Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[C:25]2[S:26][CH:27]=[CH:28][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[S:26]1[CH:27]=[CH:28][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][N:7]3[C:6]4[CH:5]=[C:4]([N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)[CH:3]=[C:2]([Br:1])[C:10]=4[N:9]=[C:8]3[CH3:11])[C:25]1=2
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: BrCc1cccc2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccsc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.8 g, 2.70 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 7-(bromomethyl)benzo[b]thiophene (0.920 g, 4.05 mmol)) and potassium carbonate (1.120 g, 8.10 mmol). The resulting reaction mixture was stirred at 90° C. for 2 h, then more 7-(bromomethyl)benzo[b]thiophene (0.920 g, 4.05 mmol) was added in and the reaction mixture was stirred at 100° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phase was washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (0.69 g, 58% %). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H) 2.95-3.07 (m, 4H) 3.66-3.72 (m, 4H) 5.69 (s, 2H) 6.81 (d, J=7.07 Hz, 1H) 7.00 (d, J=2.02 Hz, 1H) 7.09 (d, J=2.02 Hz, 1H) 7.36 (t, J=7.58 Hz, 1H) 7.53 (d, J=5.56 Hz, 1H) 7.79 (d, J=5.56 Hz, 1H) 7.85 (d, J=7.65 Hz, 1H); MS (ES+) m/e 442.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][OH:33]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:33][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([C:28]([F:27])([F:37])[F:38])[CH:30]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1cccc(C(F)(F)F)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cccc(C(F)(F)F)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 3-(trifluoromethyl)benzyl alcohol (132 mg; 0.736 mmol), example 69 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:7]([O:9]CC)=O.[CH2:16]([N:19]1[C:23]2[CH:24]=[C:25]([NH:29][C:30](OCC)=[O:31])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:35]([F:38])([F:37])[F:36])[C:17]#[CH:18].N12CCCN=C1CCCCC2.Cl>CN(C)C=O>[CH2:16]([N:19]1[C:23]2[CH:24]=[C:25]([N:29]3[C:7](=[O:9])[CH:6]=[C:5]([C:12]([F:13])([F:14])[F:15])[NH:4][C:30]3=[O:31])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:35]([F:37])([F:38])[F:36])[C:17]#[CH:18]
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: C#CCn1c(C(F)(F)F)nc2cc(F)c(NC(=O)OCC)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.4 gram (0.005 mole) of sodium methoxide in 5 mL of N,N-dimethylformamide was cooled to about 0°-5° C., and 1.8 grams (0.005 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 15 mL of N,N-dimethylformamide was added dropwise. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes. After this time, the reaction mixture was again cooled, and a solution of 1.8 grams (0.005 mole) of 1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluoro-6-ethoxycarbonylaminobenzimidazole in 20 mL of N,N-dimethylformamide was added dropwise. The reaction mixture was heated to 110° C., and 0.24 mL (catalyst) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added in one portion. Upon completion of the addition, the reaction mixture was heated to about 130° C., where it stirred for about 3.5 hours. The reaction mixture was then allowed to cool to ambient temperature as it stirred for about 72 hours, after which the reaction mixture was poured into ice-cold aqueous 3N hydrochloric acid. The resultant precipitate was collected by filtration and dried, yielding 0.6 gram of 3-[1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH:1]1([C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(=O)Cl
Reactant: Br[Mg]C1CCCCC1
Product: COC(=O)C(=O)C1CCCCC1
Yield: 65 %

Procedure:
The title compound (1.1 g, 65%) as a colorless oil was prepared from cyclohexyl-magnesium bromide and methyl chlorooxoacetate by the procedures described in F. Babudri et al., Tetrahedron, 52 (42), pp. 13512-20 (1996).
