Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])(=O)[CH3:2].C([O-])(=O)C.[NH4+:22]>C(O)(=O)C.O.[OH-].[Na+]>[CH3:8][C:7]([C:6]1[N:22]=[C:1]([CH3:2])[O:4][C:5]=1[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C(=O)C(C)(C)C)C(=O)C(C)(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(C(C)(C)C)c(C(=O)C(C)(C)C)o1
Yield: 92.5 %

Procedure:
A solution of 4-(acetyloxy)-2,2,6,6-tetramethyl 3,5-heptanedione (22 g, 0.09 mol) in acetic acid (100 mL) is treated with ammonium acetate (44 g). The reaction mixture is heated at reflux overnight. The reaction mixture is diluted with water and neutralized (to pH 5) by the addition of aqueous sodium hydroxide. The product is extracted into ethyl acetate (3×150 mL) and the combined organic layers are washed with 0.1 N NaOH, water, and then brine. The organic layer is dried and evaporated. The residue is taken up in hexane (50 mL) and applied to a pad of silica gel (500 g). The silica pad is eluted with hexane (100 mL). Then the product is eluted from the silica with hexane/ethyl acetate (4:1) to give 18.6 g (91%) of 1-[4-(1,1-dimethylethyl)-2-methyl-5-oxazolyl]-2,2-dimethyl-1-propanone as an oil. 1H-NMR (CDCl3) δ 2.60 (s, 3H, 2-Me), 1.35 (s, 9H, tbu), 1.31 (s, 9H, tbu). 13C--NMR (CDCl3) δ 195.8, 159.3, 157.6, 143.6, 44.2, 32.7, 28.4, 26.6.
Reaction SMILES: [CH3:1][Li].[CH3:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[CH:5]1>C1COCC1>[CH3:3][N:4]1[C:12]2[C:7](=[C:8]([C:13](=[O:15])[CH3:1])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: [Li]C
Reactant: Cn1ccc2c(C(=O)O)cccc21
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c1ccn2C

Procedure:
Methyl lithium (1.59M solution in ether; 13.8 ml) was added dropwise to a stirred cold (-65° to -55°) solution of 1-methyl-1H-indole-4-carboxylic acid (1.75 g) in dry THF (50 ml) under nitrogen and stirring was continued while the mixture warmed to 0° over 2 h. The reaction was then quenched with saturated ammonium chloride solution (50 ml) and the layers were separated. The aqueous layer was further extracted with dichloromethane (2×50 ml) and the combined organic layers were washed with brine (2×50 ml), dried and evaporated in vacuo. The residual solid (1.8 g) was purified by FCC eluting with dichloromethane to give the title compound (1.6 g), m.p. 63°-64°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:20]([CH:22]([NH:25][C:26](=O)[O:27]C1C=CC=CC=1)[CH2:23][CH3:24])[CH3:21]>CN(C)C=O>[CH2:20]([CH:22]([NH:25][C:26]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:27])[CH2:23][CH3:24])[CH3:21]
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: CCC(CC)NC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 25 °C
Yield: 70.7 %

Procedure:
4-(1H-5-Indolyloxy)-2-pyridinamine (1.85 g, 8.2 mmol, CAS No. 417722-11-3) which was described in WO 02/32872 was dissolved in N,N-dimethylformamide (20 ml); and sodium hydride (394 mg, 9.84 mmol) was added thereto while stirring at room temperature. The reaction mixture was cooled with ice bath after 30 minutes; phenyl N-(1-ethylpropyl)carbamate (1.87 g, 9.03 mmol); and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=3:1) to yield the title compound as crystals (1.95 g, 5.8 mmol, 71%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][C:9](=O)[CH2:8]3)=[CH:3][CH:2]=1.CN.[BH3-][C:18]#[N:19].[Na+].[ClH:21].[CH3:22][OH:23]>>[ClH:21].[CH3:18][NH:19][CH:9]1[CH2:10][CH:11]2[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:14])=[CH:2][CH:3]=3)([CH2:12]2)[CH2:8]1.[ClH:21].[CH2:22]([O:23][CH2:1][CH3:2])[CH3:18]
Reactant: CO
Reactant: [BH3-]C#N
Reactant: Cc1ccc(C23CC(=O)CC2C3)cc1
Agent: CN
Agent: Cl
Agent: [Na+]
Product: CCOCC
