Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[C:11](=[CH:20]N(C)C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH:25]([C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1)[C:26]([NH2:28])=[NH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[N:27]=[C:26]([NH:25][C@@H:29]4[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)[N:28]=[CH:20][C:11]=3[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C=C1C[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=N)N)C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc3c(n2)-c2ccccc2[C@@H](c2ccc(Cl)c(Cl)c2)C3)C1
Yield: 57 %

Procedure:
This product was prepared by using (R)-4-(3,4-dichlorophenyl)-2-((dimethylamino)methylene)-3,4-dihydronaphthalen-1(2H)-one and (R)-tert-butyl 3-guanidinopiperidine-1-carboxylate hydrochloride salt under the condition described in the general procedure 1 to afford the desired product in 57% yield as a light yellow solid. M.p.=85-87° C. 1H NMR 400 MHz (DMSO-d6) δ 8.29 (bs, 1 H), 8.12 (s, 1 H), 7.50-7.35 (m, 4 H), 7.08 (s, 1 H), 7.02-6.98 (m, 2 H), 4.39 (t, J=5.2 Hz, 1 H), 3.74 (bs, 2 H), 3.12-3.04 (m, 2 H), 2.90-2.84 (m, 2 H), 1.89-1.51 (m, 3 H), 1.38-1.24 (m, 11 H). LCMS m/e 525 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[C:15](O)[C:5]2[CH2:6][CH2:7][O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:15]1[C:5]2[CH2:6][CH2:7][O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[N:3]=[C:2]([NH2:1])[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)c2c(n1)-c1ccccc1OCC2
Product: Nc1nc(Cl)c2c(n1)-c1ccccc1OCC2

Procedure:
A mixture of Example 29C (0.63 g, 2.7 mmol) and phosphorus oxychloride (10 mL) was heated at reflux for 1 hour, cooled, concentrated under reduced pressure followed by the addition of water (20 mL). The mixture was filtered and the resulting solid was taken up in 1 M HCl (20 mL) and heated at reflux for 5 minutes. The cooled mixture was basified with 1M NaOH and extracted with CH2Cl2 (3×), filtering each extraction through diatomaceous earth. The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of CH2Cl2:EtOAc (20:1 and 10:1) to provide the title compound. 1H NMR (CDCl3) δ 2.94 (t, J=6.10 Hz, 2H), 4.52 (t, J=6.27 Hz, 2H), 5.15 (s, 2H), 7.13 (dd, J=7.97, 1.19 Hz, 1H), 7.21-7.30 (m, 1H), 7.41-7.49 (m, 1H), 7.82 (dd, J=7.80, 1.70 Hz, 1H); MS (M+H)+ m/z 248.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][C:46]([NH:21][C:18]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:47])=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CN(C)c1ccc(-c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc2N)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CN(C)c1ccc(-c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc2NC(=O)Cc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-[4-(dimethylamino)phenyl]pyrazin-2-amine (7n) (315 mg, 749 μmol) and 4-(dimethylamino)pyridine (14.8 mg, 121 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was hetated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=2/1) to give Compound 11n (200 mg, 300 μmol, 40.0%) as a yellow solid. Rf=0.26 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.23 (s, 6H), 0.95 (s, 9H), 0.97 (s, 9H), 2.95 (s, 6H), 3.50 (s, 2H), 6.52-6.65 (AA′BB′, 2H), 6.75-6.85 (AA′BB′, 2H), 6.95-7.05 (AA′BB′, 2H), 7.10-7.20 (AA′BB′, 2H), 7.56-7.66 (AA′BB′, 2H), 8.04-8.10 (AA′BB′, 2H), 8.82 (s, 1H), 10.41 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.9, 18.0, 25.5 (6C), 39.8 (2C), 41.8, 111.3 (2C), 119.5 (2C), 120.3 (2C), 124.4, 128.05, 128.07 (2C), 128.9 (2C), 129.2, 130.4 (2C), 135.8, 142.0, 147.78, 147.84, 150.5, 153.8, 156.6, 169.3; IR (KBr, cm−1) 527, 685, 781, 839, 914, 1080, 1167, 1256, 1371, 1441, 1508, 1607, 1668, 2857, 2928, 2955, 3233.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH2:12]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][OH:28])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(Cl)Cl>[CH2:12]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC/C=C\CCCOc1cccc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCC/C=C\CCCOc1cccc(C=O)c1
Yield: 99.1 %

