Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[CH:6]=[N:7][N:8]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[C:9]=2[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a solution of 6-bromo-1H-indazole-4-carbonitrile (5 g, 22.52 mmol) in N,N-dimethylformamide (50 ml) was added, in portions, sodium hydride (1.351 g, 33.8 mmol) and the mixture stirred at 20° C. for 15 mins then cooled to 0° C. when benzenesulfonyl chloride (3.16 ml, 24.77 mmol) was added dropwise. The mixture was stirred at 20° C. for 18 h then concentrated in vacuo and the residue partitioned between water (100 ml) and dichloromethane (100 ml). The organic layer was separated by hydrophobic frit and evaporated in vacuo to give the title compound as a yellow solid (7.94 g).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:13])[C:3]=1[F:14].[N+](=[CH2:17])=[N-]>CO>[CH3:17][O:7][C:6](=[O:8])[C:5]1[C:4]([F:13])=[C:3]([F:14])[C:2]([Br:1])=[C:10]([F:11])[C:9]=1[F:12]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1c(F)c(F)c(Br)c(F)c1F
Solvent: CO
Product: COC(=O)c1c(F)c(F)c(Br)c(F)c1F
Yield: 85 %

Procedure:
To a solution of 4-bromo-2,3,5,6-tetrafluoro-benzoic acid (20 g, 73.49 mmol) in methanol (20 mL) was added an ethereal solution of diazomethane gas until the starting material is completely consumed. Reaction mixture was then evaporated under reduced pressure. The crude solid obtained was purified by flash column chromatography using 5% ethyl acetate in hexane, to obtain title compound as colorless crystalline solid (18 g, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[NH:13][C:12]3=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([CH3:24])[C:12]3=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: O=C1NC(=O)c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2C1=O
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp. overnight, then was cooled to ° C. and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Rf0.61.
Reaction SMILES: [NH2:1][C:2]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]1[S:17][CH:16]=[C:15]([NH:18]C(=O)OC(C)(C)C)[CH:14]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:18][C:15]1[CH:14]=[C:13]([C:5]2[N:4]([C:2]([NH2:1])=[O:3])[C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1csc(-c2cc3ccccc3n2C(N)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)n1c(-c2cc(N)cs2)cc2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To the mixture of tert-butyl {5-[1-(aminocarbonyl)-1H-indol-2-yl]-3-thienyl}carbamate (20 mg, 0.056 mmol, 1 eq) in anhydrous DCM (1 mL) at 0° C. was added dropwise trifluoroacetic acid (0.2 mL) and the resulting reaction solution was stirred at 0° C. for 45 minutes. An additional trifluoroacetic acid (0.2 mL) was added followed by a stirring at room temperature for 15 minutes. The solution was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was isolated, washed once with brine, and dried with anhydrous sodium sulfate. The Upper solution was decanted, concentrated, and the brown oily residue was subject to a column chromatography (EtOAc-Hex 1:10 to 3:1) to yield 2-(4-amino-2-thienyl)-1H-indole-1-carboxamide as a yellow oil in amount of 11 mg.
