Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:37]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47]Br)[CH3:38].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:37][CH3:38])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCCOCCOCCBr
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCOCCOCCOCC)cc(C(=O)OCc2ccccc2)c1
Yield: 67 %

Procedure:
A mixture of 2 g (4 mmol) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester, 3.65 g (15.8 mmol) of 2-[2-(2-ethoxyethoxy)ethoxy]ethyl bromide, 1.2 g (8 mmol) of sodium iodide and 2.2 g (16 mmol) of potassium carbonate in 60 ml of acetone and 30 ml of DMF was stirred at reflux for 40 hours. The usual workup followed by chromatography of the crude product on 200 g of silica gel using 40% ethyl acetate-hexane gave 1.76 g of 3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-(octadecyloxy)benzoic acid phenylmethyl ester as an oil. The nmr and mass spectra were compatible with the structure.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.Cl.[F:12][C:13]([F:32])([F:31])[C:14]1[CH:15]=[C:16]([C:20]2[N:21]=[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[NH:23][CH:24]=2)[CH:17]=[CH:18][CH:19]=1.CO.C(N(CC)CC)C>O>[F:31][C:13]([F:12])([F:32])[C:14]1[CH:15]=[C:16]([C:20]2[N:21]=[C:22]([CH:25]3[CH2:26][CH2:27][N:28]([C:2]4[N:7]=[CH:6][N:5]=[C:4]5[NH:8][N:9]=[CH:10][C:3]=45)[CH2:29][CH2:30]3)[NH:23][CH:24]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Reactant: Clc1ncnc2[nH]ncc12
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: FC(F)(F)c1cccc(-c2c[nH]c(C3CCN(c4ncnc5[nH]ncc45)CC3)n2)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Charge 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (93.3 g; 1.00 equiv; 603.66 mmoles; 93.30 g), (4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine)-, Hydrochloride (1:1) (200.1 g; 1.00 equiv; 603.13 mmoles), and Methanol (1800 mL) to a 5000 mL 4-necked round bottom flask (fitted with nitrogen blanket, rubber septum, mechanical stirrer, heating mantle, condenser and thermocouple probe). Add Triethylamine (280 mL; 2.01 moles) via addition funnel over approximately 15 min. Heat the resulting clear orange solution to 50° C. and hold at 50° C. for 15 min. When reaction is deemed complete by HPLC, add Water (2000 mL) via an addition funnel at 50° C. Add seed crystals during this water addition and the product crystallizes. On completion of addition, heat the slurry to reflux for 1 hour. Cool to room temperature then filter and wash solids with 20% MeOH in water (2×250 mL). Dry the solids in a vacuum oven at 45° C. overnight to afford 4-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine as a tan solid (211.5 g, 0.603 mol, 85%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(O)C(N)(CO)CO.C(O)(=O)/C=C\C(O)=O.OS([O-])(=O)=O.[Na+]>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: NC(CO)(CO)CO
Agent: O=C(O)/C=C\C(=O)O
Agent: O=S(=O)([O-])O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The glucose isomerase activity of the immobilized samples was estimated at 70° C. using a batch assay technique using small particles (≈80 mesh). The assay was carried out in 125 ml. Erlenmeyer flasks in which the dry enzyme was hydrated in substrate (1 M glucose, 0.1 M Tris, 0.1 M maleic acid, 4.1 mM MgSO4.7H2O and 5 mmM NaHSO4 at pH 8.0) for 10 minutes at room temperature. The assay reaction was started by placing the flask in a 70° C. shaker water bath. At 15, 30, 45, 60 and 75 minutes, a 0.05 ml. sample of the reaction mixture was removed and added to 1.0 ml. of 0.1M HClO4 solution to stop the reaction. The amount of fructose formed in each sample was then estimated by the cysteine H2SO4 method. The activity was calculated through regression analysis of fructose formed with respect to time, where a unit of activity represents one μ mole of fructose formed per minute under conditions of the assay.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl.[CH2:22]([N:24]([CH2:33][CH3:34])[CH2:25][CH2:26][CH2:27][C:28](=O)[C:29]([OH:31])=[O:30])[CH3:23]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:28]([C:29]([OH:31])=[O:30])[CH2:27][CH2:26][CH2:25][N:24]([CH2:33][CH3:34])[CH2:22][CH3:23])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCN(CC)CCCC(=O)C(=O)O
