Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)C1C=CC=CC=1>C(O)C>[CH3:2][C:1]([N:9]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)([CH3:3])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)CC(C)(C)N1CCC(=O)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To 1.20 ml of tert-octylamine, 10 ml of ethanol, 10 ml of an aqueous solution containing 580 mg of potassium carbonate and 3.31 g of 1-benzyl-1-methyl-4-oxopiperidinium iodide were successively added, followed by 2 hours' heating at 100° C. under stirring. The reaction liquid was cooled to room temperature, from which ethanol was distilled off under reduced pressure and the formed solution was diluted with water, followed by extraction with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (hexane/ethyl acetate=5/1) to provide 500 mg of the title compound as a colorless oily substance.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: COC(=O)C(C)(C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Yield: 100 %

Procedure:
A solution of methyl 3-hydroxy-2,2-dimethylpropanoate (5.00 g, 38 mmol), N,N-diisopropylethylamine (7.30 g, 57 mmol) and tert-butyldimethylchlorosilane (6.80 g, 45 mmol) in dry DMF (70 mL) was stirred at room temperature for 12 h. The reaction solution was quenched with water (225 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), then dried over MgSO4. Concentration under reduced pressure afforded methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate as colorless oil (9.36 g, 100%). It was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.64 (s, 3H), 3.55 (s, 2H), 1.13 (s, 6H), 0.85 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:37][CH3:38])[C:21]([Cl:39])=[CH:20][N:19]=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:37][CH3:38])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)ncc1Cl

Procedure:
The title compound was prepared in an analogous manner to the preparation of example 381 by combining 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield a light yellow solid (71%). LCMS: m/z=537.23 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H, J=8.8 Hz), 8.04 (s, 1H), 7.67 (dd, 1H, J=8.7, 2.4 Hz), 7.59 (s, 1H), 7.32 (d, 1H, J=2.0 Hz), 7.10 (d, 1H, J=8.6 Hz), 6.91 (s, 1H), 6.54 (d, 1H, J=2.3 Hz), 6.48 (dd, 1H, J=8.7, 2.2 Hz), 3.92 (s, 3H), 3.89 (m, 4H), 3.29 (s, 3H), 3.14 (m, 4H), 3.89 (m, 4H), 2.30 (m, 2H), 2.05 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[K+]>CO.O>[Br:1][C:2]1[C:3]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc2cccc(C)c2c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc2sc(C(=O)O)c(Br)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 3-bromo-4-methyl-benzo[b]thiophene-2-carboxylate (23b) (640 mg, 2.14 mmol) and potassium hydroxide (1.17 g, 21 mmol) in a mixture of methanol (10 mL) and water (5 mL) was warmed at 70° C. After 1 hour, methanol was evaporated and water (10 mL) was added to the reaction mixture which was washed with diethyl ether (10 mL). The aqueous layer was acidified to pH 2 with a hydrochloric acid solution 1N and extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired acid (23c) as a white solid without further purification (420 mg, 1.55 mmol, 72%).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].Cl.[CH2:17](O)[CH3:18]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([O:12][CH2:17][CH3:18])=[O:11])([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Reactant: CCO
Agent: Cl
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Temperature: 35 °C
Yield: 82 %