Reaction SMILES: [N:1]([C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[O:7][C:6]([CH3:19])([C:15]([F:18])([F:17])[F:16])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[Br:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][C:6]([CH3:19])([C:15]([F:16])([F:18])[F:17])[CH2:5][C@@H:4]2[NH2:1]
Reactant: CC1(C(F)(F)F)C[C@H](N=[N+]=[N-])c2cc(Br)ccc2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC1(C(F)(F)F)C[C@H](N)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (4S)-4-azido-6-bromo-2-methyl-2-(trifluoromethyl)chroman (190 mg, 565 μmol) was added triphenylphosphine (222 mg, 848 μmol). The mixture was stirred at RT for 4 h. Water (15 ml) was added and the reaction was heated at refluxing for 24 h. The resulted mixture was concentrated to dryness and extracted with CHCl3. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated and dried in vacuum to afford the title compound. MS m/z: 293, 295(M−NH2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:32][C:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[NH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:38]3[CH:37]=[C:36]4[C:41]([C:33]([CH3:32])=[N:34][NH:35]4)=[CH:40][CH:39]=3)[C:3]=12
Reactant: Cc1n[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1n[nH]c2cc(-c3nn(C(C)c4oc5ccccc5c(=O)c4-c4cccc(F)c4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 23.6 %

Procedure:
To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), 3-Methylindazole-6-boronic acid pinacol ester 97 (0.391 g, 1.517 mmoles) and sodium carbonate (0.401 g, 3.79 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.172 g, 0.149 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as yellow solid (0.095 g, 23% yield). MP: 214-217° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.75(s,1H), 8.08(s,1H), 8.05(dd, J=7.9,1.4 Hz, 1H), 7.86(m,2H), 7.68(d, J=8.3 Hz, 1H), 7.62(s,1H), 7.53(t, J=7.3 Hz, 1H), 7.33(d, J=8.5 Hz, 1H), 7.31(br s, 1H), 7.07(dt, J=8.9,2.1 Hz, 1H), 6.93(m, 2H), 6.07(q, J=6.7 Hz, 1H), 2.51(s,3H), 1.91(d, J=7.0 Hz, 3H). Mass: 532.03(M++1).
Reaction SMILES: [H-].[Na+].O1CCCC1.[NH2:8][C:9]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:11]([O:13]CC)=O.[N:20]([C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH:30]([CH3:32])[C:29](=[O:33])[N:28]([CH2:34][C:35]#[CH:36])[C:27]=2[CH:37]=1)=[C:21]=[O:22]>C(O)(=O)C>[CH3:32][CH:30]1[C:29](=[O:33])[N:28]([C:34]#[C:35][CH3:36])[C:27]2[CH:37]=[C:23]([N:20]3[C:11](=[O:13])[CH:10]=[C:9]([C:16]([F:17])([F:18])[F:19])[NH:8][C:21]3=[O:22])[CH:24]=[CH:25][C:26]=2[O:31]1
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: C#CCN1C(=O)C(C)Oc2ccc(N=C=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC#CN1C(=O)C(C)Oc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A slurry of 1.4 g. of sodium hydride in 25 ml. of dry tetrahydrofuran (THF) was cooled to -10° C. To the cooled and stirred slurry was added a solution of 10.0 g. of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 50 ml. of THF. The addition of this solution was made over a period of 30 minutes. The resultant light brown reaction mixture was cooled to -70° C. A solution of 13.3 g. of 6-isocyanato-2- methyl-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine in 75 ml. of THF was added to the chilled reaction mixture over a period of 10 minutes. After stirring at -70° C. for 30 minutes, the temperature was allowed to rise slowly to 10° C. At that point 3.6 ml. of acetic acid was added to the mixture. A beige solid precipitated. 19.0 Grams of the solid was recovered by filtering it from the reaction mixture.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=CC(OC)=CC=1>>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COc1ccc(Br)cc1
Product: COc1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)cc1