Product: CNC1CC2CC2(c2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-p-tolyl-bicyclo[3.1.0]hexan-3-one (90 mg; 0.48 mmol) in methanol (3 mL) was added methylamine (33% in ethanol; 1 mL) and NaCNBH3 (39.2 mg; 0.62 mmol; 1.3 eq). The mixture was stirred at room temperature overnight. The reaction mixture was cooled to 10° C., and acidified with 1 N HCl (6 mL). The reaction mixture was concentrated at 30° C., and the resulting aqueous layer was diluted with H2O (10 mL). The aqueous layer was then extracted with ethyl acetate (15 mL) to remove nonpolar impurities. The aqueous layer was then adjusted to pH 9 with 1N NaOH, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to an oily residue. The oil was then dissolved in diethyl ether (5 mL), and the HCl salt was formed by slowly adding HCl/diethyl ether solution (0.5 mL). The slurry was stirred for 30 minutes before filtration. The solids were rinsed with diethyl ether (5 mL) and the compound was quickly transferred to a vacuum dessicator and dried under vacuum for 12 hours to give the title compound as a beige solid (65 mg; 57%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.71-0.91 (m, 1 H) 1.20-1.29 (m, 1 H) 1.34-1.42 (m, 1 H) 1.64-1.75 (m, 1H) 2.01-2.14 (m, 1 H) 2.24-2.34 (m, 4 H) 2.35-2.51 (m, 2 H) 2.59-2.84 (m, 6 H) 3.70-3.86 (m, 1 H) 6.96-7.14 (m, 4 H) 9.23-9.68 (m, 1 H). 13C NMR (100 MHz, CHLOROFORM-d) δ ppm 16.90 (s, 1 C) 21.15 (s, 1 C) 24.06 (s, 1 C) 26.15 (s, 1 C) 26.73 (s, 1 C) 30.34 (s, 1 C) 31.52 (s, 1 C) 32.18 (s, 1 C) 32.54 (s, 1C) 33.93 (s, 1C) 36.22 (s, 1C) 38.99 (s, 1 C) 57.07 (s, 1C) 63.61 (s, 1C) 126.60 (s, 2 C) 129.30 (s, 2 C) 135.83 (s, 1 C) 140.61 (s, 1 C). MS (M+1) 202, HPLC Purity 98% (AUC).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH3:17])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].Cl>O.CCCCCC.O1CCCC1>[CH2:1]([S:8][C:9]1[N:10]=[C:11]([N:15]([CH2:16][CH3:17])[S:24]([CH3:23])(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1cccc(SCc2ccccc2)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(c1cccc(SCc2ccccc2)n1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a mixture of 6 g of 2-benzylthio-6-ethylaminopyridine and 60 ml of tetrahydrofuran was added dropwise 17.3 ml of a 1.65 mol/l hexane solution of n-butyl lithium at -10° to 0° C. in a nitrogen stream. To the reaction mixture was added 3.4 g of methysulfonyl chloride at 0° to 15° C., followed by reacting for 0.5 hour. After completion of the reaction, the reaction mixture was poured into water, made weakly acidic with hydrochloric acid, and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate/hexane=1/19 by volume) to obtain 3.4 g of N-(6-benzylthiopyridine-2-yl)-N-ethylmethylsulfonamide as an orange crystal.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
1.52 g (10 mmol) of methyl 4-hydroxybenzoate was dissolved in 40 ml of N,N-dimethylformamide and 2.16 g (15 mmol) of 2-dimethylaminoethyl chloride hydrochloride and 4.15 g (30 mmol) of potassium carbonate were further added. The mixture was heated at 80° C. and stirred overnight. After cooling, water was added to the reaction mixture, the obtained mixture was extracted twice with ethyl acetate, and the extract was washed with brine. The organic phase was dried (Na2SO4) and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=70:1 to 15:1 (v/v)) to obtain 0.69 g (3.09 mmol) of methyl 4-(2-dimethylaminoethoxy)benzoate as a pale brown oily substance. Its spectroscopic data are as follows:
Reaction SMILES: C(OC1(CC2C3C(=CC=CC=3)NC=2)C2C(=CC=C(Cl)C=2)N(CCC)C1=O)(=O)C1C=CC=CC=1.C([O:42][CH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([CH3:52])[CH:50]=2)[N:45]([CH2:53][CH2:54][CH3:55])[C:44]1=[O:56])(=O)C1C=CC=CC=1.C(O[CH2:66][C:67]1[C:75]2[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=2)[N:69]([C:76](=[O:83])[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH:68]=1)(=O)C1C=CC=CC=1>>[C:76]([N:69]1[C:70]2[C:75](=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:67]([CH2:66][C:43]2([OH:42])[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([CH3:52])[CH:50]=3)[N:45]([CH2:53][CH2:54][CH3:55])[C:44]2=[O:56])=[CH:68]1)(=[O:83])[C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: O=C(OCc1cn(C(=O)c2ccccc2)c2ccccc12)c1ccccc1