Procedure:
3.0 grams of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid (formula III) from Example 4, and 30 ml of ethanol were added into 100 ml three-necked flask, anhydrous hydrogen chloride gas was supplied while the temperature was maintained at 30-40° C. until the reaction completed. The reaction mixture was then allowed to cool to ambient temperature, the solvent was evaporated, 30 ml of ethyl acetate and 30 ml of water were added, and the mixture was adjusted to basic using sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with 10 ml×3 of ethyl acetate. The organic portion was washed once with saturated saline solution, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated to give 2.8 grams of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate, resulting in a yield of 82%.
Reaction SMILES: [OH-].[K+].[N:3](OCCCC)=[O:4].[CH3:10][C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][C:18]#[N:19].Cl>CC(C)=O>[OH:4][N:3]=[C:17]([C:18]#[N:19])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[CH2:14][O:13][C:12]1[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=1[CH3:10]
Reactant: CCCCON=O
Reactant: Cc1ccccc1OCc1ccccc1CC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccccc1OCc1ccccc1C(C#N)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Acetone (5 ml), 85% potassium hydroxide (powder)(0.40 g, 6 mmol) and butyl nitrite (0.62 g, 6 mmol) were added to 2-(2-methylphenoxymethyl)benzyl cyanide (1.19 g, 5 mmol). The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 1N aqueous hydrochloric acid solution (100 ml) was added. The mixture was extracted with toluene (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromtography (ethyl acetate/n-hexane/chloroform) to give α-hydroxyimino-2-(2-methylphenoxymethyl)benzyl cyanide (1.23 g, Yield: 92.4%, E/Z=35/65) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]2[NH:19][C:18]3[C:20]([O:28][CH3:29])=[C:21]([CH3:27])[C:22]([CH3:26])=[C:23]([O:24][CH3:25])[C:17]=3[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1>CN(C=O)C>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:19]2[C:18]3[C:20]([O:28][CH3:29])=[C:21]([CH3:27])[C:22]([CH3:26])=[C:23]([O:24][CH3:25])[C:17]=3[N:16]=[C:15]2[CH:14]=[CH:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(C=Cc2nc3c(OC)c(C)c(C)c(OC)c3[nH]2)cc1OC
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(C=Cc3ccc(OC)c(OC)c3)nc3c(OC)c(C)c(C)c(OC)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a suspension of sodium hydride, 60% dispersion in oil (150 mg; 3.5 mmol) in 20 mL of DMF, {2-[2-(3,4-dimethoxyphenyl)-vinyl]-4,7-dimethoxy-5,6-dimethyl-1H-benzoimidazole (1.2 g; 3.25 mmol) in DMF (20 mL) was added dropwise over 5 minutes. After addition, the reaction mixture was stirred at ambient temperature for 30 minutes, then methyl-4-(bromomethyl)benzoate (745 mg; 3.25 mmol) in DMF (10 mL) was added. The reaction mixture was stirred at ambient temperature for 4 hours. The DMF was concentrated to a residue, and H2O was added. The solid was collected by filtration. Recrystallization from MeOH gave 620 mg (37% yield) of the title compound as a light yellow solid, hemihydrate, m.p. 111-114° C. Anal. Calcd. for C30H32N2O6—0.5 H2O: C, 68.56, H, 6.33; N, 5.33. Found: C, 68.51; H, 6.27; N, 5.28. Mass spectrum: (EI; M+) m/z 516.1H-NMR (DMSO-d6; 400 MHz) δ7.9(d, 2H), 7.72-7.78(d, 1H), 7.31(d, 1H), 7.2-7.26 (m, 4H), 6.95 (d, 1H), 5.9 (s, 2H), 4.12 (s, 3H), 3.81 (s 3H), 3.79 (s, 3H),3.77 (s, 3H), 3.53 (s, 3H), 2.1 ppm (d, 6H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[C:10]([NH:12][C:13]([NH2:15])=[NH:14])#[N:11].[OH-].[Na+]>O>[ClH:1].[ClH:1].[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([NH:2][C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[NH:11])=[CH:4][CH:5]=1
Reactant: Cc1ccc(N)cc1
Reactant: N#CNC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(NC(=N)NC(=N)N)cc1

