Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-:1].[Li+].Cl[SiH:4]1[N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[CH:6][N:5]1[C:13]([CH3:16])([CH3:15])[CH3:14].CCCCCC>COCCOC>[NH2:1][SiH:4]1[N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[CH:6][N:5]1[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: [NH2-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
In an argon atmosphere, 505 mg (purity: 95%, 20.9 mmol) of lithium amide was suspended in 20 mL of 1,2-dimethoxyethane and after adding 4.65 g (20.0 mmol) of Si(tBuNCHCHNtBu)(H)Cl, the mixture was stirred at room temperature for 2 hours. Subsequently, 20 mL of hexane was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 78° C./3.8×102 Pa) to obtain 2-amino-1,3-di-tert-butyl-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NH2) as a pale yellow liquid (yielded amount: 3.93 g, yield: 92%).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19]CC)=[O:18].[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][C:24]=2[O:23]1>C1COCC1>[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:3]3[C:17]([OH:19])=[O:18])=[CH:25][C:24]=2[O:23]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Reactant: Br[Mg]c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6 mmol) in THF (35 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3,4-methylenedioxyphenyl magnesium bromide (5.4 mmol). After stirring for 30 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/ hexanes to afford the title compound (1.03 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([F:9])[C:3]=1[F:10].[P:11]([O-:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C1(CNCC2CCCCC2)CCCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:5]=[C:4]([F:9])[C:3]=1[F:10]
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: CCOP([O-])OCC
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(OCC)c1cc(F)c(F)c(F)c1
Temperature: 76 °C
Reaction time: 0.08 h

Procedure:
Trifluorobromobenzene (1.70 mL, 14.2 mmol), diethyl phosphite (2.20 mL, 17.1 mmol), N,N-dicyclohexylmethylamine (4.60 mL, 21.3 mmol) and ethanol (50 mL) were all combined in a nitrogen purged round bottom flask. After stirring for 5 minutes, triphenylphosphine (223 mg, 0.85 mmol) and palladium acetate (64 mg, 0.28 mmol) were added to the flask as one. The solution was heated to 76° C. and allowed to stir overnight. The solution started as a translucent brown color but was clearer by morning. Upon cooling, a silica plug (starting with hexanes as eluent, and increasing the polarity with ethyl acetate as needed) was run and a UV-active spot (Rf=0.35 in 1:1 hexanes:ethyl acetate) was isolated. The final product is a clear oil (3.477 g, 91% yield). 1H NMR (400.14 MHz, CDCl3) δ 7.44 (dt, J=14.4, 6.50 Hz 2H), 4.19-4.07 (m, 4H), 1.34 (t, J=7.07 Hz, 6H). 13C {1H} NMR (100.62 MHz, CDCl3) δ 151.1 (dddd, J=254.7, 25.4, 10.1, 2.9 Hz, 2C), 142.5 (dtd, J=258.6, 15.1, 3.3 Hz), 125.0 (dtd, J=194.5, 5.8, 5.2 Hz), 116.3-116 (m, 2C), 62.72 (d, J=5.63 Hz, 2C), 16.16 (d, J=6.34 Hz, 2C). 31P {1H} NMR (161.97 MHz, CDCl3): δ 14.94. Analysis calculated (found) %: C 44.79 (44.51), H 4.51(4.65). MS (FAB, m/z): 283 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 283.07109 (283.07135).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=[C:4]([NH:14][CH:15]=[O:16])[CH:3]=1.[Se](=O)=[O:18]>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=[C:4]([NH:14][CH:15]=[O:16])[CH:3]=1
Reactant: CCOC(=O)Cc1nc(Cl)cc(NC=O)n1
Reactant: O=[Se]=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1nc(Cl)cc(NC=O)n1
Yield: 69 %

