Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30](B(O)O)=[CH:29]1>>[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([C:13]2[C:12]3[C:11]([S:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)=[C:10]4[CH:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][CH2:8][N:9]4[C:17]=3[CH:16]=[C:15]([F:18])[CH:14]=2)=[CH:29]1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: OB(O)c1csc2ccccc12
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3csc4ccccc34)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 1-benzothien-3-ylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: [NH2:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:20])=O>CO>[ClH:20].[NH2:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: O=S(Cl)Cl
Agent: NC1(C(=O)O)CCN(Cc2ccccc2)CC1
Solvent: CO
Product: Cl
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of 4-amino-1-benzylpiperidine-4-carboxylic acid (5 g, 21 mmol) in methanol (90 ml) is cooled down to 0° C. and treated dropwise with thionyl chloride. The mixture is then brought to reflux for 5 hours and stirred at 20° C. overnight. The mixture is concentrated under reduced pressure, the residue is taken up in toluene and concentrated again to give 6.14 g of 4-amino-1-benzylpiperidine-4-carboxylic acid hydrochloride ax58 as a hygroscopic white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[O:6].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>O(CCCC)CCCC>[CH3:23][O:22][C:20]([C:17]1[CH:18]=[CH:19][C:14]([N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:12][CH:11]=2)[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:15][CH:16]=1)=[O:21]
Reactant: O=C(Cl)CCCCCBr
Reactant: COC(=O)c1ccc(Nc2ccc(C(=O)OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COC(=O)c1ccc(N(C(=O)CCCCCBr)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil; 77.1 mg, 1.93 mmol) in anhydrous n-Bu2O (5 ml) 15a (500 mg, 1.75 mmol) is added batch wise, and the mixture is stirred for an additional two hours at RT. Then, 6-bromohexanoic acid chloride (0.314 ml, 2.10 mmol) is added, and the reaction is heated for 4 h under reflux. The mixture is allowed to cool to RT, poured into ice-water, and extracted with CH2Cl2. The organic phases are unified, washed with a saturated solution of NaHCO3 (2×) and saturated NaCl, and dried over MgSO4. Finally, the solvent is distilled off, and the crude product is crystallized from methanol. 713 mg (88%) of the desired compound 19a are obtained as a colorless solid. Melting point. 133-135° C.; IR (KBr) 2920, 1700, 1645, 1580 cm−1; 1H-NMR (CDCl3) δ 8.06 (d, 8.6 Hz, 4H), 7.30 (d, 8.6 Hz, 4H), 3.92 (s, 6H), 3.38 (t, 6.7 Hz, 2H), 2.29 (t, 7.4 Hz, 2H), 1.88-1.77 (m, 2H), 1.76-1.64 (m, 2H), 1.49-1.35 (m, 2H); MS (FD) m/z 464 (M++1 for Br81), 462 (M++1 for Br79).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CO[C:36]1[CH:37]=[C:38]([NH2:46])[CH:39]=[C:40](OC)[C:41]=1OC>>[CH2:2]1[C:40]2[C:41](=[CH:36][CH:37]=[C:38]([NH:46][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:39]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: COc1cc(N)cc(OC)c1OC
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared by a procedure similar to Example 27, Step D using N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and [3,4,5-tris(methyloxy)phenyl]amine: MS (APCI): 609 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@@H:10]([OH:22])[CH2:11][C@@H:12]([C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([NH:15][CH2:16][CH3:17])=[O:14])=O)(C)(C)C.C(OC(N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](C(O)(C)C)C(NC)=O)=O)(C)(C)C.[C:58]([O:62][C:63]([NH:65][C@H:66]([C:73](O)=[O:74])[CH2:67][C:68]1[N:69]=[CH:70][S:71][CH:72]=1)=[O:64])([CH3:61])([CH3:60])[CH3:59].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>>[C:58]([O:62][C:63]([NH:65][C@H:66]([C:73]([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@@H:10]([OH:22])[CH2:11][C@@H:12]([C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[O:74])[CH2:67][C:68]1[N:69]=[CH:70][S:71][CH:72]=1)=[O:64])([CH3:60])([CH3:61])[CH3:59]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Yield: 80.5 %

