Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(Cl)(Cl)=O.[CH3:21]O>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH3:21])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CO
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of 4-methyl-3,5-dinitro-benzoic acid (3) (35.1 g, 155 mmol) in anhydrous methanol (250 mL) is slowly added thionyl chloride (4 mL, 54 mmol). The resulting solution is heated to reflux for 16 hours. The solution is cooled to room temperature and then further cooled in an ice-water bath. The solid that forms is filtered and dried to give 4-methyl-3,5-dinitro-benzoic acid, methyl ester (32) (33.5 g, 139.5 mmol, 90% yield), as a white crystalline solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:35]=[O:36]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH:35]=[O:36])[N:7]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C=O)n3)c2)cc1

Procedure:
A solution of 6-bromo-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine (15.1 mmol) in 100 mL of dry THF is added dropwise to a solution of n-butyl lithium (15.5 mmol) in 20 mL of tetrahydrofuran (THF) at -78° C. under H2 over 12 minutes. After 10 minutes the reaction mixture is treated with dimethylformamide (7.5 mL) in THF (15 mL), and quenched after 15 minutes with aqueous 10% HCl. The product is extracted into cold chloroform which is washed with saturated sodium chloride solution, filtered, and the solvent is evaporated. The residue is triturated with CH3CN, filtered, and recrystallized from ethyl acetate to provide the desired compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12]3)([OH:8])[CH2:4][CH2:3]1.[ClH:37]>CO>[ClH:37].[ClH:37].[CH2:14]1[C:15]2[C:11](=[CH:10][C:9]([C:5]3([OH:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:17][CH:16]=2)[CH2:12][NH:13]1
Reactant: CN1CCC(O)(c2ccc3c(c2)CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C3)CC1
Agent: Cl
Solvent: CO
Product: CN1CCC(O)(c2ccc3c(c2)CNC3)CC1

Procedure:
A mixture of 1-methyl-4-(2-trityl-2,3-dihydro-1H-isoindol-5-yl)-piperidin-4-ol (1.42 g, 3.0 mmol), 5N hydrochloric acid (5 mL) and methanol (10 mL) was placed under nitrogen then heated to reflux for 80 minutes. After cooling, the mixture was concentrated in vacuo to remove methanol, diluted with water and washed with ethyl acetate (×2). The aqueous phase was concentrated to dryness to afford the title compound in quantitative yield as a black solid. 1H NMR (MeOH-d4) 7.62 (1H, s), 7.57 (1H, d), 7.45 (1H, d), 4.64 (2H, s), 4.63 (2H, s), 3.49-3.46 (4H, m), 2.95 (3H, s), 2.40-2.32 (2H, m), 1.97 (2H, dd).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH:30](=[O:33])[CH2:31][CH3:32].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:30]([OH:33])[CH2:31][CH3:32])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: CCC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(O)CC)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 20 g (70.6 mmol) dibenzylamino-acetic acid ethyl ester in 240 ml tetrahydrofuran was stirred at −78° C. with 38.8 ml (77.6 mmol) lithium diisopropylamide (2M in heptane) for 30 minutes. 5.83 ml (77.6 mmol) Propionaldehyde in 5 ml tetrahydrofurane were added and stirring was continued overnight. The mixture was allowed to warm to room temprature, water was added and most of the organic solvent was removed by distillation. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1/5 yielded as first eluting fraction 6.85 g (28%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester, MS m/e (%): 342.3 (M+H+, 100) and as second eluting fraction 6.15 g (26%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester, MS m/e (%): 342.2 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:29][C:30]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:5]3[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]5[NH:14][CH:15]=[CH:16][C:9]=45)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[CH:18][CH:19]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCC1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)NC3CCCC3)cc2)n1

