Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[O:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH:38]=[O:39])[CH2:33][CH2:32]1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:38]([OH:39])[CH2:37][CH:34]2[CH2:35][CH2:36][O:31][CH2:32][CH2:33]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)cnc21
Reactant: O=CCC1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCOCC2)cc2cc(F)cnc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a suspension of 1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 3.62 mmol) in dry tetrahydrofuran (30 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (1.6M, 2.72 mL, 4.35 mmol). The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-pyran-4-yl)-acetaldehyde (0.7 g, 5.43 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanol (1.23 g, 84%): LC/MS m/e calcd for C20H21FN2O4S [M+H]+ 405.46, observed 405.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:10]=1)=[O:8].Br[CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]/[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:10]=1)=[O:8]
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCCC(=O)c1ccc(O)c(CCC(=O)OC)c1
Product: COC(=O)CCCC(=O)c1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(CCC(=O)OC)c1
Yield: 81.7 %

Procedure:
Under the conditions of example 1A, 500 mg of 5-[4-hydroxy-3-(2-methoxycarbonylethyl)-Phenyl]-5-oxo-pentanoic acid methyl ester is reacted with 436 mg of (1E)-6-bromo-l-(4-methoxyphenyl)-1-hexene, worked up and the crude product is chromatographed on silica gel with hexane/ethyl acetate (0-15% ethyl acetate). 657 mg of 5-[3-(2-methoxycarbonylethyl)-4-[6-(4-methoxyphenyl)-( 5E)-5-hexenyloxy]-phenyl]-5-oxo-pentanoic acid methyl ester is obtained as oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,4-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.52-7.67 (m, 2 H), 8.12 (ddd, J=8.7, 4.3, 1.5 Hz, 1 H), 8.19 (ddd, J=10.8, 7.5, 2.0 Hz, 1 H), 8.55 (dt, J=8.1, 1.9 Hz, 1 H), 8.74 (dd, J=5.1, 1.7 Hz, 1 H), 9.29 (dd, J=2.0, 0.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3B3OC(C)(C)C(C)(C)O3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:43]1[S:44][CH:45]=[C:46]([Br:48])[N:47]=1.COCCOC.C([O-])([O-])=O.[Na+].[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.CCO>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:43]3[S:44][CH:45]=[C:46]([Br:48])[N:47]=3)[C@H:14]2[CH3:39])[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(Br)cs1
Temperature: 100 °C

Procedure:
In a tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (59 mg, 0.099 mmol), 2,4-dibromothiazole (60 mg, 0.247 mmol), DME (420 μL), EtOH (140 μL), and 1M Na2CO3 (296 μL, 0.296 mmol). The mixture was degassed with N2 and then Pd(PPh3)4 (5.7 mg, 4.94×10−3 mmol) was added. The mixture was degassed with N2 again, and then the tube was sealed, and the reaction was heated at 100° C. for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with water and brine (10 mL) each, dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-bromo-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.33 (25% EtOAc/hexanes). LCMS=635.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (bs, 2H), 7.78 (s, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.68 (dd, J=8.1, 1.0 Hz, 1H), 7.41 (s, 1H), 5.66 (d, J=8.0 Hz, 1H), 5.02 (d, J=15.8 Hz, 1H), 4.84 (J=15.8 Hz, 1H), 4.20 (m, 1H), 0.78 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1>O1CCOCC1>[N:1]1([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: C1COCCO1
Product: c1ccc2c(CCN3CCCC3)c[nH]c2c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (3.17 g, 3.7 ml, 44.6 mmol) was dissolved in abs. dioxane (100 ml), 3-(2-bromo-ethyl)-1H-indole (5 g, 22.3 mmol) was added at RT and the mixture was stirred at 70° C. for 8 h. The solution was concentrated, the residue was taken up in CHCl3 (150 ml) and the mixture was washed with water (2×50 ml). The organic phase was dried over Na2SO4, filtered and concentrated i. vac.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16]C)=[O:15])[C:9]2=[O:18])=[C:4]([CH3:19])[CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:18])=[C:4]([CH3:19])[CH:3]=1
Reactant: COC(=O)c1cccn(-c2ccc(F)cc2C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(F)ccc1-n1cccc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 186.1 %

