Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5](=[O:15])[CH2:4]1.[CH3:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]([OH:36])[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:22][C:20]=2[N:21]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:36][C@@H:28]([CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:19]2[S:18][C:17]([CH3:16])=[N:21][C:20]=2[CH:22]=1)[CH2:29][N:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH:3]2[CH2:7][N:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:5](=[O:15])[CH2:4]2)[CH2:34][CH2:35]1
Reactant: O=C1CC(CBr)CN1c1ccc(F)cc1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CC4CC(=O)N(c5ccc(F)cc5)C4)CC3)ccc2s1

Procedure:
A solution of 4-(bromomethyl)-1-(4-fluorophenyl)pyrrolidin-2-one (0.04 g, 0.15 mmol), (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol 2×HCl (0.09 g, 0.24 mmol), and potassium carbonate (0.150 g, 1.15 mmol) in N,N′dimethylformamide (2 ml) was heated to 70° C. for 16 hours. The solution was filtered and the filtrate concentrated. The residue was purified using preparative chromatography (15:1 DCM:MeOH) to yield 4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one (M+1=498.99).
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.C(Cl)CCl.[C:15]([O:19][C:20](=[O:50])[CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)[CH:37]=[CH:38][CH:39]=2)=[CH:28][CH:27]=1)[C:23](O)=[O:24])([CH3:18])([CH3:17])[CH3:16].[OH-].[NH4+]>ClCCl>[C:15]([O:19][C:20](=[O:50])[CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)[CH:37]=[CH:38][CH:39]=2)=[CH:28][CH:27]=1)[C:23]([NH2:2])=[O:24])([CH3:18])([CH3:17])[CH3:16]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(C(N)=O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Yield: 96.1 %

Procedure:
1-hydroxybenzotriazole (225 mg, 1.65 mmol) and EDC (315 mg, 1.65 mmol) were added sequentially to compound 50.3 (750 mg, 1.5 mmol) in dichloromethane (25 mL). The resulting mixture was stirred for 1 h before ammonium hydroxide (25% in water, 630 mg, 4.5 mmol) was added dropwise. The reaction was quenched after 30 min. with water (10 mL). The reaction mixture was extracted with dichloromethane (10 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The product was purified via flash chromatography (50% ethyl acetate in hexanes) to yield 51.1 (720 mg) as a white solid. MS ESI (pos.) m/e: 500 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.68 (1H, s); 7.57-7.48 (3H, m); 7.29-7.25 (2H, m); 7.0-6.97 (2H, d, J=6.8 Hz); 5.14 (2H, s); 3.91-3.88 (1H, m); 3.19-3.13 (1H, m); 2.60-2.55 (1H, m); 1.4 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=O)[CH2:11]Br)[S:7][CH:6]=1)=[O:4].S(=O)(=O)(O)O.[CH:19]([NH2:21])=[O:20]>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:21]=[CH:19][O:20][CH:11]=2)[S:7][CH:6]=1)=[O:4]
Reactant: NC=O
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1csc(-c2cocn2)c1
Temperature: 150 °C

Procedure:
5-(2-Bromo-acetyl)-thiophene-3-carboxylic acid methyl ester (0.60 g, 2.28 mmol) was suspended in formamide (10 mL) then sulfuric acid (1 mL) was added and the tube purged with nitrogen then sealed. The mixture was heated at 150° C. by microwave irradiation for 15 minutes. The resultant solution was diluted with HCl (1 N) and water and extracted with ethyl acetate (×3). The organic phase was dried over sodium sulfate and evaporated then purified by chromatography on a silica II cartridge, eluting with 1:1 DCM: cyclohexane to afford 5-oxazol-4-yl-thiophene-3-carboxylic acid methyl ester as a pale yellow solid (0.197 g). LCMS m/z 210.14 [M+H]+ R.T.=3.64 min (Analytical Method 9).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:53])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:54][C:55]1[O:56][C:57]([CH3:63])=[C:58]([C:60](Cl)=[O:61])[N:59]=1>>[CH3:3][O:4][C:5](=[O:53])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]5[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][N:26]1[C:60]([C:58]1[N:59]=[C:55]([CH3:54])[O:56][C:57]=1[CH3:63])=[O:61])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3