Procedure:
A procedure similar to that described in Example 9(a) was repeated, except that 280 mg (0.675 mmoles) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-ethylhexanamide (prepared as described in Preparation 24) were used instead of the (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide, and 190 mg (0.7 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine, 0.4 ml (2.88 mmoles) of triethylamine, and 0.11 ml (0.688 mmoles) of diethyl cyanophosphate were also used, to give a powdery substance, which was then recrystallized from a mixture of diisopropyl ether and methylene chloride, to afford 309 mg of the title compound, melting at 189°-191° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=4[N:21]=[C:20]3[C:29]([OH:32])([CH3:31])[CH3:30])[CH2:15][CH2:14]1)=O)[CH2:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:13]1[CH2:14][CH2:15][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=4[N:21]=[C:20]3[C:29]([OH:32])([CH3:30])[CH3:31])[CH2:17][CH2:18]1)[CH2:5]2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(C(=O)C2Cc3ccc(N)cc3C2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a solution of (5-amino-indan-2-yl)-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidin-1-yl}-methanone (150 mg, 0.35 mmol) in THF (10 mL) was added dropwise of 1 M lithium aluminum hydride (0.76 ml, 0.76 mmol) in THF. After stirring for 30 minutes, the reaction mixture was heated up to 80° C. and stirred for 20 minutes. The reaction mixture was quenched with water (0.3 ml) and 4 M NaOH solution (0.1 ml) at 0° C. The mixture was warmed up to rt and stirred for 45 minutes. The suspension was filtered over a Celite® pad, washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford 2-{1-[1-(5-amino-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazol-2-yl}-propan-2-ol (87 mg, 60%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]1[CH2:18][CH:17]1[CH2:19]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[O:16]1[CH2:18][CH:17]1[CH2:19][N:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:14]1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Product: c1ccc(CCCN2CCN(CC3CO3)CC2)cc1
Yield: 80 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from 1-(3-phenylpropyl)-piperazine and 3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after Biotage chromatography the title compound as a yellow oil in a 80% yield.
Reaction SMILES: [NH2:1][C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Fe+2:12].C=O.[BH3-][C:16]#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:16][N:1]([C-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH3:2].[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Fe+2:12]
Reactant: [BH3-]C#N
Reactant: N[c-]1cccc1
Agent: [Fe+2]
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)[c-]1cccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 182.1 %

Procedure:
A solution of aminoferrocene (1.07 g, 5.32 mmol) in acetic acid (15 mL) under argon was treated with paraformaldehyde (1.59 g, 53.2 mmol) and NaBH3CN (1.67 g, 26.6 mmol) and stirred at room temperature for 16 h. The reaction mixture was brought to pH 12 by addition of 6 M aqueous NaOH solution, and extracted with hexanes (3×20 mL). The combined organic extract was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to approx. 5% of its original volume under reduced pressure. The solution was filtered through basic alumina (20 mL) with hexanes, concentrated back to its pre-filtration volume and left to crystallize in a freezer to give N,N-dimethylaminoferrocene (11) (1.11 g, 91%) as orange flakes; mp 69-70° C. (hexanes); IR (KBr) vmax 3106, 2981, 2952, 2857, 2827, 2782, 1508 cm−1, 1H NMR (300 MHz, CDCl3) 4.25 (s, 5H), 3.93 (s, 2H), 3.78 (s, 2H), 2.59 (s, 6H); 13C NMR (75.5 MHz, acetone-d6) 115.8, 66.5, 63.0, 54.6, 41.5; EIMS [m/z(%)] 229 (M+, 100), 186 (18), 121 (17); HRMS (EI) calcd for C12H16N56Fe: 229.0554. Found 229.0553. Anal. Calcd for C12H16N56Fe: C, 62.91; H, 6.60. Found: C, 62.95; H, 6.60.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.[NH2:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40])=[O:6]
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)c(Cl)c1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)cc2Cl)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 87.6 %

