Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22]C(=O)C(F)(F)F)=[CH:19][CH:18]=1.Cl.ClCCl.CO>CO>[NH2:22][CH2:21][C:20]1[CH:29]=[CH:30][C:17]([NH:16][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: C#CCNc1nc(Cl)ncc1C(F)(F)F
Reactant: Nc1ccc(CNC(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C#CCNc1nc(Nc2ccc(CN)cc2)ncc1C(F)(F)F
Yield: 37.4 %

Procedure:
A mixture of 2-chloro-4-(prop-2-ynylamino)-5-trifluoromethyl-pyrimidine (235 mg), N-(4-aminobenzyl)-2,2,2-trifluoro-acetamide (410 mg) and hydrochloric acid (37% in water, 0.2 mL) in methanol (5 mL) was refluxed for 1 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the aqueous phase extracted with ethyl acetate, the combined organic phases dried (Na2SO4), concentrated, filtered through silica using dichloromethane/methanol, and the filtrate evaporated. To a solution of the residue in methanol (9 mL), tetrahydrofuran (9 mL) and diethyl ether (4-5 mL) was added lithium hydroxide (150 mg) and the mixture was refluxed for 6 h, after which it was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with additional ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (120 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCOCCO)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (470 mg, 1.7 mmol) was suspended in dimethylformamide (100 ml). To the suspension were added potassium carbonate (350 mg, 2.5 mmol) and 2-(2-chloroethoxy)ethanol (0.27 ml, 2.6 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (7% methanol/chloroform) to give the subject compound (159 mg, yield 27%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C:18]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:20])[CH2:14]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
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: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (51 μL, 1.03 mmol) was added to a solution of (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.93 mmol), HATU (391 mg, 1.03 mmol) and DIPEA (410 μL, 2.35 mmol) in DMF and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a pale brown oil (110 mg, 70%). 1H NMR (CDCl3, 400 MHz) δ 4.01 (m, 3H); 3.52-3.41 (m, 3H); 3.25-3.11 (m, 2H); 3.10-2.97 (m, 2H); 2.89 (dt, J=11.4, 7.5 Hz, 1H); 2.11-1.99 (m, 1H); 2.01-1.91 (m, 2H) and 1.93-1.82 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([C:18]#[N:19])=[CH:15]2)=[CH:10][CH:9]=1.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[C@@H:31]1[CH2:33][O:32]1>CCO>[OH:32][C@H:31]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[O:30])[O:27][CH2:28][C:29]=2[C:21]=1[CH3:20])[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][C:14]([C:18]#[N:19])=[CH:15]3)=[CH:10][CH:9]=2)[C:2](=[O:1])[CH2:7]1
Reactant: N#Cc1ccc2ccc(N3CCNCC3=O)cc2c1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(c3ccc4ccc(C#N)cc4c3)C(=O)C2)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
A mixture of 7-(2-oxopiperazin-1-yl)naphthalene-2-carbonitrile [I-7] (35 mg, 0.14 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (40 mg, 0.21 mmol) in EtOH (2 mL) in a 5 mL microwave tube was heated to 145° C. for 2 hours. LC showed formation of the title product, which was purified by silica gel flash chromatography. LC-MS (IE, m/z): 442 [M+1]+.
Reaction SMILES: C([O:4][CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:6]=[CH:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=1)[S:10]([CH3:13])(=[O:12])=[O:11])(=O)C.[OH-].[Na+]>O.CO>[OH:4][CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:6]=[CH:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CCCCCC(C=CCN(CCCc1ccc(C(=O)OCC)cc1)S(C)(=O)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(O)C=CCN(CCCc1ccc(C(=O)O)cc1)S(C)(=O)=O

Procedure:
Ethyl 4-{3-[N-(4-Acetoxy-2-nonenyl)methanesulfonamido]propyl}benzoate (23.4 g., 0.05 mole) is added to a solution of sodium hydroxide (6.0 g., 0.15 mole) in water (30 ml.) and methanol (300 ml.). The resulting solution is boiled under reflux for 2 hours.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43]1)=[O:16]
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 44 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (312 mg, 1.84 mmol), a white solid required compound (381 mg, 0.81 mmol, 44%) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19](Br)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>>[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1cccnc1
Product: c1cncc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 3-pyridylboronic acid (206 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Yellow solid. Yield: 144 mg, 0.61 mmol, 73%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.20 (s, 2H), 6.93 (t, J=1.5 Hz, 1H), 7.13 (t, J=0.9 Hz, 1H), 7.40 (ddd, J=7.9, 4.7, 0.9 Hz, 1H), 7.52 (dd, J=8.2, 2.2 Hz, 1H), 7.60 (s, 1H), 7.75 (d, J=8.2 Hz), 8.29-8.32 (m, 1H), 8.61 (m, 1H), 8.66 (dd, J=4.7, 1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 119.0, 120.6, 123.6, 130.5, 131.0, 134.0, 134.3, 135.9, 137.3, 148.2, 148.9, 150.3, 155.0. MS (ESI): m/z=237.03 [M+H]+.
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH2:24][CH3:25])[CH:18]=1)/[C:6]([O:8]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH2:24][CH3:25])[CH:18]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(/C=C(/NC(C)=O)C(=O)OCc2ccccc2)ccc1N
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C[C@H](NC(C)=O)C(=O)O)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl (2E)-2-(acetylamino)-3-(4-amino-3-ethylphenyl)-2-propenoate (5 g) and 10% Pd—C (100 mg) in methanol (50 mL) was stirred under an atmosphere of hydrogen (4 atmospheres) at ambient temperature overnight to provide the titled compound. MS (ESI(+)) m/e 251 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.02 (d, 1H), 6.77-6.70 (m, 2H), 6.50 (d, 1H), 4.31-4.21 (m, 1H), 2.84 (dd, 1H), 2.65 (dd, 1H), 2.39 (q, 2H), 1.78 (s, 3H), 1.10 (t, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].C(OCC)C>C(Cl)Cl.C(#N)C>[ClH:32].[NH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC#N
Product: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1