Agent: Cl
Solvent: CO
Product: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Reaction time: 2 h

Procedure:
To a stirred solution of 2.85 g. (0.01 mole) of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 100 ml. of methanol is added 2.24 g. (0.01 mole) of 5-(diethylamino)-2-oxo-valeric acid, hydrochloride [prepared by the method of Libman and Kutznetsov J. Gen. Chem. (USSR), 33, 1938 (1963)]. The mixture is kept under nitrogen at ambient temperature for 2 hours and then concentrated in vacuo. The residue is mixed with aqueous sodium bicarbonate and extracted with methylene chloride. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue of 7-chloro-2-[[1-carboxy-4-(diethylamino)-butylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine is used without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][C:6]=1[NH:7][C:8](=[O:10])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:37]1([C:43]#[CH:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>[Pd].C(O)C.[Cu]I>[C:37]1([C:43]#[C:44][C:2]2[CH:3]=[N:4][NH:5][C:6]=2[NH:7][C:8](=[O:10])[CH3:9])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Nc1[nH]ncc1I
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Nc1[nH]ncc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Nitrogen was bubbled through a suspension of N-(4-iodo-1H-pyrazol-5-yl)acetamide (30 g, 120 mmol), 10% palladium on carbon (50% water, 7.4 g, 3 mmol), copper(I) iodide (1.14 g, 6 mmol), triphenylphosphine (6.3 g, 24 mmol) and triethylamine (50 mL, 360 mmol) in ethanol (600 mL) for 20 min. Phenyl acetylene was added and nitrogen bubbled through the mixture for a further 25 min. The reaction mixture was then heated and stirred under reflux conditions in an atmosphere of nitrogen for 3 d and cooled to room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, iso-hexanes/ethyl acetate 9:1 to 0:1) yielding the title compound as a solid (17.6 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH:16]1[C:20]2=[N:21][CH:22]=[CH:23][N:24]=[C:19]2[C:18]([NH2:25])=[N:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:25][C:18]2[C:19]3=[N:24][CH:23]=[CH:22][N:21]=[C:20]3[NH:16][N:17]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1n[nH]c2nccnc12
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1n[nH]c2nccnc12

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2)(0.212 g, 0.740 mmol), 1H-pyrazolo[3,4-b]pyrazin-3-amine (0.10 g, 0.740 mmol), HATU (0.281 g, 0.740 mmol) and N-methylmorpholine (0.146 ml, 1.480 mmol) in DMF (5 ml) was stirred at RT for 45 minutes. The reaction mixture was diluted with water (25 ml) and the resulting orange precipitate was filtered under vacuum and washed with water (10 ml). The solid was purified by chromatography on silica, eluting with iso-hexane:EtOAc (gradient of 0 to 100% EtOAc) to afford the title compound as a yellow solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][CH:14]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[NH:16][C:15]1=[O:26].[F:27][C:28]([F:33])([F:32])[C:29](O)=[O:30]>CN(C)C1C=CN=CC=1.CN(C)C=O.C(O)(C)C.C(Cl)(Cl)Cl>[O:21]=[C:20]1[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[NH:16][C:15](=[O:26])[CH:14]1[NH:13][C:29](=[O:30])[C:28]([F:33])([F:32])[F:27]
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: O=C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2NC(=O)C1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.67 g, 40.0 mmol), and 4-(dimethylamino)pyridine (0.244 g, 2.00 mmol) to a solution of 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (7.65 g, 40.0 mmol) in anhydrous N,N-dimethylformamide (50 mL). Rinse solids into reaction with anhydrous N,N-dimethylformamide (50 mL), and cool reaction to 0° C. in an ice/water bath. Add via syringe trifluoroacetic acid (3.08 mL, 40.0 mmol). After 10 minutes, remove cooling, and after 5.5 hours at ambient temperature, add an additional 0.2 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.53 g) and trifluoroacetic acid (0.62 mL) and stir at ambient temperature. After an overnight period, concentrate under reduced pressure to give a residue. Reconstitute the residue in isopropanol: chloroform (1:3, 20 mL) and set 5 minutes. Collect solid formed by suction filtration, wash with isopropanol: chloroform (3:1), and dry at ambient temperature under vacuum to give the title compound. Filter the filtrate, which contained precipitated solid and dry this solid at ambient temperature under vacuum to give a second crop of the title compound: mass spectrum (ES neg., m/e): 286.0 (M−1); NMR (1H, 300 MHz, DMSO-d6): δ 10.93 (s, 2H), 9.42 (d, 1H, J=6.9 Hz), 7.29-7.15 (m, 4H), 4.91 (d, 1H, J=7.2 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:34]=[CH:33][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:32])[C@@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:2]([C:3]1[CH:34]=[CH:33][C:6]2[N:7]=[C:8]([N:10]3[CH2:11][CH2:12][N:13]([C:16](=[O:32])[C@@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:18][C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:15]3)[S:9][C:5]=2[CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(CO)cc3s2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(C=O)cc3s2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-tert-butyl 1-(4-(6-(hydroxymethyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (0.859 g) and Dess-Martin reagent (1.09 g) were combined in dry DCM (20 mL) and the resulting mixture stirred at room temperature for 24 hours. The resulting mixture was diluted with saturated aqueous sodium bicarbonate and then extracted with DCM. The combined organic layers were washed with saturated aqueous Na2S2O3, concentrated, and chromatographed (0 to 5% MeOH in DCM) to yield (S)-tert-butyl 1-(4-(6-formylbenzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:21])[N:5]([C:12]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:6]2=[O:11].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.[I:41]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:41])=[C:7]2[C:3]=1[CH:4]([OH:21])[N:5]([C:12]([CH3:13])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:20])[C:6]2=[O:11]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2cccc(Cl)c2C1O
Reactant: II
Agent: CN(C)CCN(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(Cl)c2C1O
Reaction time: 2 h
Yield: 84.7 %

Procedure:
4-Chloro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (6.86 g, 22.7 mmol) was dissolved in THF (274 mL), and the solution was added with TMEDA (7.55 mL, 50.0 mmol), then added with sec-butyllithium-hexane solution (0.99 mol/L, 50.5 mL, 50.0 mmol) by drops at −78° C. over 20 minutes under argon atmosphere, followed by stirring at the same temperature for 2 hours. Then, the mixture was added with iodine (6.92 g, 27.3 mmol) and warmed from −78° C. to room temperature for 2.5 hours. The reaction mixture was added with 10% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=100/0, 85/15) to obtain 4-chloro-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (8.22 g, yield 85%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25])[CH:16]=1)[CH3:2].[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([CH2:2][CH2:1][NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:27])([F:28])[C:24]([OH:26])=[O:25])[CH:16]=1)(=[O:31])[CH3:30]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)C(=O)O)ccc1OC
Reactant: CC(=O)Cl
Product: COc1ccc(C(F)(F)C(=O)O)cc1-c1ccc(C(F)(F)F)cc1CNCCC(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-difluoro-acetic acid and acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:17]C)[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]CCC3CCCCN3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(CC2c3ccc(O)cc3CN2c2ccc(F)cc2)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 2-(4-fluorophenyl)-5-methoxy-1-{4-[(2-piperidyl)ethoxy]benzyl}isoindoline (0.14 g, 0.3 mmol) in CH2Cl2 (8 mL) under nitrogen at −10° C. was added a 1.0 M solution of boron tribromide in CH2Cl2 (0.6 mL, 0.6 mmol) dropwise. After stirring at −10° C. for 1 hour, the reaction was quenched with ice and saturated sodium bicarbonate, then extracted with methylene choride. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was then purified by HPLC (C-18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid) to provide the title compound (0.084 g, 84% yield): 1H NMR (DMSO-d6) 7.04 (t, 2H), 6.88 (d, 1H), 6.69 (dd, 1H), 6.61-6.65 (m, 5H), 6.56 (d, 1H), 5.21 (m, 1H), 4:67 (s, 1H), 4.51 (s, 1H), 4.29 (d 1H), 4.10 (dd, 1H), 3.00-3.14 (m, 2H); ES-MS (m/z) 336 [M+H]+.