Procedure:
(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg) was reacted with 2,5-dimethyl-oxazole-4-carbonyl chloride according to General Procedure F to give (S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (20 mg). This ester was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 800.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[I:17])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[I:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7]
Reactant: COc1cccc(I)c1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(I)c1S(N)(=O)=O
Temperature: 0 °C

Procedure:
42.40 g (114.84 mmol) N-(tert-butyl)-2-iodo-6-methoxybenzenesulfonamide are stirred in 265 ml of trifluoroacetic acid at room temperature for 3 h. Thereafter the reaction mixture is poured into ice-water and the precipitate is isolated by filtration and washed to neutrality with water. This gives 32.40 g (90% of theory) of 2-iodo-6-methoxybenzenesulfonamide.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=3)[CH:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccc(Cl)cc3)c2c1
Yield: 87 %

Procedure:
This compound was prepared from 6b using 4-chlorophenylboronic acid according to method P. Orange powder; Yield: 87%; mp 140–147° C.; 1H-NMR (400 MHz, DMSO-d6) δ 7.03 (d, J=2.7 Hz, 1H), 7.06 (t, J=8.8 Hz, 1H), 7.32 (dd, J=9.1, 2.7 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.87 (s, 1H), 7.93–7.98 (m, 2H), 8.07 (dd, J=13.0, 2.1 Hz, 1H), 9.94 (s, 1H), 10.20 (s, 1H); MS (ESI) m/z 364/366 ([M−H]−), 366/368 ([M+H]+); Anal. Calcd for C21H13ClFNO2: C: 68.95, H: 3.58, N: 3.83. Found: C: 68.23, H: 3.54, N: 3.78.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(N2CCOCC2)n1
Temperature: 70 °C

Procedure:
2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole (150 mg, 0.39 mmol), morpholine (41 μL, 0.47 mmol), Pd2(dba)3 (8.2 mg, 0.0078 mmol), BINAP (9.8 mg, 0.016 mmol), and NaOtBu (53 mg, 0.55 mmol) were combined in a sealable tube evacuated and backfilled with argon. Toluene (4 mL) was added and the mixture was degassed with a stream of argon for 5 min. The tube was sealed and the mixture was heated to 70° C. for 18 h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[3-methoxy-4-(6-morpholin-4-ylpyridin-2-yl)phenyl]-1,3-benzoxazole as an orange solid: 1H NMR (CDCl3, 300 MHz) δ 8.07–8.05 (d, 1H), 7.96–7.95 (m, 1H), 7.88 (s, 1H), 7.83–7.78 (m, 1H), 7.65–7.58 (m, 2H), 7.42–7.36 (m, 3H), 6.65–6.62 (d, 1H), 4.02 (s, 3H), 3.88–3.85 (t, 4H), 3.61–3.58 (t, 4H). MS (ESI) 388 (M+H)+.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=4)[CH2:18][NH:19][C:20]([C:22]4[C:23](=[O:37])[N:24]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=5)[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1.[O:41]1C=CC(B(O)O)=C1.B(O)O>>[O:41]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=4)[CH2:18][NH:19][C:20]([C:22]4[C:23](=[O:37])[N:24]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=5)[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1
Reactant: OB(O)c1ccoc1
Reactant: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4ccsc4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: OBO
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4ccoc4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-furan-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 91, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using Furan-3-boronic acid as boronic acid to yield the product. 1H NMR (500 MHz, DMSO-d6) d ppm 11.973 (s, 1H) 10.118 (t, J=5.7 Hz, 1H) 8.568 (s, 1H) 8.400 (d, J=7.2 Hz, 1H) 8.374 (s, 1H) 8.248 (s, 1H) 8.221 (d, J=6.7 Hz, 1H) 7.863 (d, J=2.6 Hz, 1H) 7.755 (m, 2H) 7.622 (d, J=7.7 Hz, 1H) 7.439-7.308 (m, 3H) 7.198 (d, J=7.7 Hz, 1H) 7.144-7.100 (m, 1H) 7.073 (s, 1H) 6.586 (t, J=6.7 Hz, 1H) 5.168 (s, 2H) 4.593 (d, J=6.2 Hz, 2H); MS m/z=537.36 M+H.
Reaction SMILES: C([O:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[OH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: CC(=O)OC=Cc1ccccc1
Agent: C1=Cc2ccccc2C1
Product: OC=Cc1ccccc1

