Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH:19][CH3:20])[CH:13]=2.[F:21][CH:22]([F:26])[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[F:21][CH:22]([F:26])[C:23]([N:19]([C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[NH:11]2)=[CH:16][CH:15]=1)[CH3:20])=[O:24]
Reactant: O=C(O)C(F)F
Reactant: CNc1ccc2cc(-c3c(I)ccnc3OC)[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nccc(I)c1-c1cc2ccc(N(C)C(=O)C(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-methyl-amine (30 mg, 0.08 mmol) in CH2Cl2 (5 mL) was added 2,2-difluoroacetic acid (11 mg, 0.12 mmol) and HATU (45 mg, 0.12 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 2,2-difluoro-N-[2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-N-methyl-acetamide (12 mg, 33%) as a white solid. MH+ 457.8.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:64]=[CH:63][N:62]=[CH:61][N:60]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][N:60]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccncn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccncn2)cc1[N+](=O)[O-]
Yield: 30.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 150 mg, 0.439 mmol), triethylamine (0.184 mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (291 mg, 0.659 mmol), and 4-aminopyrimidine (63 mg, 0.659 mmol) in methylene chloride (4 mL) was stirred at 25° C. overnight. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40M, Silica, 1/2 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrimidin-4-yl-propionamide (56 mg, 30%) as a pale yellow foam: mp 91-95° C. (foam to gel); EI-HRMS m/e calcd for C19H22N4O5S (M+) 418.1311, found 418.1310.
Reaction SMILES: [OH:1][CH:2]([CH:28]1[CH2:32][O:31]C(C)(C)[O:29]1)[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:26])(=[O:25])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[CH:7]=1>CO.O>[OH:1][CH:2]([CH:28]([OH:29])[CH2:32][OH:31])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:25])(=[O:26])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:22])[F:23])[CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2cccc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)c2)O1
Solvent: O
Solvent: CO
Product: O=C(NCC(O)C(O)CO)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1

Procedure:
2.53 g (5 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in 20 ml of methanol/water 1:1, about 100 mg of cation exchanger Amberlyst 15 is added and warmed to boiling temperature in 1 hour. The ion exchanger is then filtered off and the filtrate is evaporated to dryness in a vacuum. 1.94 g (4.18 mmol)=83.5% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=3)=[CH:12][N:11]=1)[CH2:2]2.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][N:11]=1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(OC3CN4CCC3CC4)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cnc(OC3CN4CCC3CC4)nc2)cc1

Procedure:
The product of Example 18B (340 mg, 0.86 mmol) in CH2Cl2 (6 mL) was treated with trifluroacetic acid (Aldrich, 2 mL) at ambient temperature for 30 minutes and concentrated under reduced pressure. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.07) as solid (150 mg, yield, 58%). 1H NMR (300 MHz, MeOH-d4) δ 1.88-2.22 (m, 3H), 2.31-2.45 (m, 1H), 2.56-2.64 (m, 1H), 3.27-3.51 (m, 5H), 3.84-3.96 (m, 1H), 5.36-5.45 (m, 1H), 6.87 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 8.77 (s, 2H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][NH:11][C:12](=[O:18])[C:13](OCC)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:9][C:3]1[C:2]2[N:1]=[C:13]([C:12](=[O:18])[NH:11][CH3:10])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=O)NC
Reactant: Cc1cccc(N)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc2c(C)cccc2[nH]1
Temperature: 175 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2,3-diaminotoluene (2.0 g) and ethyl N-methyloxamate (2.36 g) in N,N-dimethylformamide (10 ml) was stirred at 175° C. for 8 hours. After being cooled to ambient temperature, the mixture as poured into a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixtue of chloroform and methanol (50:1) to give 4-methyl-2-(N-methylcarbamoyl)-1H-benzimidazole (1.17 g) as a powder.
Reaction SMILES: [NH2:1][N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=[NH2+:8].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[OH-].[Na+].[OH:24][CH2:25][C:26](OC)=O>CCO>[N:8]1[C:26]([CH2:25][OH:24])=[N:1][N:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=12
Reactant: COC(=O)CO
Reactant: Nn1ccccc1=[NH2+]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1nc2ccccn2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a solution of 1-aminopyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (1.24 g, 4 mmol) in EtOH (15 mL) was added NaOH (320 mg, 8 mmol). The mixture was heated to 60° C. and stirred for 1 h. Then methyl 2-hydroxyacetate (720 mg, 8 mmol) was added and the mixture was heated to 80° C. and stirred for 3 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was washed with water (10 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a pale yellow solid (350 mg, 59% yield). ESI MS: m/z 150 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][C:12]([OH:14])=O.[CH:23]([C@H:26]1[C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][C:28](=[S:43])[NH:27]1)([CH3:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C.P([O-])(O)(O)=O.[Na+]>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[F:22][C:2]([F:1])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][C:12]([N:27]1[C@@H:26]([CH:23]([CH3:25])[CH3:24])[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:29][C:28]1=[S:43])=[O:14]
Reactant: CC(C)[C@@H]1NC(=S)OC1(c1ccccc1)c1ccccc1
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCC(F)(F)CCCCCC/C=C/CC(=O)N1C(=S)OC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C
Temperature: 0 °C
Reaction time: 19 h
Yield: 34 %