Reaction SMILES: [Si]([O:18][CH2:19][CH:20]([N:22]([CH3:61])[C:23]([C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([C:42]3[C:50]4[CH2:49][CH2:48][C:47]([CH3:52])([CH3:51])[CH2:46][C:45]=4[N:44](COCC[Si](C)(C)C)[N:43]=3)[N:31]2COCC[Si](C)(C)C)=[CH:27][CH:26]=1)=[O:24])[CH3:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O>[OH:18][CH2:19][CH:20]([N:22]([CH3:61])[C:23]([C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([C:42]3[C:50]4[CH2:49][CH2:48][C:47]([CH3:52])([CH3:51])[CH2:46][C:45]=4[NH:44][N:43]=3)[NH:31]2)=[CH:27][CH:26]=1)=[O:24])[CH3:21]
Reactant: CC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(C)C(=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(CO)N(C)C(=O)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Temperature: 90 °C
Yield: 88.1 %

Procedure:
A solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid [2-(tert-butyldiphenylsilyloxy)-1-methylethyl]methylamide (145 mg, 0.17 mmol) in N,N-dimethylformamide (1.2 ml) was added to tetrabutylammonium fluoride (1.7 ml, 1.7 mmol) concentrated in advance under reduced pressure. Ethylenediamine (0.29 ml) was added, and the mixture was stirred with heating at 90° C. for 14 hr. After cooling, to the mixture were added water and ethyl acetate, and the organic layer was separated, washed successively with water, 10% aqueous citric acid solution and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (57 mg, yield 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:32][C:33](=[O:45])[C:34]([F:44])([F:43])[C:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:45])[C:34]([C:35]1[CH:36]=[CH:37][C:38]([CH2:41][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22](=[O:23])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:3]=2)=[CH:39][CH:40]=1)([F:43])[F:44])[CH3:31]
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)C(F)(F)c1ccc(C=O)cc1
Product: CCOC(=O)C(F)(F)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and difluoro-(4-formyl-phenyl)-acetic acid ethyl ester according to the procedure of step 1, Example 66. MS (ES) m/z 605.3.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]1[O:30][C@@H:29]1[CH2:31][OH:32]>C(Cl)Cl>[C:2]1([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:32][CH2:31][C@@H:29]2[CH2:28][O:30]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CO1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(C(OC[C@@H]2CO2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
A 5 L 3-neck round bottom flask was charged with trityl chloride (133.8 g, 0.48 mol) and methylene chloride (400 ml). It was cooled to 0° C. under N2 and treated with triethylamine (70.7 g, 0.70 mol). After an hour of stirring at 0° C., a solution of (R)-glycidol (88% ee, 37.03 g, 0.5 mol) in methylene chloride (100 ml) was added over 0.75 hour. The resulting solution was allowed to warm to ambient temperature and was stirred for 3 hours. It was then filtered, and the filtrate was washed with water (2×500 ml) and brine (2×500 ml). The organic phase was dried over MgSO4 and concentrated to a foam, which on crystallization from isopropyl alcohol gave the title compound (116.2 g, 76.5%) as an off-white powder.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1.I[CH3:28]>>[CH3:28][S:24][C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:25])([F:1])[F:26])=[CH:5][CH:6]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1
Reactant: CI
Reactant: FC(F)(F)Oc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: CSc1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Yield: 80 %

Procedure:
In the same manner as in Example 1 and using 5-[3-[4-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using iodomethane instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](OS(C)(=O)=O)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:1]([C:8]1[N:9]=[CH:10][N:11]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2c[nH]cn2)cc1
Reactant: CS(=O)(=O)OCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CCn2cnc(Cc3ccccc3)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-benzyl-1H-imidazole (example 110C) (1.23 g, 7.78 mmoles) in ACN (20 mL) are added K2CO3 (1.29 g, 9.34 mmoles), Cs2CO3 (253 mg, 0.778 mmole) and methanesulfonic acid phenethyl ester (example 4D) (1.86 g, 9.34 mmole). The reaction mixture is heated at reflux overnight, then cooled to room temperature, filtered, cake washed with ACN and filtrate concentrated under reduced pressure. The residue is purified by silica gel chromatography using (toluene:acetone) (90:10) to give 4-benzyl-1-phenethyl-imidazole.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@H:15]1[CH2:19][N:18](C(OC(C)(C)C)=O)[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]1)=[O:13])[CH2:7]2)=[CH2:2].[ClH:31].O1CCOCC1>>[ClH:31].[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:16][C@@H:17]([C:27]([O:29][CH3:30])=[O:28])[NH:18][CH2:19]1)=[O:13])[CH2:7]2)=[CH2:2]
Reactant: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)C2
Agent: Cl
Solvent: C1COCCO1
Product: C=Cc1cccc2c1CN(C(=O)O[C@H]1CN[C@H](C(=O)OC)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A mixture of 1-t-butyl 2-methyl (2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (18.0 g, 43.2 mmol) and HCl/dioxane (4 M) (43.2 mL, 173 mmol) was stirred at RT for 2 h. The reaction mixture was concentrated to remove the dioxane followed by concentration from Et2O to give (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride as an off-white solid (15 g) which was used without further purification. LRMS (ESI) m/z 317 [(M+H)+; calcd for C17H21N2O4: 317].