Procedure:
A stirred mixture of 4.3 g. (.03 mole) of p-toluidine hydrochloride and 2.5 g. (0.03 mole) of cyanoguanidine is immersed in a a 210° C. oil bath for fifteen minutes. The resulting amber glass-like reaction product is dissolved in 100 ml of water, alkalized with 40% sodium hydroxide solution, and extracted with 250 ml of ether. The ether layer is backwashed twice with 10 ml of water, dried over sodium carbonate, filtered, and the ether solution made strongly acidic with a saturated etheral hydrochloric acid solution. The precipitate is collected on a filter, washed twice with 50 ml of anhydrous ether, and dried in vacuo at 25°C to obtain 1-(p-tolyl)biguanide dihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].C([N:28]([CH2:31][CH3:32])CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:15][CH:3]1[CH2:2][CH2:7][CH2:6][CH2:32][CH:31]1[NH2:28])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: NC1CCCCC1NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.900 g, 2.47 mmol), (DL)-trans-l,2-diaminocyclohexane (0.282 g, 2.47 mmol), triethylamine (0.250 g, 2.47 mmol) and benzene (20 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the resulting crude product was recrystallized from hexane to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-aminocyclohexyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.340 g, 28.8% yield).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([C:22]([O:24][CH2:25][C@@H:26]([C:34]([O:36]CC1C=CC=CC=1)=[O:35])[NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[O:23])[NH:11]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:11][C@H:10]([C:22]([O:24][CH2:25][C@@H:26]([C:34]([OH:36])=[O:35])[NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[O:23])[CH2:9][OH:8]
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N[C@@H](CO)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reaction time: 6 h

Procedure:
A mixture of benzyl O-(O-benzyl-N-benzyloxycarbonyl-L-serinyl)-N-trifluoroacetyl-L-serinate (1 g) and 10% palladium on activated carbon (1 g) in acetic acid (30 ml) was hydrogenated under hydrogen at 40 psi at room temperature for 6 hours. The reaction mixture was filtered with Celite (filter aid, trade mark, made by Nakarai Chemicals) and the filtrate was concentrated in vacuo and the residue was diluted with water (50 ml) and lyophylized to give O-(L-serinyl)-N-trifluoroacetyl-L-serine (430 ml).
Reaction SMILES: [OH-].[K+].CC(C)=O.[C:7]([N:9]=[C:10]([NH2:12])[NH2:11])#[N:8].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH2:21][C:22](Cl)=[O:23]>O.C(O)(=O)C>[NH2:11][C:10]([NH:9][C:7]#[N:8])=[N:12][C:22](=[O:23])[CH2:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20]
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: N#CN=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: N#CNC(N)=NC(=O)Cc1c(Cl)cccc1Cl
Yield: 46.6 %

Procedure:
Potassium hydroxide (1.12 g, 0.02 m) was dissolved in water (4 cm3). Acetone (5 cm3) and dicyandiamide (1.05 g, 0.0125 m) were added and the solution cooled in ice. 2,6-Dichlorobenzeneactyl chloride (2.23 g, 0.01 m) was rapidly added to the stirring cooled solution. After the addition, water (40 cm3) was added and the solution was acidified with glacial acetic acid to give a white precipitate. The precipitate was filtered off, washed well with water and recrystallised from ispropyl alcohol to give the title compound as a white solid (1.26 g), melting point 210°-212° C.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C@:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].Cl.O1CCOCC1>ClCCl>[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C@@:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:38])[CH3:39])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 69.8 %

Procedure:
To a solution of the product of Example 49-5 (185.0 g, 0.334 mol) in dichloromethane (220 mL) was added 4 M HCl in dioxane (430 mL, 1.72 mol) and the solution was mixed at room temperature for 3.5 h. The reaction was quenched by addition of ethyl acetate (1 L) and pH 7 phosphate buffer (1.5 L) and the layers were separated. The organic layer was concentrated and chased with ethanol to a final volume of approximately 1100 mL. The product precipitated and was isolated by filtration and dried to give the title compound (105.79 g, 70%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(O[C:14](=O)[CH:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(O)C.C(O)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH2:14][NH:30][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: NCc1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH3-]C#N
Agent: [H-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(CC)CNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 21.8 %