Yield: 84 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(4-methoxyphenyl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (67 mg, 0.101 mmol) and 1-bromo-4-methoxybenzene following General Procedure B. Flash chromatography (5% EtOAc/hexanes) yielded the title compound as a clear oil (41 mg, 84%): 1H NMR (CDCl3, 500 MHz) δ 7.66 (d, 2H, J=9.0 Hz), 7.37-7.34 (m, 3H), 7.27-7.23 (m, 3H), 7.03 (d, 2H, J=9.0 Hz), 4.91 (t, 1H, J=5.5 Hz), 3.93 (s, 3H), 2.68 (t, 2H, J=7.5 Hz), 2.06-1.96 (m, 2H), 1.71-1.68 (m, 2H), 1.46-1.42 (m, 6H), 0.98 (s, 9H), 0.19 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 164.6, 160.2, 151.6, 143.2, 128.8, 128.7, 126.1, 126.0, 121.3, 120.3, 114.8, 69.1, 55.8, 36.8, 36.3, 31.9, 29.6, 26.2, 26.2, 25.6, 18.7, −4.5, −4.7.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([NH2:8])[CH:4]=1)[CH3:2].Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:16][C:14]1[CH:15]=[C:10]([NH:8][C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[O:7][N:6]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CCc1cc(N)no1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1cc(Nc2cc(Br)cn(C)c2=O)no1
Temperature: 100 °C
Yield: 45.1 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirred and a reflux condenser was charged with 5-ethylisoxazol-3-amine (250 mg, 2.23 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (893 mg, 3.35 mmol), Pd2(dba)3 (102 mg, 0.112 mmol), Xantphos (129 mg, 0.223 mmol), Cs2CO3 (1.45 g, 4.46 mmol), and dioxane (20 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 158a (300 mg, 45%) as a white solid. MS-ESI: [M+H]+ 297.8
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[S:16][C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(-c2ccc(NC(=O)OC(C)(C)C)nc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(NC(=O)OC(C)(C)C)nc2)sc1C(=O)O
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixture of ethyl 2-(2-tert-butoxycarbonylamino-5-pyridyl)-4-methyl-5-thiazolecarboxylate (180 mg), 1N NaOH (2 ml) and EtOH-THF (2:1, 6 ml) was stirred at 70° C. for 1 hour, to which was added 1 N HCl (2 ml) to give the title compound (151 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:28]([OH:30])=O)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[NH:54][C:55](=[O:62])[C:56](=[CH:60][CH:61]=2)[C:57]([OH:59])=[O:58])=[CH:49][CH:48]=1.C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:28]([NH:46][C:47]1[CH:48]=[CH:49][C:50]([C:53]2[NH:54][C:55](=[O:62])[C:56](=[CH:60][CH:61]=2)[C:57]([OH:59])=[O:58])=[CH:51][CH:52]=1)=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1)OCc1ccccc1
Reaction time: 0.67 h
Yield: 75.7 %

Procedure:
A solution of 29.0 g (70 mmol) of N,N'-bis(benzyloxycarbonyl)-L-lysine [Helv. Chem. Acta, 41, 1778 (1958)] in 200 ml of dichloromethane is stirred at -10° and 7.2 g (70 mmol) of N-methylmorpholine is added. The temperature is lowered to -14° and 9.55 g (70 mmol) of isobutyl chloroformate is added dropwise over a period of 10 min and stirring is continued at -14° to -11° for 40 min. A suspension of 8.0 g (35 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 10.5 g (35 mmol) of triethylamine and 200 ml of dichloromethane is stirred at 5° and 12.0 g (35 mmol) of chlorotrimethylsilane is added. After 1 hr at room temperature this solution is added over a period of 30 min at -12° to -14° to the mixed anhydride formed above. After 3 hrs at 0°, the solution is allowed to stir overnight at room temperature. The reaction mixture is filtered and the filtrate is stirred with 15 ml of isopropanol for 30 min. The resulting yellow precipitate is filtered, washed, and dried to give 16.6 g of 6-[4-(N,N'-bis(benzyloxycarbonyl)-L-lysylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp 199°-200°, [α]D23 +24.2° (cl, DMSO).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2].[C:38](OC(=O)C)(=[O:40])C.C([O-])=O.[Na+]>C(O)=O.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[CH:38]=[O:40])[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(C=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.4 %

Procedure:
