL). Concentrate the organic layer in vacuo to give a white solid, 3.2 g, 89% yield. MS(ES+): m/z=185.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]2[C:12](=[O:30])[NH:13][C:14]3[C:19]([C:10]=2[CH:9]=1)=[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27](O)=[O:28])[N:22]=1)[CH:17]=[CH:16][N:15]=3)=[O:7].CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[F:58][C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][CH:65]=1)[NH2:62]>C(Cl)Cl>[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]2[C:12](=[O:30])[NH:13][C:14]3[C:19]([C:10]=2[CH:9]=1)=[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([NH:62][C:61]2[CH:63]=[CH:64][CH:65]=[C:59]([F:58])[CH:60]=2)=[O:28])[N:22]=1)[CH:17]=[CH:16][N:15]=3)=[O:7]
Reactant: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4ccn(CC(=O)O)n4)c3c2c1
Reactant: Nc1cccc(F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4ccn(CC(=O)Nc5cccc(F)c5)n4)c3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
299 (18 mg, 0.04 mmol), DIEA (16 mg, 0.12 mmol), BOP-Cl (13 mg, 0.05 mmol), and 3-fluoroaniline (13 mg, 0.12 mmol) were suspended in CH2Cl2 (1 mL), and stirred overnight at room temperature. The crude reaction mixture was purified directly via HP-LC to provide 300 (10 mg, 37% yield) as a solid. LC-MS (M+H=543, obsd.=543).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[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].O.[OH-].[Li+].Cl>O1CCCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To methyl 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylate (32 g, 68.6 mmol) in a 1 L round-bottom flask under nitrogen in tetrahydrofuran (THF) (600 mL) was added water (150 mL), then lithium hydroxide (2.464 g, 103 mmol). After 22 min the slightly cloudy mixture was filtered and the THF was evaporated off to give a slight suspension. The aqueous mixture was cooled in an ice-bath and taken to pH 6 using 2M hydrochloric acid. This mixture was stirred for 10 min in an ice-bath, the pH re-checked but not much material seemed to have come out of solution. So the pH was further reduced to pH 5 and this seemed to bring more material out of solution. The solid was collected by vacuum filtration, washed with water then dried under high vacuum at 40° C. to give 19.2 g (62%) of a white solid that the Lab HPLC showed to be 98.7% pure with a retention time of 1.76 min. LC-MS m/z 453 (M+H)+, 0.72 min (ret time) [split peak].
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1.[CH2:17]([NH:24][CH:25]([CH3:38])[CH2:26][O:27][C:28]1[CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]([OH:37])=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:33]([C:32]1[CH:36]=[C:28]([CH:29]=[CH:30][C:31]=1[OH:37])[O:27][CH2:26][CH:25]([N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1)[CH3:38])(=[O:34])[NH2:35]
Reactant: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1
Reactant: COCCOc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: COCCOc1ccc(OCC(O)CN(Cc2ccccc2)C(C)COc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
A solution of 10.2 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene and 11.0 g of 5-[2-(benzylamino)propoxy]salicylamide in 200 ml of isopropanol is refluxed for 24 hours. By concentration of the solution by evaporation, crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-[4-(2-methoxyethoxy)phenoxy]propan-2-ol is obtained as an oil which is used in its crude state for debenzylation.