Procedure:
A mixture of ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate (24.3 g) and selenium dioxide (16.65 g) in N,N-dimethylformamide (243 ml) was stirred for an hour at 70° to 75° C. The precipitated solid was filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (500 ml), washed with water and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diisopropyl ether to give a powder of ethyl 6-chloro-4-formamidopyrimidin-2-ylglyoxylate (17.74 g).
Reaction SMILES: [C:1]([N:4]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:18]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2].O.[OH-].[Li+]>CO>[C:1]([N:4]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:18]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)on1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(OCC(=O)O)no2)c2ccccc21
Yield: 60 %

Procedure:
Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was prepared following the procedure for N-(4-chlorophenyl)-N-{(2S,4R)-1-[(1-isopropyl-1H-pyrazol-4-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide substituting ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate for 1-isopropyl-1H-pyrazole-4-carbonyl chloride. (Ethyl {[15-chlorocarbonyl)isoxazol-3-yl]oxy}acetate was prepared in 4 steps from methyl 3-hydroxy 5-isoxazole carboxylate. Methyl 3-hydroxy 5-isoxazole carboxylate (1.00 g, 6.95 mmol) was alkylated using ethyl bromoacetate (0.850 mL, 7.64 mmol) in presence of potassium carbonate (1.05 g, 7.64 mmol) and catalytic potassium iodide in DMF (3.00 mL) at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate (60%). (Ref: WO 03/063800 PCT/US03/03224). Methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate was further treated with aqueous 5% sodium hydroxide in methanol to yield 3-(carboxymethoxy)isoxazole-5-carboxylic acid (86%). This diacid (0.700 g, 3.76 mmol) was selectively esterified in the presence of catalytic p-toluenesulfonic acid monohydrate (100 mg) in ethanol at room temperature. Water was added to the reaction and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid (90%). 3-(2-Ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid was treated with oxalyl chloride and catalytic DMF in dichloromethane to yield the desired ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate). Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was treated with a solution of lithium hydroxide monohydrate (aq) in methanol at room temperature overnight to afford [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NCC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C1CC(=O)N(c2ccc(CNC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 30 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-chlorobenzoyl chloride (14 μL, 0.114 mmol), the title compound (13 mg, yield 30%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=[O:19])[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12](Cl)=[O:13]>CCO>[OH:1][C:2]1[C:7]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:19])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: Oc1ccccc1O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2c1ccc(O)c2O
Yield: 55 %

Procedure:
The method was similar to Example 1, using 11.0 g (0.1 mol) of 1,2-dihydroxybenzene and 20.2 g (0.1 mol) of phthalic acid dichloride. The product was 13.2 g (55% yield) of 1,2-dihydroxy-9,10-anthraquinone (8), m.p.=288°-289° C. (literature 288°-289° C. EtOH).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29]>CCO>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([NH:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:34])[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CNc1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 45.6 %

Procedure:
To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) in EtOH (8 mL) was added glycine ethyl ester hydrochloride (46 mg, 0.44 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 3 d. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl N-(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)glycinate (43 mg, 46%): LCMS RT: 2.16 min, MH+: 429.3.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[N:34]=[C:35]=[O:36]>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[NH:34][C:35]([NH:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4])=[O:36]
Reactant: COC(=O)C(N)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 36 %

