Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([CH3:18])[CH:5](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:6]>C1CCN2C(=NCCC2)CC1.CCOCC>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([CH3:18])[CH:5]=[CH2:6]
Reactant: COC(=O)C(C)(C)C(C)OS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC(C)(C)C(=O)OC
Temperature: 25 °C
Yield: 130 %

Procedure:
A solution of 2,2-dimethyl-3-(toluene-4-sulfonyloxy)butyric acid methyl ester (18.06 g, 0.06 mol) in DBU (15 ml) was heated at 140-160° for 3.5 h. The mixture was allowed to cool to room temperature and was then diluted with ether. The mixture was washed with HCl (1 M), sodium bicarbonate, then brine. The ethereal layer was dried and partially evaporated to give a concentrated solution of 2,2-dimethyl-but-3-enoic acid methyl ester (10 g). (Savu and Katzenellenbogen, J Org. Chem, 46:239-250 (1981)). Further evaporation was avoided due to the volatility of the product (bp 102°). (Tsaconas et al., Aust. J Chem., 53:435-437 (2000)).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:22][OH:23])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClC(Cl)(Cl)C(=N)O[CH:28]1[O:53][C@H:52]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:43]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:29]1[O:30][C:31](=[O:33])[CH3:32]>>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:22][O:23][C@@H:28]1[O:53][C@H:52]([CH2:54][O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C@@H:43]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@H:34]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C@H:29]1[O:30][C:31](=[O:33])[CH3:32])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)O[C@H]1C(OC(=N)C(Cl)(Cl)Cl)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO)OC
Product: CCCCCCCCCCCCCCCCOC[C@H](CO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(C)=O)OC
Yield: 76 %

Procedure:
1-O-Hexadecyl-2-O-methyl-sn-glycerol (433.3 mg, 1.3 mmol) prepared as described above, was glucosylated with 2-O-acetyl-3,4,6-tri-O-benzyl-α, β-D-glucopyranosyl trichloroacetimidate (930 mg, 1.4 mmol) to give 1-O-Hexadecyl-2-O-methyl-3-O-(2′-O-acetyl-3′,4′,6′-tri-O-benzyl-β-D-glucopyranosyl)-sn-glycerol in 76% yield (805 mg). [α]D −8.5 deg. 1H-NMR: δ7.32-7.15 (m, 15H, 3PhCH2) 4.99 (dd, 1H, J1′,2a′=2.5 Hz, J1′,2e′−1.0 Hz, H-1′), 3.93 (m, 1H, H-5′), 3.44 (s, 3H, OCH3), 2.15 (ddd, 1H, J2e′,3′=4.7 Hz, J2e′,2a′=11.5 Hz,H-2e′), 1.7 (ddd, 1H, H-2a′, 1.25 (s, 26H, CH2), 0.87 (t, 3H, CH3). 13C-NMR: δ98.05 (C-1′), 79.33, (C-5′), 62.07 (C-6′), 57.94 (OCH3), 37.36 (C-2′), 31.90, 29.64, 29.48, 29.31, 26.06, 22.67 (CH2), 14.06 (CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([NH:13][C:14](=O)[CH3:15])=[C:5]([N+:17]([O-])=O)[CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]2[N:13]=[C:14]([CH3:15])[NH:17][C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)c2nc(C)[nH]c2c1
Reaction time: 5 h

Procedure:
A mixture of 0.55 g (1.98 mmol) N-(4-methoxy-2-nitro-6-trifluoromethyl-phenyl)-acetamide and 100 mg Pd/C in 30 mL acetic acid was hydrogenated for 5 h under a hydrogen atmosphere at 80° C. until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[C:19]1([CH3:32])[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH:27]=[CH:28][C:29](=[O:31])[CH3:30])=[CH:21][CH:20]=1>>[C:29]([C:28]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:26]([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH3:32])=[CH:24][CH:23]=2)[CH:27]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Reactant: CC(=O)C=CNCc1ccc(C)cc1
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccc(C)cc3)C=C1C(C)=O)C2=O

