Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[NH:21][C:22](=[O:23])[NH:20][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(-c2ccncc2)c(-c2cccc(F)c2)nc1N
Solvent: C1CCOC1
Product: O=c1[nH]c2nc(-c3ccncc3)c(-c3cccc(F)c3)nc2[nH]1
Yield: 44 %

Procedure:
A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 72, 200 mg, 0.71 mmol), 1,1′-carbonylbis-1H-imidazole (138 mg, 0.85 mmol) in THF (3 mL) was stirred and heated at reflux overnight. Solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The separated organic phase was dried (MgSO4) and evaporated to dryness. The residue was recrystallized from ethanol to give the title compound as a white solid (96 mg, 44%).
Reaction SMILES: C([CH:3]([OH:14])[CH2:4][CH2:5][C:6]1[C:7]([Cl:13])=[N:8][C:9](Cl)=[CH:10][CH:11]=1)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:34]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[C:32](B4OC(C)(C)C(C)(C)O4)=[CH:31][C:25]=3[C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[CH:18][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1(C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[Cl:13][C:7]1[N:8]=[C:9]([C:32]2[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][C:24]3[O:23][C:22]([C:19]4[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=4)=[C:26]([C:27]([NH:29][CH3:30])=[O:28])[C:25]=3[CH:31]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][CH2:3][OH:14]
Reactant: CCC(O)CCc1ccc(Cl)nc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCCO)c(Cl)n3)cc12
Temperature: 70 °C

Procedure:
To a mixture of ethyl 3-(2,6-dichloropyridin-3-yl)propan-1-ol (180 mg, 0.873 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (439 mg, 0.873 mmol), XantPhos Biphenyl precatalyst (78 mg, 0.087 mmol), and cesium carbonate (854 mg, 2.62 mmol) was added 1,4-Dioxane (7.3 mL) and water (1.5 mL). A steady stream of N2 was bubbled through the reaction mixture for 5 minutes then the mixture was heated to 70° C. for 4 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc/CH2Cl2 as eluent. Further purification by preparative TLC using 50% EtOAc/CH2Cl2 as eluent provided the title compound. 1H NMR δ (ppm) (CHCl3-d): 8.01˜7.96 (3H, m), 7.72 (1H, d, J=7.68 Hz), 7.68 (1H, s), 7.56 (1H, d, J=7.70 Hz), 7.23 (2H, t, J=8.6 Hz), 5.95 (1H, br s), 3.78 (2H, q, J=5.76 Hz), 3.24 (3H, s), 3.03 (3H, d, J=4.88 Hz), 2.93 (2H, t, J=7.76 Hz), 2.88 (3H, s), 2.03˜1.97 (2H, m). MS (M+H)+: 545.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:32])[CH3:31]>>[C:30]([N:22]1[C@H:18]([CH2:17][O:16][C:14]2[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=[C:10]3[C:15]=2[C:6]([NH:5][C:4]2[CH:26]=[CH:27][C:28]([F:29])=[C:2]([Cl:1])[CH:3]=2)=[N:7][CH:8]=[N:9]3)[CH2:19][C@@H:20]([OH:23])[CH2:21]1)(=[O:32])[CH3:31]
Reactant: COc1cc(OC[C@@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CC(=O)O
Product: COc1cc(OC[C@@H]2C[C@@H](O)CN2C(C)=O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 92 %