Procedure:
Under a nitrogen atmosphere, (E)-11,11-difluoro-octadec-3-enoic acid (No. 6893453; 502.7 mg, 1.58 mmol) obtained in step B-4 and a commercially available reagent (S)-4-isopropyl-5,5-diphenyl-oxazolidine-2-thione (469.5 mg, 1.58 mmol) were dissolved in dichloromethane (7.5 mL), and the solution was cooled to 0° C. While maintaining the temperature at 0° C., N,N-dimethyl-4-aminopyridine (4-DMAP; 19.3 mg, 0.158 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (WSCl; 393.4 mg, 2.05 mmol) were sequentially added, and the mixture was stirred at 0° C. for 2 minutes and at room temperature for 19 hours. An aqueous solution (9.0 mL) of 10% sodium dihydrogen phosphate and ethyl acetate were added to the reaction solution before extraction. The organic layer was sequentially washed with water and a saturated brine, and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the resulting residue was purified with SP1 (SiO2 cartridge, 10% ethyl acetate/n-hexane, Rf=0.6) to obtain (E)-11,11-difluoro-1-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-octadec-3-en-1-one (No. 5547308; 647.9 mg, 3 steps, 34% yield).
Reaction SMILES: [Cl-].[Li+].[C:3]1(=[O:16])[O:15][C@@H:6](/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4]1.Cl[Si](C)(C)C>O1CCCC1.[Cu]>[C:3]1(=[O:16])[O:15][C@@H:6](/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][CH2:4]1
Reactant: CCCCCC/C=C\[C@H]1C=CC(=O)O1
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCCC/C=C\[C@H]1CCC(=O)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
In an argon atmosphere, 40 ml of anhydrous tetrahydrofuran were added to 1.95 g (10.2 mmol) of copper (LiCl) iodide (CuI) and 1.09 g (25.7 mmol) of lithium chloride dried at a reduced pressure and 130° C., and the resultant solution was stirred at room temperature for about 15 minutes. The resultant transparent solution was cooled to about -60° C., and a solution obtained by dissolving 1.16 g of the compound (27) obtained in step h' in 21 ml of tetrahydrofuran was added to the above cooled solution. Subsequently, 2.72 ml (20.4 mmol) of chlorotrimethylsilane (TMSCl) were added to the resultant solution, this solution mixture was stirred for 10 minutes, and 5.04 ml (16.0 mmol) of distilled and purified n-Bu3SnH were added to stirred solution mixture in a small amount each time over about 5 minutes. Cooling was then stopped, and the temperature of the reaction solution was raised to 0° C. at room temperature over about 30 minutes. 60 ml of a 10% aqueous potassium fluoride (KF) solution were added to the above reaction solution, the mixture was stirred, and the produced precipitate was filtered. The organic layer was separated from this filtrate, and the remaining water layer was extracted with 100 ml of ether three times. The extracted solution was concentrated, 90 ml of a 10% aqueous potassium fluoride solution were added to the resultant residue, and the solution mixture was stirred for 15 minutes. Ether was added to this solution and stirred for 15 minutes. The resultant solution was filtered, the filtrate was separated, and its water layer was extracted with 100 ml of ether three times. These organic layers were collected, sequentially washed with water and brine solution, and dried with anhydrous magnesium sulfate. The organic layers were concentrated to obtain a crude product, and the crude product was purified by a column chromatograph using a developing solvent (hexane: diethyl tether=91:9 to 83:17), thereby obtaining 875 mg (4.46 mmol) of a compound (28) as a colorless transparent oily substance (yield:74%). The physical data of the resultant compound (28) were as follows:
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32]([S:34][C:35]4[C@H:36]([CH3:59])[C@@H:37]5[C@@H:54]([C@H:55]([OH:57])[CH3:56])[C:53](=[O:58])[N:38]5[C:39]=4[C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=4)=[O:41])[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:18][CH:19]1[CH2:22][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32]([S:34][C:35]4[C@H:36]([CH3:59])[C@@H:37]5[C@@H:54]([C@H:55]([OH:57])[CH3:56])[C:53](=[O:58])[N:38]5[C:39]=4[C:40]([O:42][CH2:43][C:44]4[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=4)=[O:41])[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:20]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CC(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)C5)co4)C3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CC(O)C5)co4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 96 h
Yield: 37.9 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-(1-{4-[3-(t-butyldiphenylsilyloxy)-azetidin-1-ylcarbonyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.20 g, 1.43 mmol) (obtained as described in Example 78(1)) in tetrahydrofuran (60 ml) was added to acetic acid (240 μl, 4.30 mmol) and 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (4.30 ml, 4.30 mmol) and the mixture was stirred at room temperature for 4 days. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium chloride solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate:methanol(95:5→9:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(3-hydroxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (325 mg, yield 38%) as a pale yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.O.[C:43](#[N:45])C>[C-]#N.[Zn+2].[C-]#N>[C:43]([C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])#[N:45]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC#N
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(C#N)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 90 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
4-Trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (300 mg, 0.505 mmol) was dissolved in acetonitrile (15 mL), and the solution was added with zinc cyanide (178 mg, 1.52 mmol) and [bis(diphenylphosphino)ferrocene]dichloropalladium (33 mg, 0.0404 mmol), followed by stirring at 90° C. for 17 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=8/1) to obtain 4-cyano-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (198 mg, yield 83%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[S:31][C:30](/[C:32](/[CH2:42][CH3:43])=[CH:33]/[CH2:34][CH2:35][C:36]([CH2:40][CH3:41])([OH:39])[CH2:37][CH3:38])=[CH:29][CH:28]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[S:31][C:30](/[C:32](/[CH2:42][CH3:43])=[CH:33]/[CH2:34][CH2:35][C:36]([CH2:40][CH3:41])([OH:39])[CH2:37][CH3:38])=[CH:29][CH:28]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC/C(=C\CCC(O)(CC)CC)c1ccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC/C(=C\CCC(O)(CC)CC)c1ccc(CCc2ccc(CO)c(CO)c2)s1