Procedure:
4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 3.11 mmol) from Step 4 was dissolved in CH2Cl2 (30 mL) and treated with HCl in diethyl ether (10 mL, 2.0 M, 20 mmol). After 16 hours the reaction was concentrated in vacuo to form a residue and the residue was suspended in acetonitrile (10 mL) to yield a solid. Filtration of the solid provided the title compound as a white solid (1.1 g). 1H NMR (400 MHz, CD3OD) δ ppm 2.62 (td, J=6.11, 0.91 Hz, 2H) 2.67-2.81 (m, 2H) 3.14-3.21 (m, 2H) 3.22-3.29 (m, 2H) 6.56 (s, 1H) 6.99-7.09 (m, 2H) 7.10-7.18 (m, 2H) 7.42 (t, J=7.91 Hz, 1H) 8.09 (ddd, J=8.74, 2.60, 0.33 Hz, 1H) 8.41 (td, J=1.63, 0.74 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](C(=O)C2C=CC(I)=C([N+]([O-])=O)C=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].C1C(=O)N(Br)C(=O)C1>C1COCC1>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)Cc1ccsc1Br
Yield: 96.7 %

Procedure:
To a solution of the above ester (10.00 g, 64.02 mmol) in THF (100 mL) was added NBS (11.40 g, 64.02 mmol). The resulting mixture was refluxed for two and a half hours. The solvent was removed in vacuo. MPLC purification (Hex:EtOAc/9:1) of the residue gave methyl 2-(2-bromothiophen-3-yl)acetate as a colorless oil (14.55 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=5.6 Hz, 1H). 6.93 (d, J=5.6 Hz, 1H), 3.72 (s, 3H), and 3.64 (s, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([OH:8])[CH2:3]1.[OH-].[Na+].CS(O[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:27]2[CH2:30][CH:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][CH:40]=4)=[C:33]([O:47][CH3:48])[CH:32]=3)[CH2:28]2)=[O:26])[CH:20]=1)(=O)=O.O>C(O)CC>[OH:8][C@@H:4]1[C@@H:5]([OH:7])[CH2:6][N:2]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:27]3[CH2:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]5[CH:40]=[CH:41][C:42]([CH2:45][CH3:46])=[CH:43][CH:44]=5)=[C:33]([O:47][CH3:48])[CH:32]=4)[CH2:30]3)=[O:26])[CH:20]=2)[CH2:3]1
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Reactant: O[C@H]1CNC[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCN5C[C@H](O)[C@@H](O)C5)ccn4)C3)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
a solution of (3S,4S)-pyrrolidine-3,4-diol monohydrochloride (0.14 g) in 1-propanol (3.0 mL) was added aqueous 4 N NaOH (0.25 mL). The mixture was stirred at RT for 1 hr. To the mixture was added 2-(2-{3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-yloxy)ethyl methanesulfonate (0.1 g) prepared in Example 6 (1). The reaction mixture was stirred at 100° C. for 5 hr. Water was added to the reaction mixture. The precipitated solid was collected on a filter and dried to give the title compound (0.05 g, 50%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:18][C:11]1([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC(=O)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 1-benzyl-4-hydroxy-4-piperidinecarboxylate in methanol was treated with Pd(OH)2 (20% on carbon, 500 mg) under a hydrogen atmosphere. The mixture was allowed to stir at room temperature for 12 hours, filtered, and the filtrate was concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].II>C1COCC1.C(OCC)(=O)C.[Zn]>[CH3:26][O:25][C:23](=[O:24])[CH2:22][C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][O:20]1
Reactant: COC(=O)CBr
Reactant: O=C(CCCCl)c1ccc(OCc2ccccc2)cc1
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC1(c2ccc(OCc3ccccc3)cc2)CCCO1
Yield: 88.4 %