Procedure:
The procedure described in Example 25 was repeated using (3R,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with acetic acid (32 μl) to give the title compound as a white solid in 92% yield; NMR spectrum (DMSO-d6) 9.98 (s, 1H), 8.47 (s, 1H), 8.16-8.14 (m, 1H), 7.73-7.70 (m, 1H) 6.84 (s, 1H), 5.10 (m, 1H), 4.67-4.63 (m, 1H), 4.47-4.38 (m, 2H), 4.26-4.21 (m, 1H), 3.94 (s, 3H), 3.59 (dd, 1H), 3.41 (dd, 1H), 2.11-2.05 (m, 2H), 2.00 (s, 3H); Mass spectrum MH+ 461.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([N:6]1[CH2:17][CH2:16][CH2:15][C@H:7]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])[CH3:3].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[NH2:1][C@H:2]([C:4]([N:6]1[CH2:17][CH2:16][CH2:15][C@H:7]1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:5])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
9.36 g of Z-Ala-Pro-OtBu are hydrogenated in 100 ml of methanol in the presence of 500 mg of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 90 minutes. The solution is freed of catalyst by filtration and evaporated in a waterpump vacuum at 30° C. to give an oil. This proves to be homogeneous in a thin layer chromatogram on silica gel. Rf = 0.35 in the system chloroform-methanol (1:1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:44])=[O:43]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:50]3[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:52][CH2:51]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:37])([F:38])[F:36])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC(F)(F)F)c1
Agent: Cl
Product: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)c(OCC(F)(F)F)c1

Procedure:
[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12l) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 739.4 [(M+H)+]
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)[CH3:2].[C-:13]#[N:14].[K+]>[Cu]C#N>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:13]#[N:14])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: [C-]#N
Reactant: CCOc1ccc(C(=O)Cl)cc1
Agent: N#C[Cu]
Agent: [K+]
Product: CCOc1ccc(C(=O)C#N)cc1
Yield: 94.5 %

Procedure:
In the manner described above, 184 g (1 mol) of p-ethoxybenzoyl chloride, 62.5 g (0.96 mol) of potassium cyanide and 3.6 g (0.04 mol) of copper(I) cyanide were reacted with one another at 215° C. After working up, 159 g (91% of theory) of p-ethoxybenzoyl cyanide were obtained; melting point 43° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.O(C1C=CC(C(C=CC(O)=O)=O)=CC=1)[C:23]1C=CC=C[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([CH:13]=[CH:14][C:15]([O:17][CH2:23][CH3:24])=[O:16])=[O:12])=[CH:18][CH:19]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
The procedure in Example 13(1) was followed, except that 6.05 g of 3-[4-(4-chlorophenoxy)benzoyl]acrylic acid were used in place of 3-(4-phenoxybenzoyl)acrylic acid, to give 5.51 g of ethyl 3-[4-(4-chlorophenoxy)benzoyl]acrylate.
Reaction SMILES: [NH2:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:3]1.N[C@@H](C(O)=O)CS.[C:21]([O:25][C:26]([NH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([NH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31]([NH:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:3]1)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: N[C@@H]1CSc2ccccc2NC1=O
Agent: N[C@H](CS)C(=O)O
Product: CC(C)(CC(=O)N[C@@H]1CSc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3(S)-amino-3,4-dihydro-1,5-benzothiazepin-4(5H)-one (prepared from D-cysteine (S-cysteine) by the method of Slade, et al, J. Med. Chem., 28, 1517-1521 (1985)) and 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.38 (s,6H), 1.45 (s,9H), 2.32 (d,10 Hz,1H), 2.50 (d,14 Hz,1H), 2.70 (d,14 Hz,1H), 2.92 (t,11 Hz,1H), 3.93 (dd;7,11 Hz;1H), 4.76 (m,1H), 7.02 (d,8 Hz,1H), 7.1-7.3 (m,2H), 7.40 (t,8 Hz,1H), 7.66 (d,7 Hz,1H), 8.23 (br s,1H). FAB-MS: calculated for C19H27N3O4S 393; found 394 (M+H,36%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[C:32]5[CH:33]=[CH:34][N:35]=[CH:36][C:31]=5[N:30]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:28]=4[N:29]=3)=[N:21][CH:22]=2)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>C1COCC1.CO.Cl>[CH:37]1([N:30]2[C:28]3[N:29]=[C:24]([NH:23][C:20]4[N:21]=[CH:22][C:17]([N:14]5[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13]5)=[CH:18][CH:19]=4)[N:25]=[CH:26][C:27]=3[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][C:31]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Compound 296 (85.0 mg, 148 μmol) was dissolved in dry THF (3 mL).). Tetrabutylammonium fluoride, 1.0M in THF (1.00 mL, 1.00 mmol) was added and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo and silica gel chromatography (gradient elution hexanes+2.5%/0-100% ethyl acetate+2.5% TEA, then ethyl acetate+2.5% TEA/0-5% methanol) afforded a yellow solid. This residue was taken up in methanol (3 mL) and 1M ethanolic HCl (1 mL). Diethyl ether (20 mL) was added to precipitate the product, which was filtered and dried in vacuo to give compound 295 as a yellow solid (54 mg, 79%). 1H NMR (500 MHz, DMSO-d6) δ 10.75-10.97 (m, 2 H) 9.70 (s, 2 H) 9.47 (s, 1 H) 8.74 (d, J=3.67 Hz, 2 H) 8.16 (d, J=2.45 Hz, 1 H) 7.99-8.10 (m, 1 H) 7.84-7.99 (m, 1 H) 5.30-5.52 (m, 1 H) 3.81-3.96 (m, 4 H) 3.62-3.72 (m, 2 H) 3.20-3.36 (m, 6 H) 2.39-2.49 (m, 2 H) 2.02-2.20 (m, 4 H) 0.88 (d, J=6.85 Hz, 2 H) ppm.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].Cl[C:37]1[N:41]([CH2:42][C:43]2[O:47][C:46]([CH3:48])=[N:45][CH:44]=2)[C:40]2[CH:49]=[CH:50][CH:51]=[CH:52][C:39]=2[N:38]=1>C(Cl)Cl>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([C:37]3[N:41]([CH2:42][C:43]4[O:47][C:46]([CH3:48])=[N:45][CH:44]=4)[C:40]4[CH:49]=[CH:50][CH:51]=[CH:52][C:39]=4[N:38]=3)[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: Cc1ncc(Cn2c(Cl)nc3ccccc32)o1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Solvent: ClCCl
Product: Cc1ncc(Cn2c(N3CCN([C@H]4CCN(C(=O)c5cc(C(F)(F)F)cc(C(F)(F)F)c5)[C@@H](Cc5ccccc5)C4)CC3)nc3ccccc32)o1
Yield: 40 %