Procedure:
To a suspension of methyl 1-(4-fluoro-2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.40 g, 1.53 mmol) in methanol (9 mL) was added 2N aqueous sodium hydroxide solution (1.15 mL), and the mixture was stirred at room temperature for 3 hr. 6N Hydrochloric acid (0.5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with hexane/ethyl acetate (=1/1) to give the title compound (704 mg, 85%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(Cl)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 62.1 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (86.35 mg, 0.2553 mmol), 4-Chlorobenzaldehyde (39.5 mg, 0.281 mmol) and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 72.70 mg (63%) of the title compound. (300 MHz, DMSO-d6) 13.39 (s, 1H), 8.14 (d, J=9 Hz, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 7.63 (d, J=9 Hz, 2H), 7.21 (m, 2H), 6.41 (m, 1H), 6.37 (m, 1H), 5.21 (t, J=17 Hz, 9 Hz, 1H), 2.89 (s, 1H), 2.77 (s, 1H), 2.62 (d, J=9 Hz, 1H), 2.23 (d, J=9 Hz, 1H), 1.38 (d, J=9 Hz, 1H). MS=458 (M+H), HPLC: 2.77 min. (G Method)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1.Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:10][CH:11]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(Oc2ccc(F)c(F)c2)cc1
Product: CN1CCCn2c1cc(OCCc1ccc(Oc3ccc(F)c(F)c3)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-(3,4-difluorophenoxy)phenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].FC(F)(F)C([O-])=O.[CH3:25][C:26]1[C:31](=[O:32])[N:30]([C:33]2[CH:34]=[C:35]([CH:37]=[C:38]([N:40]3[C:44](=[O:45])[C:43]([CH3:46])=[CH:42][C:41]3=[O:47])[CH:39]=2)[NH3+:36])[C:28](=[O:29])[CH:27]=1>N1C=CC=CC=1>[S:1]([NH:36][C:35]1[CH:37]=[C:38]([N:40]2[C:44](=[O:45])[C:43]([CH3:46])=[CH:42][C:41]2=[O:47])[CH:39]=[C:33]([N:30]2[C:31](=[O:32])[C:26]([CH3:25])=[CH:27][C:28]2=[O:29])[CH:34]=1)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CC1=CC(=O)N(c2cc([NH3+])cc(N3C(=O)C=C(C)C3=O)c2)C1=O
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: O=C([O-])C(F)(F)F
Solvent: c1ccncc1
Product: CC1=CC(=O)N(c2cc(NS(=O)(=O)c3cccc4c(N(C)C)cccc34)cc(N3C(=O)C=C(C)C3=O)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.3 %

Procedure:
Dansyl chloride (139 mg, 0.517 mmol) in pyridine (3 mL) was added to a pyridine solution of 4 (200 mg, 0.517 mmol). The resulting mixture was stirred at 25° C. for 18 hours after which the volatiles were evaporated under reduced pressure. The resulting oil was taken back in CHCl3 and the organic phase was washed with aqueous saturated Na2CO3, dried over MgSO4 and evaporated. The crude was purified by flash chromatography on silica gel (Tol/EtOAc 10%) giving 5 as a light green solid (40 mg, 0.074 mmol, 16%). 1H NMR (400 MHz, (CD3)2CO) δ 9.71 (s, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.39 (dd, J1=1.2, 7.2 Hz, 1H), 7.62-7.58 (td, J=1.2, 7.2 Hz, 2H), 7.28-7.27 (m, 3H), 7.11 (t, J=2.0 Hz, 1H), 6.63-6.61 (m, 2H); 13C NMR (75 MHz, (CD3)2CO) δ 171.3, 170.4, 152.8, 135.4, 134.0, 131.7, 131.5, 130.3, 130.2, 129.6, 128.7, 124.9, 119.8, 119.6, 116.6, 115.9, 46.3, 12.1; HRMS (ESI) Calculated for C28H25N4O6S [M+H]+: 545.1516. Found: 545.1489. m.p.: 230° C.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[N:15][CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:14]=[N:15][CH:16]=1
Reactant: N#Cc1cccnc1F
Reactant: Oc1cncc(Cl)c1
Product: N#Cc1cccnc1Oc1cncc(Cl)c1