Procedure:
In one typical embodiment, the polymer can be synthesized by dissolving an acetoxystyrene monomer, a tertiary alkyl (meth)acrylate monomer and an indene monomer in an organic solvent, adding a radical initiator thereto, heat polymerizing the monomers, and subjecting the resulting polymer to alkaline hydrolysis in an organic solvent for deblocking the acetoxy group, thereby forming a ternary copolymer of hydroxystyrene, tertiary alkyl (meth)acrylate and indene. Examples of the organic solvent used in polymerization include toluene, benzene, tetrahydrofuran, diethyl ether, and dioxane. Representative of the polymerization initiator are 2,2′-azobisisobutyronitrile, 2,2′-azobis(2,4-dimethylvaleronitrile), dimethyl-2,2-azobis(2-methylpropionate), benzoyl peroxide and lauroyl peroxide. Polymerization may be effected by heating at about 50 to 80° C. The reaction time is usually about 2 to 100 hours, preferably about 5 to 20 hours. The base used in the alkaline hydrolysis is selected from aqueous ammonia and triethylamine, to name a few. The reaction temperature is about −20° C. to 100° C., preferably about 0 to 60° C. The reaction time is usually about 0.2 to 100 hours, preferably about 0.5 to 20 hours.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C@@H:4]([N:12]([CH2:20][CH:21]=[CH2:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>ClCCl>[CH3:1][NH:2][CH2:3][C@@H:4]([N:12]([CH2:20][CH:21]=[CH2:22])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN(C(=O)OC(C)(C)C)[C@H](CNC)Cc1ccccc1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
Dissolve (S)-N-methyl-2-[N'-(t-butoxycarbonyl)-allylamino]-3-phenyl-propionamide (0.31 g, 0.98 mmol) in dichloromethane (10 mL) and cool in a dry ice/acetone bath to -78° C. Add diisobutylaluminum hydride (1.96 mL, 1.5M in toluene, 2.94 mmol). Allow to warm slowly to ambient temperature and stir for 16 hours. Slowly add a 15% aqueous solution of sodium hydroxide (3.0 mL). Extract with dichloromethane, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound as a mixture which is taken on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4cccc(C)c4)CC3)c(OC)nc2c1
Yield: 86 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 2.33 (s, 3H), 3.26-3.29 (m, 4H), 3.73-3.77 (m, 4H), 3.90 (s, 3H), 4.13 (s, 3H), 6.73-6.77 (m, 3H), 7.13-7.22 (m, 4H), 7.74 (d, J=9.8 Hz, 1H).
Reaction SMILES: [CH2:1](Br)[C:2](=[CH2:4])[CH3:3].[CH2:6]([O:8][C:9](=[O:16])[C:10]([C:12]([F:15])([F:14])[F:13])=[O:11])[CH3:7].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.[Cl-].[Zn+2].[Cl-].[Mn]>[CH2:6]([O:8][C:9](=[O:16])[C:10]([OH:11])([C:12]([F:13])([F:15])[F:14])[CH2:3][C:2](=[CH2:1])[CH3:4])[CH3:7]
Reactant: C=C(C)CBr
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Mn]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.3 g of anhydrous zinc chloride and 13.2 g of granular manganese are heated to boiling in 100 ml of tetrahydrofuran and boiled with 0.2 ml of methallyl bromide for 30 minutes. Then, the solution of 25 g of methallyl bromide and 17 g of trifluoropyruvic acid ethyl ester in 80 ml of tetrahydrofuran is added in drops at boiling heat over 2 hours, and boiled for another hour. Then, while being cooled with ice, saturated ammonium chloride solution and 300 ml of ethyl acetate are added, stirred for 30 minutes at 0° C., and the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times with water. The solvent is dried (Na2SO4) and concentrated by evaporation, and the residue is distilled in a vacuum. 17.6 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester, boiling point 48° C./1 hPa, is obtained.
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19]([OH:21])=O)=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][NH2:36].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][NH:36][C:19]([C:14]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[C:4](=[O:22])[C:3]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]3[C:1]2=[O:27])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21]
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Reactant: NCCc1ccccn1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: O=C(NCCc1ccccn1)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O