Procedure:
Compound 15 (0.005 mol), 2-chloro-1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazole (0.005 mol) and Cupper (0.005 mol) were stirred at 140° C. for 2 hours. The mixture was cooled, dissolved in CH2Cl2, filtered and washed with CH2Cl2 and a diluted NH4OH solution. The organic layer was separated, washed with a diluted NH4OH solution, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5, 99/1, 98.5/1.5 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 1.42 g (40%) (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 70).
Reaction SMILES: S(Cl)(Cl)=[O:2].[CH2:5]([O:8][C:9]([N:11]1[C@H:15]([CH:16](O)[C:17]2[N:24]3[C:20]([S:21][CH:22]=[CH:23]3)=[CH:19][N:18]=2)[C:14](C)(C)[C@@H:13](C(C)(C)C)[CH:12]1O[SiH3])=[O:10])[CH:6]=[CH2:7].ClCCl>CN(C=O)C.C(O)(=O)C.[Zn]>[CH2:5]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][C:17]2[N:24]3[C:20]([S:21][CH:22]=[CH:23]3)=[CH:19][N:18]=2)[CH2:14][C@@H:13]([OH:2])[CH2:12]1)=[O:10])[CH:6]=[CH2:7]
Reactant: C=CCOC(=O)N1C(O[SiH3])[C@H](C(C)(C)C)C(C)(C)[C@H]1C(O)c1ncc2sccn12
Reactant: O=S(Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ncc2sccn12
Reaction time: 0.33 h