Procedure:
10 mL of anhydrous DCM and then 190 mg of PCC (881 μmol) are added under argon to 120 mg of alcohol 16 (434 μmol) dried by coevaporation with toluene. The reaction is heated to the reflux point of the DCM for 1 hour. After cooling, the reaction medium is diluted with ether and filtered through Florisil. After concentrating, 118 mg of a yellow oil are obtained, i.e. a yield of 99%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[NH2:20][C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23].N[C@@H](CC)C(O)=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:20][C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: CC[C@H](N)C(=O)O
Agent: Cl
Product: CC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and methyl (S)-2-aminobutanoate hydrochloride prepared from (S)-(+)-2-aminobutyric acid (Aldrich) using General Procedure H), the title compound was prepared as a solid (mp=154-157° C.).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][CH2:7]1.[CH2:15](O)[CH3:16]>>[CH2:15]([O:13][C:12]([C@@H:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:5])[NH:11]1)=[O:14])[CH3:16]
Reactant: O=C1CCC[C@@H](C(=O)O)N1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Absolute ethanol (300 mL) was cooled at −5° C. then thionyl chloride (14.01 mL, 192.1 mmol) was added keeping the temperature below 0° C., followed by portionwise addiction of (S)-6-oxopiperidine-2-carboxylic acid (25.0 g, 174.6 mmol). The mixture was stirred at room temperature for 6 hours. The solvent was evaporated, then toluene (300 mL) and Et3N (48.7 mL) were added. After 0.5 hour the precipitate was filtered and washed with toluene and Et2O. The filtrate was evaporated and the residue treated with Et2O. The precipitate was eliminated and the solution was concentrated to give the title compound as yellow oil. Yield (29.9 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[C:3]([C:4]3[NH:24][C:23]4[CH:22]=[CH:21][CH:20]=[C:19]([CH3:25])[C:18]=4[N:17]=3)[C:2]([NH2:1])=[N:9][CH:8]=2)=[CH:11][CH:12]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)cc1C=O
Reactant: Cc1cccc(N)c1N
Product: Cc1cccc2[nH]c(-c3cc(-c4ccc(F)cc4)cnc3N)nc12

Procedure:
Using the procedure of step (b) in Example 15, utilizing 2-amino-5-(4-fluorophenyl)nicotinaldehyde and 2,3-diaminotoluene gave 5-(4-fluorophenyl)-3-(4-methyl-1H-benzimidazol-2-yl)pyridin-2-amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=NN(C)C)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CN(C)N=C(C(=O)C(F)(F)F)c1ccc(Br)cc1
Product: O=C(C(=O)C(F)(F)F)c1ccc(Br)cc1
Temperature: 45 °C
Yield: 92 %

Procedure:
3-(4-bromophenyl)-3-(2,2-dimethylhydrazono)-1,1,1-trifluoropropan-2-one (2.0 g, 6.2 mmol) was suspended in 5N sulfuric acid (60 mL) and heated at 45° C. for 6 h. The temperature was raised to 85° C. for 2 h, and upon cooling a precipitate formed. This material which was isolated by filtration to give 1-(4-bromophenyl)-3,3,3-trifluoropropane-1,2-dione 1.6 g (92%) as a yellow solid. The dione (1.6 g, 5.7 mmol) was taken up in methanol (30 mL), N-(tert-butoxycarbonyl)-L-prolinal (1 g, 5.0 mmol) was added, followed by addition of 28% ammonium hydroxide solution (10 mL). The reaction was stirred at room temperature for 18 h, poured onto dichloromethane (200 mL), washed with water and dried with MgSO4. Filtration, concentration and application to a 40 M Biotage cartridge, gradient elution with 5%-30% ethyl acetate/Hexanes, gave J32.a 1.3 g (50%). 1H NMR (300 MHz, DMSO-d6) δ 12.88 (br.s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.84-4.70 (m, 1H), 3.57-3.49 (m, 1H), 3.39-3.29 (m, 1H), 2.31-2.20 (m, 1H), 1.98-1.78 (m, 3H), 1.39/1.13 (m, 9H). LRMS: Anal. Calcd. for C19H20BrF3N3O2 458.07. found: 458.06 and 460.06 (M−H)−. HRMS: Anal. Calcd. for C19H22BrF3N3O2 460.0847. found: 460.0866 and 462.0840 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[C:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:37][CH:36]=1.[Br-]>CN(C)C=O>[CH3:53][C:50]([O:49][C:47]([C:42]1[C:41]([C:38]2[CH:37]=[CH:36][C:35]([CH2:34][N:19]3[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C@@H:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([CH3:30])([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH3:29])[C:18]3=[O:28])=[CH:40][CH:39]=2)=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:48])([CH3:51])[CH3:52]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)C1=O)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 85.8 %