Agent: CCCN1C(=O)C(Cc2c[nH]c3ccccc23)(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Product: CCCN1C(=O)C(O)(Cc2cn(C(=O)c3ccccc3)c3ccccc23)c2cc(C)ccc21

Procedure:
This compound was made in a method analogous to 3-((1H-indol-3-yl)methyl)-5-chloro-2-oxo-1-propylindolin-3-yl benzoate using 5-methyl-2-oxo-1-propylindolin-3-yl benzoate and (1-benzoyl-1H-indol-3-yl)methyl benzoate. 1H-NMR δ 8.33 (d, 1H), 7.53 (m, 2H), 7.45-7.39 (m, 4H), 7.31 (dd, 1H), 7.29 (m, 1H), 7.17 (s, 1H), 7.08 (d, 1H), 6.59 (m, 2H), 3.53 (m, 1H), 3.40 (d, 1H), 3.29 (d, 1H), 3.20 (m, 1H), 2.77 (s, OH), 2.30 (s, 3H), 1.15 (m, 2H), 0.56 (t, 3H). Calculated mass for C28H26N2O3, 438.19. Observed 461.2 (M+Na).
Reaction SMILES: [Ca].[C:2]1([C@H:12]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)[CH2:16]2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(Cl)(Cl)[Cl:41]>>[ClH:41].[C:2]1([C@H:12]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:31][CH:32]=3)[CH2:16]2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)OC(C)(C)C)cc2)C1)c1cccc2ccccc12
Reactant: ClC(Cl)Cl
Agent: [Ca]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In the same manner as in the above-mentioned Example 1.001, tert-butyl 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl] benzoate (the compound of Example 1.020 in the following Table A2) was obtained. (2) To a solution of 103 mg of tert-butyl 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoate in 5 ml of a chloroform was added 20 ml of trifluoroacetic acid, and the mixture was stirred under room temperature for 16 hours. The reaction mixture was concentrated, toluene was added to the residue and the mixture was evaporated again. The residue was dissolved in 10 ml of chloroform, 20 ml of a solution of 4M hydrochloric acid in dioxane was added and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and after collecting the precipitates by filtration, it was washed with diethyl ether and dried to obtain 89.2 mg of 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride (Example 3.001 in the following Table A3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5]2.C([O-])(O)=O.[Na+].[I:26]Cl>C(Cl)Cl.CO>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:26])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:5]2
Reactant: Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc2c(cc1I)CN(C(=O)OCc1ccccc1)C2
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate (560 mg, 2.09 mmol) in a mixture of CH2Cl2 (10 mL) and MeOH (2.5 mL), was added NaHCO3 (263 mg, 3.13 mmol) followed by 1M ICl in CH2Cl2 (2.1 mL, 2.1 mmol). The mixture was stirred for 30 min and then quenched with sat. aq. NaHSO3. The resulting mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-amino-6-iodo-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=395.0; found=394.7 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.58-7.51 (2 s, 1H); 7.45-7.35 (m, 5H); 6.70-6.64 (2 s, 1H); 5.24 (s, 2H); 4.67 (s, 2H); 4.65 (s, 2H); 4.15 (br, s, 2H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9])[CH:2]([CH3:4])[CH3:3].C([CH:16]([C:20](Cl)=[O:21])[C:17](Cl)=[O:18])C.[CH2:23]([O:25]CC)[CH3:24]>>[CH2:23]([O:25][C:20]([C:16]1[C:17](=[O:18])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]2[C:7]([C:8]=1[NH2:9])=[CH:10][CH:11]=[CH:12][N:13]=2)=[O:21])[CH3:24]
Reactant: CC(C)CNc1ncccc1C#N