Procedure:
Thionyl chloride (0.39 ml) is added to a solution of 774 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethyl-silyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidine (stereoisomer A) in 0.014 ml of dry DMF and 5.3 ml of dry dichloromethane under ice cooling, and the mixture is stirred in this state for 25 min. The solvent and the excess reagent are removed by evaporation under reduced pressure, and the residue is dried under reduced pressure by means of a vacuum pump to give a bright yellow amorphous material which is then dissolved in 17.7 ml of 90% acetic acid. Zinc (1.156 g) is added to the solution under ice cooling, and the mixture is stirred in this state for 20 min. Further, the ice bath is removed, and stirring is continued for additional 10 min. Distilled water and ethyl acetate are added, and the mixture adjusted to pH 6 under stirring by addition of sodium hydrogencarbonate. The organic layer is separated, and the residual aqueous layer is adjusted to pH 8 by addition of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The combined organic layers are washed twice with an 5% aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate and potassium carbonate and filtered. The solvent is removed by evaporation under reduced pressure. The residue, together with acetonitrile, is once subjected to azeotropic evaporation, the residue is redissolved in 17.7 ml of acetonitrile, 0.70 ml of concentrated hydrochloric acid is added thereto under ice cooling, and the mixture is stirred in this state for 15 min. The mixture is diluted with 200 ml of ethyl acetate, the diluted solution is washed with 50 ml of a 5% aqueous sodium hydrogencarbonate solution, the organic layer is dried over magnesium sulfate, filtered, and the solvent is removed by evaporation under reduced pressure to give a yellowish orange amorphous material. The amorphous material is successively purified by column chromatography on silica gel (first, ethyl acetate:methanol=9:1; second, chloroform:methanol 9:1) and on Sephadex LH-20 (chloroform:methanol=1:1) to give 138 mg of (3R,5R)-1-allyloxycarbonyl-3-hydroxy-5-(imidazo[5,1-b]thiazol-5-yl)methylpyrrolidine as a colorless amorphous material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=1[CH3:22].B(Br)(Br)Br.C1CCCCC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH3:22]
Reactant: COc1ccc(-c2nn(C(C)C)c3c(F)cccc23)c(C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cc(O)ccc1-c1nn(C(C)C)c2c(F)cccc12
Yield: 101.3 %

Procedure:
Prepared according to Method D step C from 7-fluoro-1-isopropyl-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.151 g, 0.500 mmol), boron tribromide (0.118 mL, 1.25 mmol) and 1.0 mL of cyclohexene to give the product (0.144 g) as a white solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1
Reactant: CCCCC[Mg]Br
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
n-Pentyl magnesium bromide (2.0 M in THF, 27 mL, 54 mmol) was added to a solution of 4-bromobenzaldehyde (5.0 g, 27 mmol) in THF (20 mL) at 0° C. under nitrogen. After 1 h, the reaction was quenched with 3 N HCl and extracted with Et2O (3×120 mL). Combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5% EtOAc/Hex) afforded 5.1 g (74%) of 1-(4-bromophenyl)-hexan-1-ol.
Reaction SMILES: [H-].[Na+].Cl.Cl[C:5]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:6]=1[CH2:7][NH:8][CH2:9][CH2:10][SH:11]>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:5]2[S:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(CNCCS)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)CNCCS2
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a slurry of sodium hydride (1.06 g, 0.01 mol) in anhydrous DMF (175 mL) under nitrogen was added 2-(2-chloro-5-nitro-benzylamino)-ethanethiol hydrochloride (3.0 g, 0.01 mol), stirred 3 hrs. and evaporated. The residue was treated with water (15 mL) giving 2-nitro 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene (1.05 g, 47%) as a tan solid. MP: 104-5° C.; 1H-NMR (DMSO-d6) δ 8.13 (s, 1H), 7.97-8.00 (d, 1H), 7.69-7.10 (s, 1H), 4.04 (s, 2H), 3.12-20 (d, 2H), 2.82-8 (d, 2H), 2.54-65 (br, 1H); LC/MS (ESI+): 210 (M).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][N:12]=3)[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-:23].[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([S:9]([CH2:10][C:11]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][N:12]=3)=[O:23])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1ccnc(CSc2nc3ccc(F)cc3[nH]2)c1C
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3ccc(F)cc3[nH]2)c1C
Reaction time: 0.08 h