Procedure:
To a solution of 1.22 g (3.0 mmol) of 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step F) in 10 mL of dry dimethylformamide under nitrogen was added 131.6 mg (3.92 mmol) of 60% sodium hydride in oil. After stirring for 20 minutes, a solution of 1.14 g (3.29 mmol) of t-butyl 4'-bromomethyl-1,1'-biphenyl-2-carboxylate (prepared according to the procedure of D. J. Carini, et. al. EPO publication 324.377) in 2.5 mL of dimethylformamide was added by cannula. The flask which originally contained the bromide was rinsed with 2.5 mL dimethylformamide which was added to the reaction mixture. After stirring at room temperature for 2 hours, the reaction has diluted with 400 mL of ethyl acetate, washed with 100 mL of water and 100 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (55:45) to afford 1.74 g (96%) of the product as a white foam. 1H NMR (200MHz,CDCl3): 1.15 (s,9H), 1.45 (s,3H), 1.48 (s,3H), 1.76 (m,1H), 2.35-2.62 (m,5H), 4.48 (m,1H), 4.79 (d,14Hz,1H), 5.04 (t,12Hz,2H), 5.35 (d, 14Hz,1H), 6.70 (d,6Hz,1H), 7.10-7.45 (m,17H), 7.72 (m,1H). FAB-MS: calculated for C41H45N3O6 675; found 683 (M+Li).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[CH2:13])=[CH:2]1.B1C2CCCC1CCC2.[Cl:31][C:32]1[C:37](/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[CH:36][C:35](I)=[CH:34][N:33]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CN(C=O)C.Cl[Pd]Cl>[Cl:31][C:32]1[N:33]=[CH:34][C:35]([CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:36][C:37]=1/[CH:38]=[CH:39]/[C:40]1[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=1
Reactant: C=C[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reactant: Clc1ncc(I)cc1/C=C/c1ccncc1
Agent: Cl[Pd]Cl
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCc1cnc(Cl)c(/C=C/c2ccncc2)c1)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
A solution of Example 21C (100 mg, 0.35 mmol) in THF (3 mL) at 0° C. was treated with 9-BBN (0.5 M solution in THF, 0.70 mL, 0.35 mmol), stirred overnight while gradually warming to room temperature, cannulated into a mixture of Example 21B (108 mg, 0.32 mmol), PdCl2 (dppf) (26 mg, 0.032 mmol) and Cs2CO3 (228 mg, 0.7 mmol) in DMF, purged with nitrogen, and stirred at 50° C. for 8 hours. The mixture was treated with ethyl acetate (50 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The residual oil was purified by flash column chromatography on silica gel with 80% ethyl acetate/hexanes to provide the desired product (69 mg, 40%).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].CC(C)([O-])C.[K+].[C:35]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=O)[CH:36]([CH3:38])[CH3:37].[Cl-].[Na+].[BH4-].[Na+]>O1CCCC1.C(O)C.O>[C:40]1([C:35]([CH:36]([CH3:38])[CH3:37])=[CH:9][CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)C(=O)c1ccccc1
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [BH4-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCC=C(c1ccccc1)C(C)C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
3-Ethoxycarbonylpropyltriphenylphosphonium bromide (73.3.g, 160 mmol) was added to a solution of potassium tert-butoxide (18.5 g, 160 mmol) in tetrahydrofuran (1000 ml) and stirred for 3 hours, and then isobutyrophenone (20.0 g, 135 mmol) was added thereto and stirred for 3 days. After water (200 ml) was added thereto and stirred for 30 minutes, the reaction mixture was added to an aqueous sodium chloride solution and extracted twice with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was treated by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20) to obtain crude ethyl 5-phenyl-5-(2-propyl)-4-pentenoate (24.6 g; containing starting isobutyrophenone). This crude product was treated with sodium tetrahydroborate (2.83 g) in ethanol and then purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/40) to obtain 10.0 g of ethyl 5-phenyl-5-(2-propyl)-4-pentenoate.
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[S:31])[C@@H:10]2[CH2:14][C@H:13]([C:15](=[O:17])[CH3:16])[CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]([N:11]2[CH2:12][C@@H:13]([C:15](=[O:17])[CH3:16])[CH2:14][C@H:10]2[C:9]([OH:8])=[S:31])=[O:19])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: COc1ccc(COC(=S)[C@@H]2C[C@H](C(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)[C@H]1C[C@@H](C(O)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
9.76 g of cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline p-methoxybenzyl ester and 4.32 g of anisole were stirred together with 35 ml of trifluoroacetic acid at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
Combine methyl-4-bromobenzoate (1.0 g, 4.65 mmol), 2-chlorophenylboronic acid (799 mg, 5.1 mmol), Pd(OAc)2 (51 mg, 0.46 mmol) and sodium carbonate (1.5 g, 13.9 mmol) in DMF (20 mL) and water (2.0 mL) with stirring. Purge the reaction mixture with argon, add triphenylphosphine (61 mg, 0.23 mmol) and purge again with argon. Place the sealed reaction in an oil bath maintained at 80° C. and allow to stir for 1 hour. Cool the reaction to room temperature, dilute with ethyl acetate and filter through a short plug of celite with additional ethyl acetate. Wash the organics with water, dry over MgSO4, filter and evaporate. Purification by flash column chromatography yields 2′-chlorobiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in THF (0.25M) and add an equal volume of 1M NaOH. Stir vigorously at room temperature for 15 hours. Upon completion, acidify the reaction with conc. HCl and extract with ethyl acetate. Evaporation of the solvent yields 762 mg (67%) of the title compound. MS (ES): m/z 231.1 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]#[N:32])[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23]S(C)(=O)=O.[H-].[Na+].O.O[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[N:9][C:8]=2[CH2:22][O:23][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[C:31]#[N:32]
Reactant: OCCN1CCOCC1
Reactant: CS(=O)(=O)OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COCCN2CCOCC2)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
120 mg Methanesulfonic acid 5-(3-chloro-4-cyano-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester was dissolved in 5 ml N-(2-hydroxyethyl)morpholine. 10 mg sodium hydride were added and the reaction mixture stirred at 50° C. for one hour. 10 ml water was added and the reaction mixture extracted 50 ml ethyl acetate. The organic layer was separated and washed twice with 20 ml brine. The organic layer was dried over MgSO4 and the solvent was then removed in vacuo. The residue was purified by RP-HPLC to obtain 40 mg 2-chloro-4-[4-(2-morpholin-4-yl-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as its trifluoro-acetate salt.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:28]#[C:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2cccnc21
Temperature: 95 °C
Yield: 53.2 %