Procedure:
The title compound 57 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 58 (110 mg, 0.57 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 57 as a yellow oil. (Yield 63.0 mg, 37%).
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([NH:38][C:39]([NH:41][C:42]2[CH:46]=[C:45]([CH3:47])[O:44][N:43]=2)=[O:40])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:37]=[C:36]([NH:38][C:39]([NH:41][C:42]2[CH:46]=[C:45]([CH3:47])[O:44][N:43]=2)=[O:40])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][CH2:30][CH2:31][O:32][CH3:33])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(CCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)nc1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Compound 182 (0.17 g, 0.26 mmol) was suspended in dichloromethane (50 mL) and TFA (1 mL) was added. This solution was stirred for 1 h then the mixture was concentrated. The residue was partitioned between ethyl acetate and water, washed with 3M NaOH and brine, then dried over anhydrous MgSO4, filtered and concentrated. The residue was triturated with diethyl ether and dried in vacuo to afford title compound 183 (0.125 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.74 (s, 1H); 9.33 (s, 1H); 8.52 (d, J=5.5, 1H): 8.51-8.50 (m, 1H); 8.29 (s, 1H); 8.18 (d, J=8.0, 1H): 7.81 (dd, J=8.2, 2.2, 1H); 7.74 (J=12.9, 2.5, 1H); 7.46 (t. J=9.0, 1H); 7.30-7.27 (m, 1H); 6.66 (d, J=5.5, 1H); 6.55 (s, 1H); 3.37 (t, J=5.7, 2H); 3.22 (s, 1H); 2.82-2.75 (m, 4H); 2.68 (t, J=5.5, 2H); 2.37 (s, 3H). LRMS (M+H): 563.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]=2OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]=2[C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(OC)c2c(OS(=O)(=O)C(F)(F)F)c3ccccc3nc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c(C#C[Si](C)(C)C)c3ccccc3nc12
Yield: 96.2 %