Reaction SMILES: OCCS(CCN[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)(=O)=O.[C:48]([O:52][C:53]([NH:55][CH2:56][CH2:57][CH2:58][NH:59][C@:60]12[CH2:95][CH2:94][C@@H:93]([C:96]([CH3:98])=[CH2:97])[C@@H:61]1[C@@H:62]1[C@@:75]([CH3:78])([CH2:76][CH2:77]2)[C@@:74]2([CH3:79])[C@@H:65]([C@:66]3([CH3:92])[C@@H:71]([CH2:72][CH2:73]2)[C:70]([CH3:81])([CH3:80])[C:69]([C:82]2[CH:91]=[CH:90][C:85]([C:86]([O:88]C)=[O:87])=[CH:84][CH:83]=2)=[CH:68][CH2:67]3)[CH2:64][CH2:63]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>>[C:48]([O:52][C:53]([NH:55][CH2:56][CH2:57][CH2:58][NH:59][C@:60]12[CH2:95][CH2:94][C@@H:93]([C:96]([CH3:98])=[CH2:97])[C@@H:61]1[C@@H:62]1[C@@:75]([CH3:78])([CH2:76][CH2:77]2)[C@@:74]2([CH3:79])[C@@H:65]([C@:66]3([CH3:92])[C@@H:71]([CH2:72][CH2:73]2)[C:70]([CH3:81])([CH3:80])[C:69]([C:82]2[CH:83]=[CH:84][C:85]([C:86]([OH:88])=[O:87])=[CH:90][CH:91]=2)=[CH:68][CH2:67]3)[CH2:64][CH2:63]1)=[O:54])([CH3:49])([CH3:50])[CH3:51]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCNC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCCS(=O)(=O)CCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCCNC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the hydrolysis method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(tert-butoxycarbonylamino)propylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (5 mg, 0.007 mmol) as starting material. The title compound was isolated as a white solid (3 mg, 58%). LCMS: m/e 687.54 (M+H)+, 2.69 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.87 (s, 1H), 4.74 (s, 1H), 3.38-3.17 (m, 4H), 3.04-2.86 (m, 1H), 2.36-1.17 (m, 24H), 1.77 (s, 3H), 1.50 (s, 9H), 1.25 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]O.C(N(CC)CC)C.CS([Cl:23])(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][Cl:23]
Reactant: COc1ccc(CO)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CCl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
To a solution of 3-chloro-4-methoxybenzyl alcohol (1.1 g, 6 mmol) in tetrahydrofuran (5 mL) were added under ice-cooling triethylamine (1.67 mL, 12 mmol) and methanesulfonyl chloride (0.51 ml, 6 mmol) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (700 mg, 61%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[NH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].[CH2:14]([O:16][CH2:17]Cl)[CH3:15]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH2:14]([O:16][CH2:17][N:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:3]1[C:2]([F:1])([F:10])[F:11])[CH3:15]
Reactant: N#Cc1cc[nH]c1C(F)(F)F
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOCn1ccc(C#N)c1C(F)(F)F
Reaction time: 0.33 h

Procedure:
A stirred solution of 2-trifluoromethyl-3-cyanopyrrole (1.0 g, 6.2 mmol) in dry tetrahydrofuran is treated with NaH (0.30 g, 7.5 mmol) as a 60% dispersion in mineral oil, under nitrogen, at room temperature. After 20 minutes, the reaction mixture is treated dropwise with a solution of chloromethyl ethyl ether (0.77 g, 8.1 mmol) in dry tetrahydrofuran, stirred vigorously for 3 hours and treated with a mixture of 1N HCI and ethyl acetate. The phases are separated and the organic phase is washed with brine, dried over Mg SO4 and concentrated in vacuo to afford a residue. Flash chromatography of the residue using silica gel and 3.5:1 hexane: ethyl acetate yields the title compound as a pale yellow oil, 0.83 g (61%).
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:16]([O:18][C:19]([CH:21]=[CH:22][CH:23]1[NH:28][CH:27]([C:29]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=2)[CH2:26][N:25]([C:38]([O:40][CH3:41])=[O:39])[CH2:24]1)=[O:20])[CH3:17].[CH:42]([CH2:44][C:45](O)=[O:46])=[CH2:43].Cl>C1COCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:45]([N:28]1[CH:27]([C:29]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=2)[CH2:26][N:25]([C:38]([O:40][CH3:41])=[O:39])[CH2:24][CH:23]1[CH:22]=[CH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])(=[O:46])[CH2:44][CH:42]=[CH2:43]
Reactant: CCOC(=O)C=CC1CN(C(=O)OC)CC(c2cc(F)c(F)c(F)c2)N1
Reactant: C=CCC(=O)O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(=O)N1C(C=CC(=O)OCC)CN(C(=O)OC)CC1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
BOPCl (557 mg) was added to a solution of methyl 3-(2-ethoxycarbonylvinyl)-5-(3,4,5-trifluorophenyl)piperazine-1-carboxylate (422 mg), triethylamine (0.61 mL), and vinylacetic acid (0.19 mL) in THF (15 mL), and the reaction solution was stirred at room temperature for 20 hours. 1 N aqueous hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 643 mg of an E/Z isomer mixture crude product of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[CH2:27].C(N(CC)CC)C.ClCCl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([CH:27]=[CH:26][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(I)cc1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1
Temperature: 100 °C
Yield: 58.5 %

Procedure:
A mixture of the (4-iodo-2-phenylbenzoyl)methionine methyl ester prepared in Example 210D (655 mg, 1.40 mmol), the vinylpyridine prepared in Example 210E (221 mg, 1.5 mmol), triethylamine (0.29 mL, 2.10 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complexed to dichloromethane (1:1) (114 mg, 0.14 mmol) in DMF (2 mL) was degassed with nitrogen, and heated at 100° C. for 14 hours. The reaction mixture was diluted with ether (100 mL), washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate) to give {4-[2-(pyrid-3-yl)ethenyl]-2-phenylbenzoyl}methionine methyl ester (366 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 8.75 (d, 1H), 8.51 (dd, 1H), 7.85 (dt, 1H), 7.76 (d, 1H), 7.59 (dd, 1H), 7.48 (dd, 1H), 7.44 (m, 5H), 7.31 (dd, 1H), 7.22 (d, 1H), 7.16 (d, 1H), 5.94 (br d, 1H), 4.69 (m, 1H), 3.68 (s, 3H), 2.08 (m, 2H), 2.02 (s, 3H), 1.93 (m, 1H), 1.76 (m, 1H). MS (APCI+) m/e 447 (M+H)+.