Procedure:
A mixture of 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.20 g, 0.53 mmol), phenylacetylene (0.06 mL, 0.55 mmol), bis(triphenylphosphine)palladium(II) chloride (25 mg, 0.04 mmol), and triethylamine (0.16 mL, 1.14 mmol) in 3 mL of N,N-dimethylformamide was heated at 95° C. under argon for 19 hours. Workup as described in Example 1h and purification by flash chromatography, eluting with ethyl acetate/dichloromethane, afforded 0.1 g of the title compound.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH2:50][OH:51])[CH2:48][OH:49])C1C=CC=CC=1.Cl>CO.[Pd]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@@H:12]2[O:11][C:10]([CH2:50][OH:51])([CH2:48][OH:49])[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@H:13]2[OH:23])=[CH:32][C:33]=1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3OC(CO)(CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.6 %

Procedure:
To a solution of {(3S,4R,5S,6S)-3,4,5-Tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-hydroxymethyl-tetrahydro-pyran-2-yl}-methanol (125 mg, 0.16 mmole) in methanol (3 mL), 10% Pd/C (65 mg) and 2 drops of con. HCl were added and stirred under hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered through cetlie bed, washed with methanol (20 mL). The crude product was purified by preparative HPLC to furnish 25 mg of (3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-2,2-bis-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.