Procedure:
To 0.62 g of methyl 2-amino-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 33 in CH2Cl2 (10 ml) are added 0.343 g of 2,6-dichlorophenyl isocyanate. The solution is stirred at RT and reduced to the half by evaporation. The solid residue is filtered and washed with CH2Cl2 and hexane to give a white powder that is recrystallised in hot CH3CN. The compound is purified over silica gel using CH2Cl2/CH3OH 99.5/0.5 as eluent. The obtained white powder is once more washed with CH3CN to give methyl 2-{[(2,6-dichloroanilino)carbonyl]amino}-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 52.
Reaction SMILES: N[C@H](C(O)=O)CCC(=O)N.P([O-])([O-])([O-])=O.Cl.NO.[NH2:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24]>>[NH2:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: NO
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Glutaminase activity was measured by partly modifying the method described in Japanese Provisional Patent Publication No. 332553/1999. That is, to 250 μl of 2% (w/v) L-glutamine solution were added 500 μl of 0.2M phosphate buffer (pH 6.5) and 250 μl of an enzyme solution, and the mixture was reacted at 37° C. for 30 minutes, and then the reaction was terminated by adding 250 μl of 0.75N perchloric acid solution, and 125 μl of 1.5N sodium hydroxide solution was added thereto to neutralize the reaction mixture. The above reaction mixture was then centrifuged (10,000 rpm, 10 minutes). To 100 μl of the resultant supernatant were added 1.0 ml of 0.1M hydrochloric acid-hydroxylamine buffer (pH 8.0), 1.0 ml of 20 mMNAD+ solution (manufactured by Oriental Yeast Co.), and 50 μl of 500 U/ml L-glutamate dehydrogenase solution, and the mixture was reacted at 37° C., for 30 minutes and the absorbance at 340 nm was measured with a spectrophotometer. An amount of the enzyme forming 1 μmol of glutamic acid per one minute under the above conditions is determined as 1 unit (U).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 460 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O.CNCCNC>CN(C=O)C.[Cu]I>[N:11]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: c1ncn(-c2ccc3[nH]ccc3c2)n1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
To a stirred solution of 5-iodo-1H-indole (2.0 g, 8.2 mmol), 1H-1,2,4-triazole (0.511 g, 7.4 mmol), CuI (0.15 g, 0.82 mmol), K2CO3 (2.27 g, 16.46 mmol) and L-proline (0.511 g, 7.4 mmol) in DMF (20 mL), N,N′-dimethylethylenediamine (2.375 g 16.46 mmol) was added and stirred at 120° C. for 2-3 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was separated, concentrated in vacuo and the residue was purified by flash column chromatography to give 5-(1H-1,2,4-triazol-1-yl)-1H-indole (0.790 g, 52%); MS: 185 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]([CH:11]([CH3:14])[CH2:12][NH2:13])=[CH:9][CH:10]=2)=[CH:2]1.[S:15](C[N+]#[C-])([C:18]1[CH:24]=CC(C)=C[CH:19]=1)(=[O:17])=[O:16].CC(C)([O-])C.[K+].O>COCCOC.C(O)(C)(C)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]([CH:11]([CH3:14])[CH2:12][NH:13][S:15]([CH:18]([CH3:24])[CH3:19])(=[O:17])=[O:16])=[CH:9][CH:10]=2)=[CH:2]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(CN)c1ccc(-c2ccsc2)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccsc2)s1
Temperature: -5 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
2-[2-(thien-3-yl)-5-thienyl]propylamine To a −15° C. solution of 1.1 g (5.3 mmol) of the material prepared in step A and 1.05 g (5.35 mmol) of tosylmethyl isocyanide in 18 ml of DME, a hot solution of 1.07 g (9.54 mmol) of potassium tert-butoxide in 5 ml of tert-butanol was added slowly. The mixture was stirred at −5° C. for 45 min and 2 h at ambient temperature. Water was added and extracted three times with diethyl ether. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was dissolved in 15 ml of diethyl ether and then was added to a suspension of 218 mg (5.75) of lithium aluminum hydride in 5 ml of diethyl ether. The mixture was stirred at ambient temperature for 2 h. Na2SO410H2O was added, and the mixture stirred for 30 min at ambient temperature. The solid was filtered and the organic solution was concentrated in vacuo. Chromatography (150 g of silica gel, ethyl acetate/hexane/methanol 10/10/1) of the residue afforded 250 mg (22%) of the title compound.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:20][C:3]=1[CH:4]([OH:19])C1C=CC=C(NC(OC(C)(C)C)=O)C=1.C(OC1C=CC(C=O)=CC=1)C1C=CC=CC=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[C:28]1([CH2:27][CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][CH:2]=[C:3]([CH:20]=2)[CH2:4][OH:19])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(O)c2cc(OCCCc3ccccc3)ccc2N)c1