Procedure:
In a manner similar to that of Example 6(l), by reaction of 710 mg (1.1 mmol) of (E)-7-{5-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol with 3.3 mL (3.3 mmol) of 1.0 M tetrabutylammonium fluoride solution, the desired product is obtained in the form of a white powder (m.p.=77° C.; m=380 mg; Y=83%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11](O)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH2:52])[CH2:47][O:46]1.[NH4+].[Cl-]>C(Cl)Cl>[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH:52][C:11]([C:4]2[C:3]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])=[C:2]([F:1])[C:7]3[N:8]=[CH:9][O:10][C:6]=3[CH:5]=2)=[O:12])[CH2:47][O:46]1
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Reactant: CC1(C)OCC(CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)OCC(CONC(=O)c2cc3ocnc3c(F)c2Nc2ccc(I)cc2F)O1
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid (500 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added HOBt (254 mg, 1.63 mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (238 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts was washed by water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (488 mg) was used directly in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:31][CH3:32])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.Cl>ClCCl>[NH2:23][CH:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][CH:2]([OH:1])[CH2:31][CH3:32])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:18][CH2:19]1
Reactant: CCC(O)C[C@H]1CCc2sc3ncnc(NC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Agent: Cl
Solvent: ClCCl
Product: CCC(O)C[C@H]1CCc2sc3ncnc(NC4CCC(N)CC4)c3c21
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A 50-mL round-bottom flask was charged with 30.1 (130 mg, 0.28 mmol, 1.00 equiv) and dichloromethane (10 mL) and cooled to 0° C. Then hydrochloric acid (12 M, 2.0 mL) was added and the resulting solution was stirred for 3 h at room temperature. After 3 h, the mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with saturated aqueous sodium carbonate and then the solution was extracted with 2×40 mL of ethyl acetate. The organic layers were combined and dried over sodium sulfate and concentrated under vacuum to give 1-[(3R)-12-[(4-aminocyclohexyl)amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]butan-2-ol (80 mg, crude) as a colorless oil. To a solution of this material (80 mg, crude) in methanol (5 mL) was added HCHO (37%, 0.8 mL). The reaction was stirred for 1 h at room temperature. Then NaBH3CN (33.9 mg, 0.54 mmol, 2.44 equiv) was added and the resulting solution was stirred for an additional 2 h at ambient temperature and concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC(SHIMADZU) under the following conditions: column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.1% HCOOH and CH3CN; UV detection at 254 nm. The product-containing fractions were collected and evaporated to remove the water and CH3CN to give (2R)-1-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]butan-2-ol formate (I-52, 8.6 mg) as a white solid and (2S)-1-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]butan-2-ol formate (I-54, 5.9 mg) as a grey solid, respectively.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Li][CH3:18]>C1COCC1>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:18])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCc1sc(C(=O)O)cc1-c1ccccc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CCc1sc(C(C)=O)cc1-c1ccccc1
Reaction time: 1 h