A solution of cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 3E) (2.0 g, 3.65 mmol) in 20 mL of formic acid was treated with acetic anhydride (11.29 g, 111 mmol) and sodium formate (1.25 g, 18.5 mmol). After stirring for 24 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent to afford 1.8 g of the title product. MS m/z 571.2 (M+ +1); 1H NMR (~5:1 mixture of formamide rotamers, CDCl3) δ 0.75 (t, 3H), 1.28 (t, 3H), 1.42 (m, 1H), 1.6-1.75 (M, 2H), 2.3 (bm, 1H), 4.15-4.3 (m, 2H), 4.3-4.4 (m, 1H), 4.5-4.7 (bm, 1H), 4.8-5.8 (bm, 2H), 7.14 and 7.08 (s, 1H), 7.5-7.6 (m, 2H), 7.74 (s, 2H), 7.80 and 7.86 (s, 1H), 8.47 and 8.62 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[N:22][CH:23]=1)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[N:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(NC(C)=O)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, N-(5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:40]([C:39]3[CH:43]=[CH:44][C:36]([Cl:35])=[CH:37][CH:38]=3)=[O:41])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)c1ccc(Cl)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 4-chlorobenzoyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H36N2O3Cl3 [(M+H)+] 633.1837, observed 633.1838.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH2:35]([N:37](CC)CC)C.C(Br)#N.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:30]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]1[CH:33]=[CH:34][C:16]([CH2:15][N:7]([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:8][C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[CH:17][CH:18]=1)[C:35]#[N:37])[CH2:31][CH3:32]
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: CCN(CC)CC
Agent: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(CCC)CCCCN(C#N)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (13.4 mg) obtained in Example 52-3 was dissolved in THF (0.26 ml) and added with triethylamine (10 μl) and bromocyan (3.65 mg) and the whole was stirred at room temperature for 2 hours under a nitrogen atmosphere. After completion of the reaction, the solution was added with a saturated aqueous sodium hydrogen carbonate solution to neutralize the solution and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with tartaric acid, thereby obtaining a tartrate (12.5 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[C:13]([OH:17])(=[O:16])[CH2:14][CH3:15].BrCC#CC>CCCCCC.CN(C)P(=O)(N(C)C)N(C)C.C1COCC1>[CH3:15][CH:14]([CH2:1][C:2]#[C:3][CH3:4])[C:13]([OH:17])=[O:16]
Reactant: CCC(=O)O
Reactant: [Li]CCCC
Agent: CC#CCBr
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC#CCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
At 20° C., 130 ml. of an approximately 1.3-molar butyllithium solution in hexane is added dropwise to a solution of 27.1 g. of diisopropylamine in 130 ml. of THF. At -20° to 0°, 6.6 ml. of propionic acid and 18 ml. of hexamethylphosphoric triamide are added dropwise to this mixture, and the latter is stirred for 35 minutes at room temperature, and then at 0° 11.6 g. of 1-bromo-2-butyne is added dropwise thereto. The mixture is then stirred for 2 hours at room temperature. Then, the reaction mixture is stirred into 300 ml. of 10% hydrochloric acid, extracted three times with a mixture of pentane/ether (1+1), the organic extract is washed neutral with water, dried with magnesium sulfate, and the solvent is removed by distillation. After distilling the remainder in a bulb tube at 12 torr and 114°, 7.8 g. of 2-methyl-4-hexynoic acid is obtained as a colorless liquid.
Reaction SMILES: [CH:1]1([N:6]([C:8]([C:10]2[CH:14]=[C:13]([CH3:15])[O:12][C:11]=2[CH3:16])=[O:9])[OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.S(OC)(O[CH3:24])(=O)=O>ClCCl>[CH3:24][O:7][N:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:8]([C:10]1[CH:14]=[C:13]([CH3:15])[O:12][C:11]=1[CH3:16])=[O:9]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(C(=O)N(O)C2CCCC2)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CON(C(=O)c1cc(C)oc1C)C1CCCC1
Reaction time: 1 h

Procedure:
14.3 Parts of N-cyclopentyl-2,5-dimethylfuran-3-hydroxamic acid is dissolved in 100 parts of dichloromethane; to this solution there is added a solution of 7.7 parts of sodium hydroxide in 50 parts of water. 16.1 parts of dimethyl sulfate is then dripped into this mixture. After stirring the mixture for 1 hour, the dichloromethane phase is separated, washed with water until neutral, dried over anhydrous sodium sulfate and evaporated. There is obtained 12.1 parts of O-methyl-N-cyclopentyl-2,5-dimethylfuran-3-hydroxamic acid having a boiling point at 0.1 mm Hg of from 103° to 105° C and the refractive index ND25 : 1.5060. ##SPC10##