Procedure:
To a solution of 1,4-dimethoxy-9-trifluoromethylsulfonyloxyacridine (prepared as described in Preparation 1 above) (1.2 g, 3.1 mmol) in dry tetrahydrofuran (10 ml) under N2 were successively added tetrakis(triphenylphosphine) palladium (0), (0.3 g, 0.3 mmol), N,N-diisopropylethylamine (1.6 ml, 9.3 mmol) and trimethylsilylacetylene (1.3 ml, 9.3 mmol). The mixture was stirred at reflux for 5 h. After this time the solvent was evaporated and the residue was dissolved in CH2Cl2 and washed with water. The organic solution was dried an evaporated affording a residue which was purified by column chromatography. Elution with hexane/CH2Cl2 (1:1) gave the title compound (1.0 g, 98%) as a red solid; m.p. 110-111° C. (CH2Cl2). IR (film): ν/cm−1=2810 (w, C≡C), 1608 (s, Ar), 1527 (m, Ar), 1468 (s, Ar); 1H NMR (200 MHz, CDCl3): δH/ppm=0.41 (s, 9H, 3×CH3), 3.99 (s, 3H, OCH3), 4.11 (s, 3H, OCH3), 6.75 (d, J=8.4 Hz, 1H, H-2), 6.93 (d, J=8.4 Hz, 1H, H-3), 7.63 (dd, J=8.0 and 7.2 Hz, 1H, H-7), 7.78 (dd, J=8.4 and 7.2 Hz, 1H, H-6), 8.35 (d, J=8.4 Hz, 1H, H-5), 8.64 (d, J=8.0 Hz, 1H, H-8); 13C NMR (50.3 MHz, CDCl3): δC=0.0 (q, CH3), 55.8 (q, OCH3), 56.1 (q, OCH3), 101.5 (s, ≡C—Si), 103.9 (d, C-2), 105.7 (d, C-3), 111.8 (s, ≡C), 120.5 (s, C-9a), 126.4 (d, C-7), 126.9 (d, C-6), 127.5 (s, C-9), 129.9 (d, C-5), 130.0 (s, C-8a), 130.3 (d, C-8), 142.1 (s, C-4a), 147.0 (s, C-1), 149.4 (s, C-4 and C-10a); MS (EI); m/z (%)=336 [M+1] (10), 335 [M+] (36), 320 (100), 306 (13), 290 (10), 262 (14); HRMS: calcd. for C20H21NO2Si 335.1341; found 335.1336; Elemental analysis: C20H21NO2Si.0.125CH2Cl2 (346.10): calcd. C 69.84, H, 6.19, N, 4.05; found C 69.70, H 6.42, N 4.09.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C>C(O)CCC>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:6][CH2:7][CH2:8][CH3:9])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Solvent: CCCCO
Product: C=CCOC(=O)NC1CC(=O)OC1OCCCC
Yield: 29 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using n-butanol to afford 878 mg (29% yield) of the title compound (313 mg of anti diastereomer, 260 mg of syn diastereomer and 305 mg of the mixture). 1H-NMR (500 MHz, CDCl3) for anti diastereomer: δ (higher Rf) 0.89-0.96 (t, 3H), 1.32-1.40 (m, 2H), 1.54-1.63 (m, 2H), 2.37-2.41 (d, H), 2.98-3.04 (q, H), 3.55-3.60 (m, H), 3.77-3.82 (m, H), 4.19-4.22 (m, H), 4.58 (br, 2H), 5.03 (br, H), 5.23-5.40 (m, 3H), 5.87-5.93 (M, H), for syn diastereomer (lower Rf) 0.91-0.95 (t, 3H), 1.34-1.39 (m, 2H), 1.56-1.63 (m, 2H), 2.42-2.50 (m, H), 2.83-2.87 (m, H), 4.07-4.11 (t, H), 4.45-4.50 (m, 0.5H), 4.51-4.70 (m, 2.5H), 5.23-5.35 (m, 2H), 5.42-5.43 (d, H), 5.80-5.95 (m, H); LC-MS: m/z=258 (M+H+) for both of diastereomers.
Reaction SMILES: [C:1]1([C:7](=[O:12])[C:8]([O:10]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[C:1]1([C:7](=[O:12])[C:8]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: COC(=O)C(=O)c1ccccc1
Solvent: CO
Product: O=C(C(=O)N1CCCCC1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Methyl phenylglyoxylate (12.50 Kg, 76.1 mol, 1 eq) was added dropwise to a stirred mixture of piperidine (19.45 Kg, 228 mol, 3 eq) and methanol (5.0 L) for 3.5 hours to maintain the temperature at 45-55° C. The mixture was stirred at the same temperature for 0.5 hour and kept overnight at +4° C. The precipitated solid was filtered off, washed on the filter with cold methanol (5 L) and dried under reduced pressure to a constant weight to give 15.90 Kg (96%) of 1-(phenylglyoxylyl)piperidine with 99.9% purity by GC.
Reaction SMILES: C(O[CH2:5][C:6]1[NH:11][C:10]2[N:12]([CH3:16])[NH:13][C:14](=[O:15])[C:9]=2[CH:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Br:24])[CH:18]=2)[C:7]=1[C:25]([O:27]CC)=[O:26])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:24][C:19]1[CH:18]=[C:17]([CH:8]2[C:9]3[C:14](=[O:15])[NH:13][N:12]([CH3:16])[C:10]=3[NH:11][C:6]3[CH2:5][O:26][C:25](=[O:27])[C:7]2=3)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CCOC(=O)C1=C(COC(C)=O)Nc2c(c(=O)[nH]n2C)C1c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)OC1)C2c1ccc(F)c(Br)c1
Yield: 54.7 %

Procedure:
The product from Example 32A (0.09 g) and potassium carbonate(0.03 g) in methanol (10 mL) were stirred at ambient temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was chromatographed on silica gel eluting with 10% EtOH/CH2Cl2 to provide 0.04 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.49 (s, 3H),4.76 (s, 1H),4.9 (q, 2H), 7.23 (m, 2H), 7.42 (dd, 1H), 9.51 (bs, 1H), 9.78 (s, 1H)
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)#[N:3]
Reactant: BrCCCCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: [K]
Product: N#Cc1ccc(OCCCCCCCBr)cc1

Procedure:
The intermediate 7-(4-cyanophenoxy)heptyl bromide was prepared from the potassium salt of 4-cyanophenol and 1,7-dibromoheptane.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=[O:5].[CH3:19][CH:20]([CH2:25][CH3:26])[CH2:21][C:22](Cl)=[O:23]>N1C=CC=CC=1>[CH3:19][CH:20]([CH2:25][CH3:26])[CH2:21][C:22]([O:1][C:2]1[CH:17]=[C:16]([O:18][C:22](=[O:23])[CH2:21][CH:20]([CH3:19])[CH2:25][CH3:26])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:22](=[O:23])[CH2:21][CH:20]([CH3:19])[CH2:25][CH3:26])=[CH:8][C:7]=1[O:13][C:22](=[O:23])[CH2:21][CH:20]([CH3:19])[CH2:25][CH3:26])=[O:5])=[O:23]
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: CCC(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CCC(C)CC(=O)Oc1ccc(C(=O)c2ccc(OC(=O)CC(C)CC)cc2OC(=O)CC(C)CC)c(OC(=O)CC(C)CC)c1