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]([O:8][C@@H:9]([C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[Cl:24])[C:10]([OH:12])=[O:11])([CH3:7])([CH3:6])[CH3:5].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[C:4]([O:8][C@@H:9]([C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[Cl:24])[C:10]([O:12][CH2:1][CH3:2])=[O:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cc2ccccc2c(Cl)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Ethyl iodide (0.35 mL, 1.5 eq.) was added to a mixture of (S)-2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetic acid (900 mg, 2.93 mmol, 1 eq.) and Cs2CO3 (1.91 g, 2 eq.) in DMF (920 mL) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. Ethyl acetate was added and organic layer separated and washed with brine (2×). The organic layer was dried (MgSO4) and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give a colorless oil (0.911 g, 93%). 1H-NMR: 300 MHz, (CDCl3) δ: 8.23 (d, 1H), 7.62 (d, 1H), 7.63 (s, 1H), 7.46 (m, 3H), 6.10 (s, 1H), 4.06 (dd, 2H), 2.42 (s, 3H), 1.18 (s, 9H), 1.08 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=2[F:32])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]4[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=4[F:32])[CH2:24][CH2:25]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 128 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.42–7.38 (m, 1H), 7.27–7.17 (m, 4H), 7.12–7.09 (m, 1H), 6.87 (t, 1H, J=8.6 Hz), 6.49 (t, 1H, J=5.4 Hz), 3.19 (q, 2H, J=5.8 Hz), 2.85–2.79 (m, 2H), 2.73–2.64 (m, 1H), 2.50–2.35 (m, 3H), 2.23 (t, 2H, J=6.6 Hz), 1.92–1.85 (m, 4H), 1.75–1.48 (m, 10H), 1.17 (d, 6H, J=6.7 Hz); ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[CH3:7].[Cl:9][C:10]1[CH:15]=[C:14](C2C=NN(C3CCCCO3)C=2)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[CH:15]=[C:14]([C:2]2[C:3]([CH3:8])=[N:4][O:5][C:6]=2[CH3:7])[CH:13]=[CH:12][N:11]=1
Reactant: Cc1noc(C)c1Br
Reactant: Clc1cc(-c2cnn(C3CCCCO3)c2)ccn1
Product: Cc1noc(C)c1-c1ccnc(Cl)c1

Procedure:
The title compound was prepared from 4-bromo-3,5-dimethylisoxazole generally according to the synthetic procedure described for 2-Chloro-4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyridine. HPLC (Rt)=0.81 min (method N)
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6]1)(=O)C.OP([O-])(O)=O.[K+].OP(O)(O)=O.[OH-].[Na+]>>[OH:4][C@@H:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6]1
Reactant: COc1cccc(CC2=C[C@H](OC(C)=O)CC2=O)c1
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Product: COc1cccc(CC2=C[C@H](O)CC2=O)c1
Reaction time: 3 h
Yield: 70 %

Procedure:
(R)-3-(3-Methoxybenzyl)-4-oxocyclopent-2-enyl acetate (0.1 g, 0.38 mmol) was added to KH2PO4—H3PO4 buffer (1 ml). The mixture was added thereto Lipase derived from Pseudomonas cepacia, and 1N NaOH was slowly added to the solution at room temperature to keep the pH=7˜7.5. After 3 hours, about 10% of (R)-3-(3-methoxybenzyl)-4-oxocyclopent-2-enyl acetate remained. The reaction mixture was filtered to remove Lipase and the filtrate was extracted with EtOAc, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-4-hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone as yellow oil: 58 mg (yield: 70%, >99.5% ee by HPLC using a chiral column)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CO.O>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:27][CH2:28]1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: NC1CCOCC1
Solvent: CO
Solvent: O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC1CCOCC1