Procedure:
Following the procedure described in Example 47a with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and cyclopentyl isocyanate provided the title compound. ESMS [M+H]+: 415.2
Reaction SMILES: [CH3:1][N:2]1[CH2:40][CH2:39][CH2:38][C@@:3]1([CH3:41])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:16]([O:32][CH3:33])[CH2:17][C:18](=[O:31])OC1C(F)=C(F)C(F)=C(F)C=1F)[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].C(N(C(C)C)CC)(C)C.Cl.[CH3:52][O:53][C@@H:54]([C@@H:60]1[CH2:64][CH2:63][CH2:62][NH:61]1)[C@@H:55]([CH3:59])[C:56]([OH:58])=[O:57]>ClCCl>[CH3:1][N:2]1[CH2:40][CH2:39][CH2:38][C@@:3]1([CH3:41])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:16]([O:32][CH3:33])[CH2:17][C:18]([N:61]1[CH2:62][CH2:63][CH2:64][C@H:60]1[C@H:54]([O:53][CH3:52])[C@H:55]([C:56]([OH:58])=[O:57])[CH3:59])=[O:31])[CH3:14])=[O:12])[CH:8]([CH3:9])[CH3:10])=[O:5]
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
To a cooled solution (0° C.) of #204 (8.0 g, 10.77 mmol, 1 eq.) in dichloromethane (25 mL) was added dropwise diisopropylethylamine (5.6 g, 43.08 mmol, 4 eq.) followed by a solution of #103 (3.22 g, 10.77 mmol, 1 eq.) in dichloromethane (15 mL). After the addition, the mixture was stirred at room temperature for 16 hours and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (Gradient: 1 to 10% methanol in dichloromethane) to give #205 (2.2 g, 33%) as a yellow solid HPLC (Protocol X): m/z 597.42 [M+H+], retention time=8.729 minutes (purity >97%), Chiral HPLC retention time: 2.87 min (purity=89%) Column: Chiralcel OD-3, 150×4.6 mm, 3 μm; Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% over 12 minutes; Flow rate: 2.5 mL/minute.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc(F)cc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A mixture of 6.1 mmol 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)), 12.2 mmol 4-fluorobenzeneboronic acid, 18.4 mmol sodium carbonate and 0.3 mmol palladium (II) acetate in 30 ml water was stirred at room temperature for 48 hours. The mixture was filtered and the filtrate was acidified with HCl 37%. The mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with water and dried to provide the title compound (92%). Yellow solid. MS (m/e): 293.2 ([M−H], 100%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][C:18](=[O:27])[C:19]2([S:25][CH3:26])[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:30])[C@:7]1([CH3:29])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:28])[CH:9]=[CH:8]1)(=O)C.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:30][C@:6]12[C@@H:5]([OH:4])[CH2:22][C@@:20]3([CH3:21])[C@@H:16]([CH2:17][C:18](=[O:27])[C:19]3([S:23][CH3:24])[S:25][CH3:26])[C@@H:15]1[CH2:14][CH2:13][C:12]1[C@:7]2([CH3:29])[CH:8]=[CH:9][C:10](=[O:28])[CH:11]=1
Reactant: CSC1(SC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CSC1(SC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a stirred solution of 1.7 g (3.76 mmole) of 11β-(acetyloxy)-9-fluoro-17,17-bis(methylthio)androsta-1,4-diene-3,16-dione in a mixture of methanol (70 ml), tetrahydrofuran (50 ml) and water (5 ml) was added 10% potassium carbonate solution dropwise until the pH of solution was about 10. The solution was allowed to stir at room temperature under nitrogen for 2 hours and quenched with a slight excess of concentrated acetic acid. The solvent was evaporated in vacuo to give a slurry. This was diluted with water and extracted with dichloromethane. The dichloromethane solution was dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.35 g of the title compound. Recrystallization of this from acetone-hexane gave 720 mg of an analytical specimen, melting point 293°-294° C., dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11]S(C)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:11])[CH2:9][O:10]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CS(C)=O
Solvent: O
Product: CC1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-(4-fluorophenyl)ethanone (1 equiv.) in DMSO is added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The reaction is monitored by TLC and at completion the reaction mixture is poured in water (100 mL) and extracted with EtOAc. The combined organic extract is washed with water, followed by brine, dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][N:36]([C:2]3[CH:3]=[CH:4][C:5]4[C:14]5[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 0.3 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.15 g, 0.40 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (100 mg, 0.42 mmol), and Cs2CO3 (0.14 g, 0.43 mmol) were suspended in DMSO (2.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (18 mg, 0.13 mmol) and copper iodide (98 mg, 0.51 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 21 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2(30 mL) and washed with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (40 mL) (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (0.55 mg, 21%) as a clear film: 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.84-7.79 (m, 2H), 7.67-7.60 (m, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.18 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 3.69-3.66 (m, 5H), 3.62-3.57 (m, 2H), 3.08-3.04 (m, 2H), 2.99-2.94 (m, 2H), 1.43-1.42 (m, 9H).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=O)[CH2:4]1)[CH3:2].[CH3:10][Li]>CCOCC>[C:7]([CH:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6]1)(=[O:9])[CH3:10]
Reactant: [Li]C
Reactant: CCC1CC(C(=O)O)C1
Solvent: CCOCC
Product: CCC1CC(C(C)=O)C1
Reaction time: 3 h