Procedure:
A solution of 1.2 g (0.005 mole) of 2,4,2',4'-tetrahydroxybenzophenone and 3 g (0.025 mole) of 3-methyl valeroylchloride was warmed to 50° C. for 4 hrs. in 50 mls of dry pyridine. Solvent removal via rotary evaporator left an oil. This was partitioned between H2O and CH2Cl2. The organic layer was washed with K2CO3 solution (5%) and dried over MgSO4. After filtration and solvent removal the product remained an oil; 2.5 g (78%) yield.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[S:24][C:23]([NH2:25])=[N:22][N:21]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:24][C:23]([NH2:25])=[N:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Nc1nnc(Br)s1
Product: Nc1nnc(NCCCOc2cccc(CN3CCCCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-(1-piperidinylmethyl)phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine. The product obtained is identical to the substance described in Example 50.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:31]#[N:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: CC(N)c1ccc(C2(C#N)CCCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C2(C#N)CCCCC2)cc1

Procedure:
2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing (7-cyano-1H-benzimidazol-1-yl)acetic acid (216 mg, 1.08 mmol) prepared according to scheme 3, 1-[4-(1-aminoethyl)phenyl]cyclohexanecarbonitrile (246 mg, 1.08 mmol) prepared according to scheme 11, Et3N (328 mg, 3.24 mmol, 0.452 mL) and HATU (411 mg, 1.08 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (443 mg, 1.08 mmol, quantitative). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.22-1.36 (m, 1H) 1.39 (d, J=6.84 Hz, 3H) 1.53-1.68 (m, 2H) 1.68-1.77 (m, 1H) 1.77-1.89 (m, 4H) 1.98-2.08 (m, 2H) 4.88-5.02 (m, 1H) 5.24 (dd, J=24.61, 17.77 Hz, 2H) 7.35 (t, J=7.91 Hz, 1H) 7.40 (d, J=8.40 Hz, 2 H) 7.46 (d, J=8.40 Hz, 2H) 7.72 (d, J=7.62 Hz, 1H) 8.01 (dd, J=8.20, 0.78 Hz, 1H) 8.35 (s, 1 H) 8.85 (d, J=7.81 Hz, 1H); MS [M+H], calcd: 412.0. found: 412.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH3:2].[CH2:22](O[Si](C)(C)C)[CH2:23][CH2:24][CH3:25].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C([SiH](CC)CC)C.Cl>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:20][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:16])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCCCO[Si](C)(C)C
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCOC(C(=O)OCC)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
6 g of oxo-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetic acid ethyl ester and 2.6 g of butoxytrimethylsilane were dissolved in 200 ml of methylene chloride. The solution was cooled to 0° C., treated with 400 mg of trimethylsilyl triflate and stirred at 0° C. for 1.5 hours. After the dropwise addition of 2 g of triethylsilane, the reaction mixture was stirred at room temperature for 26 hours, then diluted with 500 ml of water, acidified with 2N hydrochloric acid and extracted with ether. The organic phase was washed with water, dried (Na2SO4) and the solvent evaporated. The oily residue was purified with flash chromatography (silica gel, eluent hexane/tert.butyl methyl ether 3%) and preparative HPLC (YMC CN 60 Å5-15 μm, hexane) to give 3.5 g of the title product as colorless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[CH3:46][S:47]([N:2]1[CH2:3][CH:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:12]=2)=[O:10])[CH3:7])[CH2:5]1)(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a suspension of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-azetidin-3-yl-ethyl)-amide hydrochloride (65 mg, 0.11 mmol) in CH2Cl2 (2 mL) at 0° C. was added triethylamine (47 μL, 0.33 mmol) followed by methanesulfonyl chloride (10 μL, 0.12 mmol). The reaction mixture was stirred at 0° C. for 30 min then at room temperature for 1 h. The reaction was quenched with water and extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH) to afford 35 mg (50%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methanesulfonyl-azetidin-3-yl)-ethyl]-amide as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[NH2:11][OH:12].C(O)C.Cl>O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[C:5]([NH2:6])[O:12][N:11]=1
Reactant: NO
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)no1
Yield: 13.8 %