Reactant: CCOCC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Product: CCOC(=O)c1c(N)c2cccnc2n(CC(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 12.25 g (0.07 mole) of 2-isobutylaminonicotinonitrile in 300 ml. of anhydrous ethyl ether was added 5.2 g. (0.035 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 30 minutes and was filtered. The filtrate was evaporated in a rotary evaporator and the residue was dissolved in 20 ml. of ethanol. This solution was added to a solution of 1.6 g. of sodium in 150 ml. of ethanol. After stirring at room temperature for 5 minutes, the mixture was diluted with water and was acidified with conc. hydrochloric acid. The precipitate which formed was collected, air dried and was recrystallized from ethyl acetate to afford 2.1 g. of the title product, m.p. 157°-159° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH2:12]([C:19]1[C:20](=[O:28])[NH:21][C:22](SC)=[N:23][C:24]=1[CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][C:7]1[N:8]=[CH:9][NH:10][C:6]=1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:22]1[NH:21][C:20](=[O:28])[C:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:24]([CH3:25])[N:23]=1
Reactant: CSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Reactant: Cc1nc[nH]c1CSCCN
Product: Cc1nc[nH]c1CSCCNc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Yield: 65.9 %

Procedure:
An intimate mixture of 5-(2-aminoethyl)thiomethyl-4-methylimidazole (1.28 gms) and 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (1.84 gms) was heated at 150°-160° C. (oil-bath temperature) for 41/2 hours. The mixture was cooled, washed with water and recrystallised from isopropanol to give 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone (1.82 gms) m.p.=140°-141.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29]Br.CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29][N:9]([CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:11]
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1CNC(C)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)C(C)c1ccccn1

Procedure:
Using General Procedure A, reaction of (3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amine and 2-bromomethyl-5-cyano-benzoic acid methyl ester in CH3CN with DMAP, KI, and DIPEA gave 5-cyano-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzoic acid methyl ester as an amber oil. 1H NMR (CDCl3) δ 1.26 (t, 1H, J=7.3 Hz), 1.58 (d, 3H, J=6.7 Hz), 1.73 (s, 1H), 2.04 (s, 1H), 2.09 (s, 3H), 3.73-3.94 (m, 1H), 3.87 (s, 3H), 4.08-4.19 (m, 4H), 6.92-6.98 (m, 1H), 7.14-7.20 (m, 1H), 7.23 (d, 1H, J=8.0 Hz), 7.34 (d, 1H, J=7.8 Hz), 7.48-7.53 (m, 1H), 7.64-7.69 (m, 2H), 7.92 (d, 1H, J=1.6 Hz), 8.21 (d, 1H, J=3.0 Hz), 8.57 (d, 1H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH:12]1[C:19](=[O:20])[CH:18]2[CH:14]([CH2:15][CH:16]([CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:17]2)[C:13]1=[O:26])[CH3:2].Cl.[CH3:28][O:29][NH2:30].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH:12]1[C:13](=[O:26])[CH:14]2[CH:18]([CH2:17][CH:16]([CH2:21][CH2:22][C:23](=[N:30][O:29][CH3:28])[CH3:24])[CH2:15]2)[C:19]1=[O:20])[CH3:11]
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(CCCC=O)CC2C1=O
Reactant: CON
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(CCC(C)=NOC)CC2C1=O
Yield: 71.5 %

Procedure:
267 mg (0.82 mmol) of 2-(2,6-diethyl-4-methylphenyl)-5-(oxobutyl)-tetrahydropentalene-1,3-dione (example I-a-39), 102 mg (1.23 mmol) of O-methylhydroxylamine hydrochloride and 0.5 ml of triethylamine in 10 ml of acetonitrile are stirred at room temperature overnight. The mixture is then taken up in ethyl acetate, washed with water and dried (magnesium sulphate) and the solvent is distilled off Chromatography on silica gel (mobile phase ethyl acetate/hexane 1:4) gives 225 mg (77%) of the target compound in the form of colourless crystals of m.p. 79-80° C.