Procedure:
At 5° C. a solution of 5-ethyl-4-phenyl-thiophene-2-carboxylic acid (180 mg, 0.775 mmol) in THF (4 mL) is treated with MeLi (0.9 mL, 1.6 M in diethyl ether). The reaction mixture is stirred at rt for 30 min before another portion of MeLi (0.5 mL) is added. Stirring is continued for 1 h, the reaction is quenched by adding water (50 mL) and extracted with EA. The organic extract is dried over MgSO4, the solvent is removed in vacuo, and the crude product is purified by CC on silica gel eluting with heptane:EA 30:1 to give 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (64 mg) as a colourless oil; LC-MS: tR=1.03 min, [M+1+MeCN]+=272.15; 1H NMR (CDCl3): δ 7.60 (s, 1H), 7.47-7.32 (m, 5H), 2.91 (q, J=7.6 Hz, 2H), 2.54 (s, 3H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([O:23]CC)=[O:22])[CH2:14][CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].O.[OH-].[Li+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([OH:23])=[O:22])[CH2:14][CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc([C@H]2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CC[C@H](c3cccc(C(=O)O)c3)CC2)nc1Cl

Procedure:
The same operation as in Example (1i) was performed using ethyl trans-3-{4-[(4-chloro-5-ethyl-1H-imidazole-2-carbonyl)amino]cyclohexyl}benzoate obtained in Example (193b) (43 mg, 0.106 mmol) and lithium hydroxide monohydrate (44 mg, 1.06 mmol), to obtain 23 mg of the title compound as a white solid (58%).
Reaction SMILES: [CH:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:25](C1(C2C=CC(C=O)=CC=2)CC1)[CH3:26].FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH2:25]([C:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1)[CH3:26]
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Reactant: CCC1(c2ccc(C=O)cc2)CC1
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC1(c2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2)CC1

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1-ethylcyclopropyl)-benzaldehyde (124 mg, 0.71 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (135 mg, 0.71 mmol) and sodium borohydride (40 mg, 1.07 mmol). The desired product was isolated without further purification as a colorless oil. MS (ISP) 348.5 (M+H)+.