Procedure:
2-Fluoro-nicotinonitrile was reacted with 5-chloro-pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 232 (M)+, 234 (M+2)+.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[F:1][C:2]1([F:7])[CH2:6][CH2:5][N:4]([C:22]([C:21]2[CH:25]=[CH:26][N:27]=[CH:28][C:20]=2[NH:19][C:17]([C:15]2[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=[C:11]([CH:8]3[CH2:10][CH2:9]3)[N:16]=2)=[O:18])=[O:23])[CH2:3]1
Reactant: FC1(F)CCNC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(Nc1cnccc1C(=O)N1CCC(F)(F)C1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 27 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3,3-difluoro-pyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (27%) as amourphous light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10][O-:11].[Na+].Cl>>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)cc(N)n1
Agent: Cl
Agent: [Na+]
Product: COc1cc(C)nc(N)c1
Temperature: 130 °C

Procedure:
To 4-chloro-6-methylpyridin-2-amine (1.0 g, 7.0 mmol) was added sodium methoxide (25% solution in methanol, 9.2 ml, 35 mmol) under a nitrogen atmosphere. The reaction mixture was heated in a microwave at 130° C. for 12 hours. The reaction mixture was quenched with hydrochloric acid (1.0 M in water, 42 ml, 42 mmol), and the reaction mixture was partially concentrated under reduced pressure to remove methanol. The residue was diluted with ethyl acetate, and the pH was adjusted to ˜7.5 with saturated aqueous sodium bicarbonate solution. The organics were separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol with ammonium hydroxide, linear gradient) to afford 4-methoxy-6-methylpyridin-2-amine. MS ESI calc'd. for C7H11N2O [M+H]+ 139. found 139. 1H NMR (500 MHz, DMSO-d6) δ 5.96 (d, J=1.5 Hz, 1H), 5.75 (d, J=2.0 Hz, 1H), 5.70 (br s, 2H), 3.66 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)CCl.[NH2:19][C@@H:20]([CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22]>C(Cl)Cl>[C:1]([NH:19][C@@H:20]([CH2:29][N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:22])(=[O:14])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reactant: CCCCCCOCCOCC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCOCCOCC(=O)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 3 h
Yield: 47.3 %

Procedure:
Methylene chloride (40 ml), 3,6-dioxadodecanoic acid (1.086 g, 5.325 mmol) and EDC (1.167 g, 6.090 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (959.1 mg, 4.064 mmol), followed by stirring for 3 hours. EDC (719.3 mg, 3.752 mmol) was added thereto and the mixture was further stirred for 3 days. After evaporating the solvent under reduced pressure, a saturated sodium hydrogen carbonate solution (70 ml) was added, followed by extraction with ethyl acetate (100 ml). After washed with water (70 ml) and saturated brine (70 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:methanol=30:1) to obtain the title compound (812.3 mg, yield 47.4%) as colorless oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:9]#[N:10])#[N:2].[BrH:11].[OH-].[Na+]>C(O)(=O)C>[NH2:2][C:1]1[N:10]=[C:9]([Br:11])[C:8]2[CH:7]=[CH:6][S:5][C:4]=2[CH:3]=1
Reactant: Br
Reactant: N#CCc1sccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc2sccc2c(Br)n1
Yield: 70 %