Agent: N#C[Na]
Agent: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: OCc1cccc(OCCCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In methanol (12 ml) were dissolved 2-amino-α-(3-tert-butoxycarbonylaminophenyl)-5-(3-phenylpropyloxy)benzyl alcohol (0.7 g), 4-benzyloxybenzaldehyde (0.38 g) and acetic acid (0.1 g). To the solution was added cyano sodium borohydride (0.11 g). The mixture was stirred for 30 minutes at 60° C. The reaction mixture was concentrated, to which were added ethyl acetate (50 ml) and water (100 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 2-(4-benzyloxybenzyl)-α-3-tert-butoxycarbonylaminomethylphenyl)-5-(3-phenylpropyloxy)benzyl alcohol as a yellow oily product (0.95 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)([CH3:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:2]1.C([Li])CCC.CCCCCC.O1CCCC1.O1CCCC1.O1CCCC1.[Cl-:48].[Cl-].[Cl-].[Cr+3:51]>O1CCCC1>[Cl-:48].[Cl-:48].[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]([Cr+2:51])[CH:2]=1)([CH3:15])[CH2:11][CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCC(C)(C1=CCc2ccccc21)c1ccccn1
Reactant: [Cr+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCCC(C)(C1=CC([Cr+2])c2ccccc21)c1ccccn1
Temperature: -100 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of 4.81 8 (0.01747 mol) of 2-[1-(1H-inden-3-yl)-1-methyl-4-pentenyl]pyridine in 60 ml of tetrahydrofuran was cooled to −100° C. 11.5 ml of a 15% strength n-butyllithium solution in hexane (0.01834 mol) were slowly added dropwise. After the addition was complete, the reaction mixture was stirred at −100° C. for a further 1 hour. The mixture was subsequently allowed to warm to room temperature. After stirring for a further 2 hour, the solution was cooled to 60° C. and 7.07 g (0.0189 mol) of chromium trichloride tris(tetrahydrofuran) were added while stirring. The mixture was allowed to warm slowly to room temperature and was subsequently stirred at room temperature for a further 10 hours. The solid which had precipitated was filtered off, washed with diethyl ether and dried under reduced pressure. Recrystallization from a mixture of dichloromethane and diethyle ether gave 2.5 g of (3-(2-pyridyl-1-methyl-4-pentenyl)indenyl)chromium dichloride (36%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[NH:7][C:8](=[O:11])[NH:9][CH:10]=1.[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>ClCCl>[CH3:5][C:6]1[NH:7][C:8](=[O:11])[NH:9][C:10]=1[C:19](=[O:20])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1[nH]c(=O)[nH]c1C(=O)Cc1ccccc1

Procedure:
To 26.6 g (0.2 mole) of aluminum chloride in 250 ml of dichloromethane is added 9.8 g (0.1 mole) of 1,3-dihydro-4-methyl-2H-imidazol-2-one and, dropwise, 16.9 g (0.11 mole) of phenylacetyl chloride. The mixture is stirred and heated to reflux for 5 hours. The mixture is cooled and 200 ml of 2 N-hydrochloric acid is added dropwise. The resulting precipitate is collected, washed with water, and recrystallized from 50% aqueous ethanol to give the title compound, m.p. 239°-240° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Cl.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6.1 mmol of 2-(4-((6-fluoro-2-quinoxalinyl)oxy)phenoxy)propionyl chloride in 15 ml of methylene chloride was added dropwise to an ice-cooled solution of 1.43 g (6.7 mmol) of 4-(trifluoromethoxy)aniline hydrochloride and 1.54 g (15 mmol) of triethylamine in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 3 hours and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was taken up in boiling methanol, treated with charcoal and filtered through celite. The filtrate was allowed to cool to give 1.14 g (38 percent of theoretical) of the above-named product as colorless crystals which melted at 140.5°-142° C. The structure of the compound was confirmed by its IR and NMR spectrum. (Compound 8)