Yield: 70 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (60 mg, 70%) which was obtained as a white solid after trituration from methanol/water. MS: m/e=429.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[N:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(-c2cccc3cccnc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(-c2cccc3cccnc23)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 8-(3-methoxyphenyl)quinoline (900 mg, 3.83 mmol) in CH2Cl2 (50 ml) was added BBr3 (2.4 g, 14 mmol) at 0° C. The mixture was stirred for 2 h at 0° C. then until the reaction was completed. The mixture was added drop wise to iced water (50 mL), and then extracted with CH2Cl2 (2×20 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give a yellow solid which was used in next step without further purification. (720 mg, Yield 85%). LCMS (m/z): 222.1 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2([OH:14])[CH2:12][CH:11]3[NH:13][CH:8]([CH2:9][CH2:10]3)[CH2:7]2)[C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]1=2.[CH3:19][O:20][C:21]1[C:26]2[O:27][C@H:28]([CH2:31]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:29][O:30][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[S:1]1[C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([C:6]2([OH:14])[CH2:7][CH:8]3[N:13]([CH2:31][C@@H:28]4[O:27][C:26]5[C:21]([O:20][CH3:19])=[CH:22][CH:23]=[CH:24][C:25]=5[O:30][CH2:29]4)[CH:11]([CH2:10][CH2:9]3)[CH2:12]2)=[CH:5]1
Reactant: OC1(c2csc3ccccc23)CC2CCC(C1)N2
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Product: COc1cccc2c1O[C@@H](CN1C3CCC1CC(O)(c1csc4ccccc14)C3)CO2
Yield: 33 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-benzo[b]thiophen-3-yl-8-aza-bicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 33%, white solid.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH2:25][C@H:26]([OH:39])[CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1>>[OH:39][C@@H:26]([CH2:25][NH:24][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:12]=[CH:11][C:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:23])=[CH:6][CH:5]=3)(=[O:9])=[O:8])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)[CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: Cc1ccc(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1
Product: Cc1ccc(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 from 0.13 g (0.4 mmol) of Reference Example 25, 1-[4-(toluene-4-sulfonyl)-phenyl]-piperidin-4-one, and 0.13 g (0.6 mmol) of 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one, yielding 0.18 g of a white solid; m.p. 130-132° C.; MS (ES) m/z 537.0 (MH+); HRMS (FAB) Calcd. for C28H33N4O5S (MH+): 537.2166, Found: 537.2169.
Reaction SMILES: O[C@H]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+].C(N1C=C(CN(CC2N=NN(CC3C=CC=CC=3)C=2)CC2N=NN(CC3C=CC=CC=3)C=2)N=N1)C1C=CC=CC=1.[O:54]1[C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[N:56]=[C:55]1[C:63]1[C:64]([NH2:71])=[N:65][CH:66]=[C:67]([C:69]#[CH:70])[CH:68]=1.[N:72]([CH:75]1[CH2:80][CH2:79][N:78]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:77][CH2:76]1)=[N+:73]=[N-:74]>C1COCC1.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+].O>[NH2:71][C:64]1[N:65]=[CH:66][C:67]([C:69]2[N:74]=[N:73][N:72]([CH:75]3[CH2:76][CH2:77][N:78]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:79][CH2:80]3)[CH:70]=2)=[CH:68][C:63]=1[C:55]1[O:54][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[N:56]=1
Reactant: C#Cc1cnc(N)c(-c2nc3ccccc3o2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)nn2)CC1
Reaction time: 8 h
Yield: 88.9 %

Procedure:
Sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (211 mg) and tris((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (90 mg) were added to a stirred solution of 3-(1,3-benzoxazol-2-yl)-5-ethynyl-pyridin-2-amine (125 mg) in THF (15 ml) at room temperature. To the reaction mixture was then added water (5 ml), tert-butyl 4-azidopiperidine-1-carboxylate (180 mg) in THF (1 ml) and tetrakis(acetonitrile)copper(I) hexafluorophosphate (9.9 mg). The resulting solution was stirred overnight: a precipitate appeared. The precipitate was filtered, washed successively with water, THF, diethyl ether and petroleum ether, and dried under vacuum at 50° C. to afford tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]triazol-1-yl]piperidine-1-carboxylate (218 mg) as a solid; NMR Spectrum: (DMSOd6) 1.44 (s, 9H), 1.82-1.96 (m, 2H), 2.07-2.21 (m, 2H), 3.01 (bs, 2H), 3.99-4.20 (m, 2H), 4.72-4.85 (m, 1H), 7.40-7.53 (m, 2H), 7.80-8.04 (m, 4H), 8.72 (s, 2H), 8.78 (s, 1H); Mass spectrum: M+H+: 462