Procedure:
Diisobutylaluminum hydride (38.4 mL of a 1.0 M solution in toluene, 38.4 mmol) was added over 5 min to a solution of 2-ethyl-malonic acid diethyl ester (3.50 g, 19.2 mmol) in dichloromethane (35 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (35 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (1.64 g, 11.4 mmol, 59%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.30 mL, 11.4 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.43 g, 22.8 mmol) were added sequentially. The mixture was stirred at 25° C. for 20 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-60% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-butyric acid ethyl ester (0.630 g, 2.49 mmol, 22%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J=7.4 Hz), 1.27 (3H, t, J=7.0 Hz), 1.52-1.69 (2H, m), 2.47-2.54 (1H, m), 2.68 (1H, dd, J=4.7 Hz, J2=11.7 Hz), 2.86 (1H, dd, J=9.2 Hz, J2=11.7 Hz), 3.73 (1H, d, J=13.2 Hz), 3.77 (1H, d, J=13.2 Hz), 4.12-4.20 (2H, m), 6.96-7.00 (2H, m), 7.24-7.27 (2H, m).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[CH2:35]([OH:37])[CH3:36]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:36][CH2:35][OH:37])[C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: CCO
Reactant: Cc1ccccc1N1CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1CN(CCO)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=530.2 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and (3-bromoethoxy)-tert.-butyldimethylsilane. HCl in ethanol (3% conc.) cleaved the intermediate TBDMS-ether.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[C:13]=1[CH3:14].[C:17]([CH2:21][C:22](Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O>ClCCl>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:21][C:22]([NH:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[C:7](=[O:12])[C:6]=2[C:13]=1[CH3:14])=[O:23]
Reactant: Cc1c(C)c2c(c(C)c1N)C(=O)C(C)(C)O2
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one obtained in Reference Example 57 (3.00 g, 13.7 mmol) and tert-butylacetyl chloride (2.03 g, 15.1 mmol) in dichloromethane (30 mL) was added triethylamine (2.3 mL, 16.4 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the residue to separate the organic layer, and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with 1 N hydrochloric acid and a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the targeted product 2.34 g (yield 54%). Melting point: 155-156° C.
Reaction SMILES: [OH:1][C:2]([C:17]([F:20])([F:19])[F:18])([CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])([CH3:8])[CH3:7])[CH:3]=O.[C:21]1([NH2:31])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[F:20][C:17]([F:18])([F:19])[C:2]([CH:3]=[N:31][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)([OH:1])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])([CH3:7])[CH3:8]
Reactant: Nc1cccc2ccccc12
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccccc1C(C)(C)CC(O)(C=Nc1cccc2ccccc12)C(F)(F)F
Yield: 77.6 %

Procedure:
150 mg (0.517 mmol) of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is converted into imine with 74 mg (0.517 mmol) of 1-naphthylamine in toluene with the aid of titanium tetraisopropylate. After working-up and chromatography, 166.7 mg (77.7%) of the desired imine is isolated.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:19].C(N(C(C)C)CC)(C)C>C(#N)C.[Cl-].[Na+].O>[N:8]1([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([O:12][CH2:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)=[O:19])=[O:11]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of BOC-L-Proline (0.485 g, 2.25 mmol) and 2-Bromo-4′-nitro acetophenone (0.500 g, 2.05 mmol) in acetonitrile (20 mL) was added diisopropylethylamine (0.39 mL, 2.25 mmol) dropwise at ambient temperature. After stirred for four hours, the solution was poured into brine and extracted into ethyl acetate, dried over sodium sulfate, filtered, and the filtrate was concentrated to give a crude material that was used without purification (100% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH2:40][OH:41])[N:30]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH:40]=[O:41])[N:30]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[CH:26][CH:25]=1
Reactant: OCc1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
Dess-Martin periodinane (1.3 g, 2.9 mmol) was added to a solution of [6-chloro-1-(3-fluorophenyl)-1H-indol-2-yl]methanol (0.53 g, 1.9 mmol) in methylene chloride (10 mL). The solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane, washed with 1:1 aqueous saturated Na2S2O3 and NaHCO3. The organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-20% EtOAc in hexane) to give the desired product (50 mg). LCMS calculated for C15H10ClFNO(M+H)+: m/z=274.0. Found: 274.0.