Procedure:
To a solution of 2-chloro-4-(1-phenoxyethyl)benzoic acid (262 mg, 1.0 mmol), 1-hydroxybenzotriozole (202 mg, 1.5 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol) triethylamine (0.4 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide as a white solid (360 mg, 88%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[O:9][C:10]([CH2:20][CH2:21][CH2:22][OH:23])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:12]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([S:7][C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:9][C:10]=2[CH2:20][CH2:21][CH2:22][O:23][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[CH:14][CH:15]=1
Reactant: OCCCc1oc(Sc2ncccn2)nc1-c1ccc(Cl)cc1
Reactant: COc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccccc1OCCCc1oc(Sc2ncccn2)nc1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a mixture of 2-(2-pyrimidinylsulfanyl)-4-(4-chlorophenyl)-5-oxazolepropanol (174 mg), 2-methoxyphenol (124 mg), tributylphosphine (202 mg) and tetrahydrofuran (5 ml) was added 1,1′-(azodicarbonyl)dipiperidine (252 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-pyrimidinylsulfanyl)oxazole was obtained as an oil (182 mg. 80%) from an ethyl acetate-hexane (1:3, v/v)-eluted fraction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1[C@@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[(S)-3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a white foam, MS (ESI+): m/z=425.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:11]([O:13][C:14](=N)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]>CCO>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:14]([O:13][CH2:11][CH3:12])=[N:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[C:4]=1[CH3:10])[CH3:20]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: COc1cccc(N)c1C
Solvent: CCO
Product: CCOC(=O)CC(=Nc1cccc(OC)c1C)OCC
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To 3-methoxy-2-methylaniline (2.15 g, 15.6 mmol) in anhydrous EtOH (30 mL) was added ethyl 3-ethoxy-3-imino-propionate (3.05 g, 15.6 mmol). The reaction was stirred overnight then filtered through celite. The filtrate was concentrated then purified by column chromatography on silica (2→10% EtOAc/hexane) to afford 3-ethoxy-3-(3-methoxy-2-methyl-phenylimino)-propionic acid ethyl ester (3.84 g, 88%). LCMS found 280.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]2=[CH:15][N:14]=1.[O:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>>[O:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[N:17]([C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:14][CH:15]=3)[CH:18]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1ncc2ccc(C(=O)O)cn12
Product: Cc1onc(-c2ccccc2)c1-c1ncc2ccc(C(=O)NC3CCOCC3)cn12
Yield: 55.2 %

Procedure:
As described for example 4b, 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine-6-carboxylic acid (58 mg, 0.18 mmol), was converted, using tetrahydropyran-4-ylamine (28 mg, 0.27 mmol) instead of cyclopropyl methylamine, to the title compound (40 mg, 55%) which was obtained as a light yellow solid. MS: m/e (ESI): 403.3 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:24][CH2:25][CH:26]([OH:28])[CH3:27]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21][S:24][CH2:25][CH:26]([OH:28])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(O)CS
Product: CC(O)CSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 1, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) and 1-mercapto-2-propanol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 89% yield.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C@@H:14]([NH:20][C:21](=[O:40])[C@@H:22]([C@H:25]2[C@H:30]([OH:31])[C@@H:29](/[CH:32]=[CH:33]/[C:34]([CH3:37])([CH3:36])[CH3:35])[O:28]C(C)(C)[O:26]2)[O:23][CH3:24])[CH2:13][CH2:12]1)=[N+:2]=[N-:3].C(O)(=O)CCCCCCCCCCCCC>>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:17][N:16]([CH3:18])[C:15](=[O:19])[C@@H:14]([NH:20][C:21](=[O:40])[C@H:22]([O:23][CH3:24])[C@H:25]([OH:26])[C@@H:30]([OH:31])[C@H:29]([OH:28])/[CH:32]=[CH:33]/[C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:13][CH2:12]1)=[N+:2]=[N-:3]
Reactant: CO[C@@H](C(=O)N[C@H]1CC[C@@H](OCCCCCCN=[N+]=[N-])CN(C)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Agent: CCCCCCCCCCCCCC(=O)O
Product: CO[C@@H](C(=O)N[C@H]1CC[C@@H](OCCCCCCN=[N+]=[N-])CN(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C