Procedure:
1-(4-Benzyloxy-phenyl)-4-chloro-butan-1-one (0.3 g, 1.04 mmol) was combined with methyl bromoacetate (0.24 g, 1.56 mmol) and zinc metal (0.05 g, 2.08 mmol) in THF (15 mL), a catalytic amount of iodine was added, and the reaction was heated to reflux for 18 h. The reaction was taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate, and concentrated to give [2-(4-benzyloxy-phenyl)-tetrahydro-furan-2-yl]-acetic acid methyl ester (0.3 g, 92%) as an oil. MS found: (M+H)+=327.
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23][CH2:24][C:25]3[CH:50]=[CH:49][C:28]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46]CC)=[O:45])=[CH:39][CH:38]=5)[O:34][C:35]=4[CH3:36])=[C:27]([O:51][CH3:52])[CH:26]=3)=[N:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[C:1]([C:5]1[O:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23][CH2:24][C:25]3[CH:50]=[CH:49][C:28]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:38]=[CH:39][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:41][CH:42]=5)[O:34][C:35]=4[CH3:36])=[C:27]([O:51][CH3:52])[CH:26]=3)=[N:14][N:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(C(C)(C)C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2coc(C(C)(C)C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (320 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate. The residue was recrystallized from ethyl acetate-hexane and the precipitated crystals were collected by filtration to give {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid (181 mg, yield 59%) as colorless prism crystals. melting point: 104-106° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([CH:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH2:30][CH2:29]4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].C(Cl)Cl>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([CH:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1

Procedure:
A solution of compound 41g (0.20 g, 0.36 mmol) in TFA/CH2Cl2 (1:3, 3 mL) was stirred at rt for 2 h, and concentrated under reduced pressure. The resulting mixture was diluted with 10 mL of water. The solids formed were collected by filtration and washed with Et2O (2×30 mL). The crude solid product was then purified by re-crystallization from CH2Cl2:Et2O (1:10) to obtain the title compound 25 as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.48 (d, J=8.4 Hz, 1H), 8.24 (d, J=5.7 Hz, 1H), 8.06-8.03 (m, 2H), 7.87-7.80 (m, 2H), 7.70-7.65 (m, 1H), 6.41 (d, J=6.0 Hz, 1H), 4.19 (s, 2H), 4.08-3.95 (m, 4H), 3.82-3.64 (m, 7H), 3.42-3.29 (m, 2H), 2.70-2.57 (m, 2H), 2.23-2.19 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H28N6O3: 497.2 (M+H). Found: 497.2.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[N:33]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:24]([N:15]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[N:33]=2)[CH2:22][CH2:23]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(Cl)nc(C)n1
Reactant: c1ccc(CN(CCC2CCNCC2)Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1cc(N2CCC(CCN(Cc3ccccc3)Cc3ccccc3)CC2)nc(C)n1
Reaction time: 16 h
Yield: 49 %

Procedure:
A mixture of N,N-dibenzyl-2-(piperidin-4-yl)ethanamine trifluoroacetate (see stage 6 AMN-01) (6.372 mmol, 1.0 eq), 4-chloro-2,6-dimethylpyrimidine (1.17 g, 8.283 mmol, 1.3 eq) and K2CO3 (2.64 g, 19.116 mmol, 3.0 eq) in acetone (50 ml) was stirred for 16 hours at boiling temperature. After monitoring by TLC, the mixture was concentrated, diluted with DCM (100 ml) and washed with water (50 ml) and sat. NaCl solution (50 ml). The org. phase was dried over sodium sulfate and concentrated under reduced pressure, and the crude product so obtained was purified by column chromatography (silica gel, 2% MeOH in DCM). Yield: 49% (1.3 g, 3.14 mmol)
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](I)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(N(C(C)C)CC)(C)C>CN(C=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.[Cu]I>[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][N:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc2cnccn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A mixture of 3-Ethynylimidazo[1,2-a]pyrazine (0.075 g, 0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide, 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of CuI, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide 0.090 g of product as a solid: 487 m/z (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(F)cccc2o1
Product: Fc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 50 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (29.2 mg, 0.18 mmol) and 2-(but-3-ynyl)-4-fluorobenzo[d]oxazole (35 mg, 0.18 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 24 mg (90 μmol, 49%) of 4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid (M.P.=89-89.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[CH:36]([OH:40])[CH2:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:38]([CH2:37][CH:36]([C:29]4[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH3:26])[OH:40])[CH3:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1c(OC)cccc1OC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(O)CN(C)Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1C
Temperature: 60 °C
Reaction time: 7 h
Yield: 52.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), 1-(2,6-dimethoxyphenyl)-2-(methylamino)ethanol (PNU-149291, Arch. Intern. Pharmacodyn. 1965, 154, 26-39) (42 mg, 0.20 mmol) and diisopropylethylamine (34 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (39 mg) as a white solid.