Reaction SMILES: C1C2C(COC([NH:18][CH:19]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:22]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:21]=3[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl.C(#N)C>[CH2:65]([O:64][C:21]1[C:22]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]=[CH:25][C:20]=1[CH:19]([NH2:18])[C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC2c3ccccc3-c3ccccc32)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Solvent: CC#N
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(N)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-2,3,4-tris(octadecyloxy)benzhydryl amine (3.37 g, 2.89 mmol) was dissolved in a mixed solvent of chloroform (30 mL) and acetonitrile (15 mL), 20% piperidine [1-methyl-2-pyrrolidone solution] (28.6 mL, 57.9 mmol) was added, and the mixture was stirred at room temperature for 30 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, methanol was added, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (2.80 g, 97.9%) as a white solid.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[C:8]1([C:14]2[C:18](=O)O[CH:16]([C:20]([F:23])([F:22])[F:21])[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:25](=C)C#N.C(=O)=O>O.C(#N)C>[C:8]1([C:14]2[NH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:25][C:18]=2[C:1]#[N:3])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(Cl)C#N
Reactant: CCN(CC)CC
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccccc1
Agent: O=C=O
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
Triethylamine (4.5 g, 0.044 mol) is added dropwise to a mixture of 4-phenyl-2-(trifluoromethyl)-5(2H)-oxazolone (10.0 g, 0.043 mol), 2-chloroacrylonitrile (3.51 g, 0.43 mol) and acetonitrile (50 mL). The temperature of the reaction mixture rises to 65° C. and carbon dioxide gas evolves during the addition. After the addition is complete the reaction mixture is heated at reflux temperature for one hour, cooled to room temperature and poured into water (150 mL). The solids are collected by filtration, air-dried and dried under vacuum at 60° C. to give the title compound as a white solid (10.05 g, 97%). Identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18]([O:20]C)=[O:19])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:7]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:7]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2cc(Cl)ccc2OCc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(NC(=O)c2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 90 °C

Procedure:
A mixture of methyl {3-[({5-chloro-2-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetate (may be prepared as described in Description 46, 160 mg, 0.39 mmol), 2M HCl (3 ml) and acetic acid (3 ml) was heated at 90° C. for 4 hours and then cooled to room temperature. Water was added and the mixture was filtered to give a white solid. The crude product was purified by MDAP to yield the title compound as a white solid. 53 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[H-].[Na+].I[CH3:19].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]([CH3:19])[C:7](=[O:12])[C:8]([F:10])([F:11])[F:9]
Reactant: O=C(NCc1cccc(F)c1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cccc(F)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 3-fluoro-N-(trifluoroacetyl)benzylamine (Intermediate 105, 0.508 g) in THF (5 mL) was added to a stirred suspension of sodium hydride (60% oil dispersion, 0.096 g) in THF (5 mL). The resultant mixture was stirred at room temperature for 30 minutes. Iodomethane (0.653 g) was added and the mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 3-fluoro-N-methyl-N-(trifluoroacetyl)benzylamine (0.497 g) as a white solid.