Procedure:
Following the procedure of Example 1 m) except (R)-N-[(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide is substituted for tetradecanoic acid (3R,6S-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-yl ester. MS (ESI) 528.0 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:11]([OH:24])[CH:10]([CH:25]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:11]([OH:24])[CH:10]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4].[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([O-:5])=[O:47])=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N1CCCN(C(=O)OC(C)(C)C)CC(C2CCCCCCCC2)C(O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([O-])c1ccc(Cl)cc1
Reaction time: 2.5 h

Procedure:
To 3,7-di(tert-butoxycarbonyl)-3,7-diazabicyclononan-9-ol (475 mg, 1.39 mmol) in methylene chloride (25 mL) was added triethylamine (0.390 mL), 4-chlorobenzoyl chloride (0.23 mL, 1.81 mmol), and 4-dimethylaminopyridine (221 mg, 1.81 mmol). The reaction mixture was stirred for 2.5 h and was then diluted with methylene chloride and washed with 0.5N aqueous HCl and water. After drying over sodium sulfate the solution was concentrated and the residue was purified by column chromatography on silica gel with 25% ethyl acetate in hexanes to give the title compound (611 mg, 91%). 1H NMR (300 MHz, CDCl3) 1.18 (s, 18H), 1.80 (s, 3H), 3.00 (t, 2H), 3.31 (t, 2H), 3.99 (m, 3H), 4.30 (m, 2H); mass spectrum m/z 365 (M+Na)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([CH3:11])=[CH:7][CH2:8][C:9]#[N:10].O.Cl.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:5][C:6]([C:17]1[CH:18]=[CH:19][C:14]([CH3:20])=[CH:15][CH:16]=1)([CH3:11])[CH2:7][CH2:8][C:9]#[N:10]
Reactant: CC(C)=CCC#N
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(C)(C)CCC#N)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
Aluminum chloride (100 g, 0.75 mol) was added slowly (30 minutes) to a solution of 4-methyl-3-pentenenitrile (61.7 g, 0.65 mol) in toluene (300 ml) while maintaining the temperature below 10° C. After stirring an additional 4.0 hours at a temperature below 10° C, the mixture was poured onto an ice, water mixture containing 100 ml of 10% hydrochloric acid. The organic layer was washed (10% Na2CO3 then H2O), concentrated and distilled to yield 94.8 g (78.5%) of 4-methyl-4-p-tolylpentanenitrile (3b) which was 91% the para isomer and 9% meta isomer (glc, 20M): bp 129° (1 mm); nD20 1.5145; δTMSCDCl 3 7.13 (s, 4), 2.28 (s, 3) 1.95 (s, 4); 1.28 (s,6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[CH3:20])[N:11]=[C:10]2[CH:21]([NH:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3COCC[Si](C)(C)C)[CH3:22])[CH:6]=[CH:7][CH:8]=1.OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[CH3:20])[N:11]=[C:10]2[CH:21]([NH:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][NH:28]3)[CH3:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2c(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)nc3cccc(C)c3c2=O)c1
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Product: COc1cccc(-n2c(C(C)Nc3ncnc4[nH]cnc34)nc3cccc(C)c3c2=O)c1

Procedure:
Compound 127 was reacted in accordance with the procedure described above for compound 121 (step D) to provide compound 128. m/z=428 (M+H). The structure of compound 128 is shown below.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:17]([OH:25])[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:15][NH:14][C:12]([C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][O:9][C:10]=1[CH2:16][C:17]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=[O:25])=[O:13]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccc(C)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccc(C)cc1

Procedure:
A mixture of 41.4 g. (0.123 mole) of 3-phenyl-5-(4-methyl-β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide and 800 ml. of acetone is treated dropwise with the addition of 92.5 ml. (0.185 mole) of Jones reagent [100 g. chromium trioxide, 160 ml. concentrated sulfuric acid with water to 500 ml.] and the resulting mixture is stirred at room temperature for 2 hours. The supernatant liquid is decanted and the solvent removed in vacuo, the residue is taken up in water/methylene chloride and the layers separated. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is treated with ether to give a solid and then triturated with ethanol to give N-methyl-5-(4-methylphenacyl)-3-phenyl-4-isoxazole carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1Cc1ccccn1

Procedure:
The title compound, MS: m/e=308.1 (M+H30), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-(bromomethyl)pyridine hydrobromide.