Procedure:
From 10 g (28 mmol) of 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), by reaction with 2-(2-pyridyl)ethylamine in the presence of HOBT and DIC, 13 g of 2′-phthalimidomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained; m.p. 155° C. The product was suspended in 300 ml of methanol and treated with 20 ml of hydrazine hydrate. After stirring at 40° C. for 1 h, the cooled reaction mixture was filtered. The filtrate was concentrated and the residue was taken up in EA. The product was extracted into the aqueous phase 2 times using 2 M hydrochloric acid. The aqueous phase was then rendered alkaline with potassium carbonate and extracted 2 times with EA. After washing with water, drying and concentrating, 7.3 g of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH:25]=1>>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[O:17])=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCC#CCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCC#CCCCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
7-(4-Acetyl-3-hydroxy-2-propylphenoxy)-5-heptynoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by HPLC to give 7-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]-5-heptynamide, the title compound, mp 77°-80° (from ethyl acetate-hexane) in 53% yield.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[N:14]=[C:13]([I:15])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:10]2[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[CH3:29]O>>[NH2:5][C:6]1[N:14]=[C:13]([I:15])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:10]2[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:29])=[O:20]
Reactant: CO
Reactant: Nc1nc(I)nc2c1nc(-c1cccc(F)c1)n2CCCC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCn1c(-c2cccc(F)c2)nc2c(N)nc(I)nc21
Temperature: 2.5 °C
Yield: 100 %

Procedure:
Thionyl chloride (1.2 ml) was added dropwise into a mixture of 1.41 g of 4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoic acid and 75 ml of methanol over 15 minutes during the mixture was stirred at 0-5° C. in a nitrogen stream. This was raised to room temperature and stirred for 45 minutes and the solvent was evaporated. The resulting residue was dissolved in ethyl acetate and then the solution was washed with a saturated aqueous solution of sodium bicarbonate twice and then with brine once. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 1.45 g of the title compound. The yield was 100%.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].C([O:21][C:22](=[O:28])[CH:23](Br)[CH2:24][CH2:25][CH3:26])C>CC(C)=O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH:23]([CH2:24][CH2:25][CH3:26])[C:22]([OH:28])=[O:21])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCC(Br)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O

Procedure:
The title compound was prepared according to the method of Example 22 from potassium hydroxide flakes (3.36 g, 0.06 mole), 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (4.76 g, 0.02 mole) and ethyl-2-bromovalerate (4.18 g, 0.02 mole) in acetone (100 ml). The structure was confirmed by NMR.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:11][C:12]1(O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH3:11][C:12]1([C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[C:8]([C:4]3([CH3:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[C:7]=2[OH:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)c1ccc(O)cc1
Reactant: CC1(O)CCCCC1
Product: CC(C)c1cc(C2(C)CCCCC2)c(O)c(C2(C)CCCCC2)c1

Procedure:
38 parts of para-isopropylphenol and 96 grams 1-methylcyclohexanol were reacted as described in Example 15 to give 2,6-bis (1-methyl-cyclohexyl)-4-isopropylphenol, γmax 3620 cm-1 (--OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: O=C(O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a flask with 4-fluorophenyl boronic acid (2.1 g, 15 mmol), copper(II) acetate (1.4 g, 7.5 mmol), activated powdered molecular sieves (approximately 2 g), and methyl 4-hydroxybenzoate (1.2 g, 7.5 mmol) is added TEA (5.2 mL, 38 mmol) followed by CH2Cl2 (75 mL). The reaction is stirred for 16 hours at room temperature with air bubbling through it. The reaction mixture is diluted with CH2Cl2 and filtered through silica gel. The silica gel is washed with EtOAc-heptane. The solution is concentrated in vacuo and dissolved in dioxane (15 mL). To this solution is added aqueous LiOH (1N, 15 mL) and stirred for 18 hours at room temperature. To this reaction mixture is added aqueous HCl (1N) until acidic, having a pH less than 6. The resulting precipitate is collected by filtration and rinsed with water, and dried in vacuo to give 4-(4-fluorophenoxy)benzoic acid (1.6 g, 90%). MS for C13H9FO3 (ESI) (M−H)− m/z 231.