Procedure:
Trifluoroacetoacetonitrile (1.37 g, 0.010 mole), hydroxylamine hydrochloride (0.69 g, 0.010 mole), ethanol and water were heated under reflux for 3 hours. After the addition of hydrochloric acid (1.21 g, 0.012 mole), the mixture was further heated under reflux to give the title compound (0.21 g, 13.7%).
Reaction SMILES: C([S@@]([NH:7][C@H:8]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)[CH2:9][CH2:10][CH2:11][C:12](OCC)=[O:13])=O)(C)(C)C.C(N(CC)CC)C>CO>[F:24][C:19]1[CH:18]=[C:17]([C@H:8]2[NH:7][C:12](=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH:22]=[C:21]([F:23])[CH:20]=1
Reactant: CCOC(=O)CCC[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(F)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1CCC[C@@H](c2cc(F)cc(F)c2)N1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl (5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)pentanoate from Step A (4.42 g, 12.2 mmol) in MeOH (200 mL) was cooled to 0° C. Hydrogen chloride gas (anhydrous) was bubbled through this cold solution for about 1 minute, after which time the reaction vessel was sealed and allowed to sit in the ice bath for 15 minutes. Dry nitrogen was then bubbled through the solution for 30 minutes, prior to removal of solvent in vacuo. More MeOH (˜50 mL) was added, and then removed in vacuo. After dissolving in a third volume of MeOH (100 mL), triethylamine (6.78 mL, 48.9 mmol) was introduced and the mixture was heated to 65° C. for 3 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between diethyl ether (100 mL) and 1 M HCl (50 mL). The organics were washed with additional 1 M HCl (50 mL), water (50 mL) and saturated brine (50 mL). The ethereal solution was dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=212 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:7][C:8]([C:17]([F:20])([F:19])[F:18])=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]=12)=[O:5].[CH3:22][Li].Cl>C(OCC)C>[CH3:15][C:13]1([CH3:16])[CH2:12][CH2:11][C:10]2=[C:6]([C:4](=[O:5])[CH3:22])[S:7][C:8]([C:17]([F:20])([F:19])[F:18])=[C:9]2[CH2:14]1
Reactant: [Li]C
Reactant: CON(C)C(=O)c1sc(C(F)(F)F)c2c1CCC(C)(C)C2
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1sc(C(F)(F)F)c2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (14 g, 44 mmol) in diethyl ether (400 mL) is treated at rt with methyl lithium (80 mL, 1.6 M in diethyl ether). Upon complete addition, the mixture is stirred at rt for 15 min before it is poured onto water/ice and neutralized with aq. HCl. The ether phase is separated and the aq. phase is extracted two more times with diethyl ether (2×100 mL). The organic extracts are washed with brine, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane containing 20-30% of DCM to give 1-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (9.1 g) as a yellow oil; LC-MS: tR=1.11 min, [M+1+CH3CN]=318.34; 1H NMR(CDCl3): δ 3.04 (t, J=7.0 Hz, 2H), 2.57 (d, J=1.2 Hz, 2H), 2.53 (s, 3H), 1.58 (t, J=7.0 Hz, 2H), 0.99 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[H-].[Na+].[CH2:18](I)[CH:19]=[CH2:20].O>CN(C=O)C>[Br:1][C:2]1[C:3]([N:9]([CH2:20][CH:19]=[CH2:18])[C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: C=CCI
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)C(C)(C)C)c1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-(3-bromo-6-chloro-2-pyridinyl)-2,2-dimethylpropanamide (2.305 g, 7.907 mmol) in DMF (40 ml) at 0° C. under argon was treated with sodium hydride (0.696 g, 17.395 mmol) and then allowed warm to rt over 0.25 h, stirred at rt for 0.25 h and then treated with allyl iodide (1.61 ml, 17.395 mmol) and stirred at rt for 1 h. The reaction was then treated with water (10 ml), concentrated to approximately 5 ml, treated with more water (200 ml) and extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), filtered, evaporated and the residue chromatographed (0-20% ethyl acetate:Hexane) to give the product as a yellow oil which solidified to an off white solid (5.324 g, 67%).