Procedure:
A solution of 6.61 g of 3-ethylcyclobutane-1-carboxylic acid, in 52 ml of distilled ether was stirred under argon at 0°. Methyllithium (85.0 ml of a 1.53M solution in ether) was added dropwise over a 30 minute period. The reaction mixture was stirred for three hours at 25°, then quenched with 7.3 water-methanol. The layers were separated, and the aqueous layer extracted with ether. The combined organic layers were washed with brine, dried, filtered and the solvents evaporated in vacuo. The resultant oil was distilled (aspirator vacuum) to afford 5.5 g of 1-acetyl-3-ethylcyclobutane, as a clear oil (bp 64°-67°). The material had the following spectral characteristics: nmr (CDCl3) δ 0.80 and 0.82 (3H total, pair of t, each J=7.0 Hz), 1.10 and 1.12 (ca. 1.5H total, pair of s, side product 1-[2-hydroxyprop-2-yl]-3-ethylcyclobutane), 1.0-2.4 (7H, m), 2.07 and 2.09 (3H total, pair of s) and 2.7-3.5 ppm (1H, m); ir (CHCl3) 935, 1175, 1370, 1460, 1705, 2870, 2930 and 2970 cm-1, also small 3200-3600 broad and 3600 cm-1 for the side product noted above.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]2[CH2:12][CH2:11][N:10]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of (4-chloro-benzyl)-isobutyl-pyrrolidin-3-yl-amine (0.16 g, 0.6 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction was concentrated, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 0.80 (6H, d), 1.55 (6H, s), 1.60-1.90 (4H, m), 2.15 (1H, d), 2.20-2.60 (6H, m), 3.25-3.60 (2H, m), 5.30 (2H, br, s), 6.10 (1H, t), 6.80 (1H, dd), 7.15-7.30 (6H, m), 7.40 (1H, d), 7.55 (1H, dd), 8.45 (1H, dd). ESI-MS m/z: 560 (M+1), UV retention time: 1.66 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:2].[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([Cl:28])=[CH:20][CH:19]=1.[BH4-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.CO>[Cl:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([NH:17][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:15][CH3:16])[CH2:1][CH3:2])=[CH:8][CH:9]=2)=[CH:19][CH:20]=1
Reactant: Nc1ccc(Cl)c2ccccc12
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCN(CC)CCOc1ccc(CNc2ccc(Cl)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 2089.2 %

Procedure:
A stirred solution of 0.2 gram (0.0001 mole) of 4-(2-(diethylamino)ethoxy)benzaldehyde (prepared in the manner of Step A, Example 3), 0.22 gram (0.0001 mole) of 1-amino-4-chloronaphthalene (available from Aldrich Chemical Company), and one drop of p-toluenesulfonic acid monohydrate (available from Aldrich Chemical Company) in 5 mL of toluene was heated at reflux for ten hours. At the conclusion of this period, the reaction mixture was concentrated under reduced pressure, yielding a residue. The residue was taken up in 5 mL of methanol and about 0.2 grams (0.004 mole) of sodium borohydride was added. The resulting mixture was stirred at ambient temperature for about 18 hours. After this time, the mixture was quenched with water and extracted with several portions of diethyl ether. The extracts were combined, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.8 gram of Compound 84. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.[Si]([O:21][CH2:22][C@@H:23](/[N:28]=[CH:29]/[C:30]([F:33])([F:32])[F:31])[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C)C.[NH4+].[Cl-]>CCOCC>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C@H:29]([NH:28][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:21])[C:30]([F:32])([F:31])[F:33])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-chloropyridine (2.5 g, 13 mmol) in ether (30 mL) at −78° C. was added n-butyllithium (13 mmol, 2.5 M in hexane). The mixture was stirred at −78° C. for 1 h. (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine (3.64 g, 11.7 mmol, see Step 2, Example 8) was added. The mixture was stirred at −78° C. for 2 h. Saturated aqueous NH4Cl was added to the reaction mixture and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. MgSO4 and concentrated to an oil (5.3 g). The crude oil (2.0 g) was then treated with (Bu)4NF (6 mL, 1M in THF). The mixture was stirred at rt for 1 h, saturated aqueous NH4Cl was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. MgSO4 and concentrated to an oil. Chromatography (20% EtOAc/hexane) afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[N+:20]([O-])=O)[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[N:9]([CH3:25])[C:10]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)=[C:13]([NH2:20])[CH:14]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3[nH]2)c([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3ccc(OC)cc3n2C)c(N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
To a solution of 6-methoxy-2-(4-methoxy-2-nitrophenyl)-1H-indole (1.0 g) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride (160 mg) on an ice bath. The solution was stirred for 20 minutes at room temperature, then methyl iodide (570 mg) was added dropwise thereto on an ice bath, and the solution was stirred for 2 hours at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), the total amount of 6-methoxy-2-(4-methoxy-2-nitrophenyl)-1-methyl-1H-indole was used according to an analogous synthetic method to Example 22 to provide the title compound (720 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][NH:22][N:21]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CN(C)C=O.O.[Cu]I>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=3)[N:21]=2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: Brc1ccc(-c2nc[nH]n2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Temperature: 140 °C
Yield: 50.5 %

Procedure:
To a solution of 1-iodo-4-(trifluoromethoxy)benzene (15.0 g, 52.0 mmol) in dimethylformamide (90 mL) and water (10 mL) was added 3-(4-bromophenyl)-1H-1,2,4-triazole (C51) (11.0 g, 49.0 mmol), cesium carbonate (34.0 g, 104 mmol), copper(I) iodide (2.80 g, 14.7 mmol), and 8-hydroxyquinoline (2.20 g, 15.0 mmol), and the solution was heated at 140° C. for 8 hours. The cooled solution was decanted from a layer of solid, diluted with a ammonium hydroxide (1 N, 100 mL) solution, and extracted with of diethyl ether (2×100 mL). The combined organic layer was dried and concentrated, and the brown solid was eluted through a short silica gel column using 20% ethyl acetate/hexanes as eluent to give the title compound as a light tan solid (9.50 g, 50%): mp 111-113° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.07 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H); ESIMS m/z 384 ([M+H]+).