Procedure:
2.0 g of 5-fluoro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]benzimidazole dissolved in 100 ml of methylene chloride were treated with 1.2 g of potassium carbonate. 1.6 g of m-chloroperbenzoic acid were added thereto at -30°, the solution was stirred for a further 5 minutes and subsequently poured into a mixture of 30 ml of saturated sodium bicarbonate solution and 30 ml of water. The organic phase was separated, dried over sodium sulfate, treated with 5.0 ml of triethylamine and evaporated in a vacuum. Crystallization of the residue from methylene chloride/petroleum ether (low boiling)/ether gave 5-fluoro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]sulfinyl]benzimidazole of melting point 175°.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[OH-].[Na+].C(Cl)Cl.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27](=[O:31])[C:28](Cl)=[O:29])=[CH:19]1>O>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@H:4]([NH:3][C:28](=[O:29])[C:27](=[O:31])[C:20]1[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([CH3:17])[CH:19]=1)[CH2:5]2
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccccc21
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1cc(C(=O)C(=O)N[C@@H]2CN3CCC2CC3)c2ccccc21
Yield: 30.8 %

Procedure:
(S)-3-amino-1-azabicyclo[2.2.2]octane dihydrochloride salt (7.5 g; 37.5 mmol) and sodium hydroxide (2.0 g; 50.0 mmols) were dissolved in 50 ml of water. The solution was cooled in an ice bath and 100 ml of methylene chloride was added. The mixture was stirred while approximately one third of a solution containing 1-methy-α-oxo-3-indoleacetyl chloride (10.8 g; 48.7 mmol) was added in a dropwise fashion, after which additional sodium hydroxide (3.0 g; 75.0 mmol) in 20.0 ml of water was mixed in. The remaining 1-methy-α-oxo-3-indoleacetyl chloride was then added and the reaction mixture was stirred for 10 minutes. The aqueous layer was then separated from the organic phase and rinsed with methylene chloride. The combined organic phase was dried over potassium carbonate. Filtration and evaporation of the solvent resulted in 5.1 g of crude product. The crude product was purified by chromatography (silica gel 60; 7% MeOH in CH2Cl2 containing approximately 0.5 % NH4OH) to yield 3.6 g (11.5 mmmol) of (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-1-methyl-α-oxo-3-indoleacetamide, m.p. 186°-187° C., [α]D25 -41° (CHCl3).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:26]([O:47][Si](C(C)(C)C)(C)C)[CH2:27][NH:28][C@H:29]([CH3:46])[CH2:30][O:31][C:32]2[CH:45]=[CH:44][C:35]([CH2:36][CH:37]3[S:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])=[CH:34][CH:33]=2)[CH:23]=[CH:24][CH:25]=1>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:26]([OH:47])[CH2:27][NH:28][C@H:29]([CH3:46])[CH2:30][O:31][C:32]2[CH:45]=[CH:44][C:35]([CH2:36][CH:37]3[S:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])=[CH:34][CH:33]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: C[C@H](COc1ccc(CC2SC(=O)NC2=O)cc1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](COc1ccc(CC2SC(=O)NC2=O)cc1)NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
88 g of tetrabutylammonium fluoride were added to a solution of 46.2 g of 5-(4-{2(R)-[2(R)-(3-chlorophenyl)-2-t-butyldimethylsilyloxyethylamino]propoxy}benzyl)thiazolidine-2,4-dione [prepared as described in Preparation 3]in 500 ml of tetrahydrofuran, whilst ice-cooling, and the mixture was stirred at room temperature for 15 hours. At the end of this time, the tetrahydrofuran was distilled off under reduced pressure. The residue was then mixed with water and extracted with ethyl acetate. The extract was washed-with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was distilled off under reduced pressure. The residue was then purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent, to obtain the title compound in the form of crude crystals. These crystals were then recrystallized from a mixture of ethyl acetate and ethanol to give 27.1 g of the title compound melting at between 100° C. and 112° C.