Procedure:
2-Cyanomethyl-3-cyanothiophene (823 mg) was added to a solution (30 ml) of 25% hydrogen bromide in acetic acid, and the resulting mixture was stirred under ice-cooling for 90 min, which was neutralized with a 8N-aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with water, dried (over MgSO4) and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow solid (894 mg, yield; 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:25]1[CH2:24][CH:23]2[CH:27]([C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21][C:22]2=[O:28])[CH2:26]1)=[O:11]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3Br)CC12
Reaction time: 0.75 h
Yield: 59.9 %

Procedure:
N,N'-Carbonyldimidazole (1.13 g) is added to a solution of 2-(2-bromophenyl)acetic acid (1.5 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroiso-indolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred for 4 hours at 20° C. The reaction mixture is washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (74 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2-bromophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2.04 g) melting at 217° C. is obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH2:3]1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>C(O)(=O)C>[C:24]([C:23]1[CH:27]=[C:19]([N:18]2[C:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][C:4]=3[CH:9]=[C:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:20]=[CH:21][C:22]=1[OH:28])([OH:26])=[O:25]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Solvent: CC(=O)O
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2ccc(O)c(C(=O)O)c2)C1

Procedure:
a solution of 50 g. (0.22 mole) of 4-methyl-2-phenacylcyclohexanone, 33.7 g. (0.22 mole) of 5-aminosalicylic acid, and 257 ml. of glacial acetic acid was heated under reflux for 3 hours, cooled and filtered. The collected solid was washed with water and recrystallized from acetonitrile to provide 43.3 g. (57%) of yellow crystals, m.p. 213°-215°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.N1(O)C2C=CC=CC=2N=N1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:12])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccc(SCc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(SCc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Temperature: 0 °C
Yield: 52.3 %

Procedure:
A solution of 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoic acid (500 mg, 1.47 mmol, 1.00 equiv), EDCI (340 mg, 1.78 mmol, 1.21 equiv), 1H-1,2,3-benzotriazol-1-ol (240 mg, 1.78 mmol, 1.21 equiv), pyridin-3-ylmethanamine (190 mg, 1.76 mmol, 1.19 equiv) and triethylamine (450 mg, 4.46 mmol, 3.02 equiv) in N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of an ice/water mixture. The precipitate was collected by filtration, washed with 3×10 mL of hexane and 4×10 mL of 66% aqueous methanol to give 0.33 g (52%) of 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 471
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:9]=[C:10]2[C:33](=[CH:34][CH:35]=1)[C:14]1=[N:15][O:16][C:17]([C:18]3[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:20][N:19]=3)=[C:13]1[CH2:12][CH2:11]2)([CH3:7])[C:3]([O:5]C)=[O:4]>Cl.O1CCOCC1>[OH:1][C:2]([C:8]1[CH:9]=[C:10]2[C:33](=[CH:34][CH:35]=1)[C:14]1=[N:15][O:16][C:17]([C:18]3[C:22]([C:23]([F:24])([F:26])[F:25])=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:20][N:19]=3)=[C:13]1[CH2:12][CH2:11]2)([CH3:7])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CC(O)(C(=O)O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 48 h
Yield: 97.1 %

Procedure:
Methyl 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)propanoate (Preparation 134C, isomer 1, 85 mg, 0.175 mmol) was dissolved in 4 N hydrochloric acid in dioxane (1 mL). The reaction mixture stirred at 60° C. for 48 h before it was concentrated to yield 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)propanoic acid (80 mg, 0.17 mmol, 97% yield): LC/MS M+1=472.03. Isomer 2: Methyl 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)propanoate (Preparation 134C, isomer 2, 83 mg, 0.171 mmol) was dissolved in 4 N hydrochloric acid in dioxane (1 mL). The reaction mixture was stirred at 60° C. for 48 h before it was concentrated to yield 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)propanoic acid (80 mg, 0.17 mmol, 99% yield): LC/MS M+1=472.03.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 8.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.6 mg) was obtained.