Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C:23]23[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[O:17][CH2:16][CH2:15][C@H:14]13.[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:14]2[C@:23]3([OH:13])[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: C1CCC23O[C@H]2CCO[C@@H]3C1
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O[C@]12CCCC[C@@H]1OCC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-Fluoroaniline (0.173 g, 1.56 mmol) in CH2Cl2 (3 mL) at 0° C. was added trimethylaluminum (2M in toluene, 0.778 mL) dropwise. The mixture was warmed to rt and stirred for 30 min. Trans hexahydro-1aH,4aH-oxireno[d]chromene (0.200 g, 1.30 mmol) in CH2Cl2 (2 mL) was then added and the mixture was stirred at rt overnight. The reaction was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL). The reaction mixture was extracted 3× with CH2Cl2. The combined organics were dried, filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.90 (t, 2H, J=8.8 Hz), 6.60 (dd, 2H, J=4.2 Hz, 8.8 Hz), 3.88 (dd, 1H, J=5.4 Hz, 12.0 Hz), 3.68-3.74 (m, 1H), 3.47 (dd, 1H, J=4.8 Hz, 11.5 Hz), 3.40 (t, 1H, J=3.2 Hz), 2.30-2.40 (m, 1H), 1.69-1.78 (m, 2H), 1.54-1.68 (m, 5H), 1.45-1.48 (m, 1H), 1.20-1.30 (m, 1H), HRMS (ES) m/z M+H calc'd.: 266.1551. found: 266.1556
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[O:14]1[C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=[N:15]1.[C:22]([O:25][CH2:26][CH3:27])(=O)C>>[OH:14][C:18]1[C:17]([C:19]([C:18]2[O:14][N:15]=[CH:16][CH:17]=2)=[O:20])=[CH:16][CH:27]=[C:26]([O:25][CH3:22])[C:19]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccno1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccno2)c(O)c1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
Nitrobenzene (1 mL) and AlCl3 (154 mg, 1.15 mmol) were placed in an 8 mL vial with a stir bar and stirred at room temperature for 10 min. Isoxazole-5-carbonyl chloride (151 mg, 1.15 mmol) was added and the solution was allowed to stir at room temperature for another 30 minutes. Then adding I-81 (250 mg, 0.96 mmol) was added and the resulting solution was stirred at room temperature for 20 hours and heating for 1 hour. The reaction mixture was diluted with ethyl acetate (90 mL) washed with water, brine and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by silica gel column chromatography with ethyl acetate/hexane to yield 100 mg (32%) of P-129. 1H NMR (400 MHz, CDCl3) 3.91 (s, 3H) 6.71-6.78 (m, 1H) 7.10-7.15 (m, 1H) 7.52-7.64 (m, 1H) 7.57-7.64 (m, 1H), 7.72-7.77 (m, 1H) 8.21-8.30 (m, 1H) 8.44-8.47 (m, 1H), 8.48-8.53 (m, 1H), 12.62 (s, 1H) ppm.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][NH2:14])=[CH:8][CH:7]=2.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[F:16][C:3]([F:2])([F:15])[C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][NH:14][C:23]([C:22]1[CH:21]=[N:20][C:19]([C:18]([F:29])([F:17])[F:28])=[CH:27][CH:26]=1)=[O:24])=[CH:8][CH:7]=2
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nc1
Temperature: 5 °C
Reaction time: 0.21 h
Yield: 60.7 %

Procedure:
{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5A, 646 g, 71% free amine equivalent), 6-trifluormethylnicotinic acid (429.7 g), diisopropylethylamine (1500 mL) and tetrahydrofuran (5.1 L) were placed in a flask equipped with an addition funnel, thermometer, and nitrogen inlet. The mixture was stirred vigorously for 10-15 min. The mixture was cooled to ˜5° C. and propylphosphonic anhydride (3.2 L of 50 wt % solution) added slowly. The mixture was stirred at ˜15° C. for 2 hrs. The mixture was cooled to ˜5° C. and quenched by the addition of water (505 mL) slowly. The pH was adjusted to 5-6 by adding 20 wt % K3PO4 (2.9 L). The mixture was diluted with EtOAc (3.2 L) and the temperature adjusted to 15-20° C. The phases were separated and the organic mixture was washed sequentially with water (1.5 L) and then 5 wt % sodium bicarbonate solution (2.6 L). The mixture was filtered and the solvent removed to minimum volume under vacuum. Isopropyl alcohol (2.0 L) was added and the mixture filtered, and the solvent removed under vacuum two times. Isopropyl alcohol (980 mL) was added and the mixture heated to 70-80° C. Water (1.5 L) was added while maintaining temperature above 65° C. and monitoring turbidity. The temperature was adjusted to 65° C., seeded with product (4.5 g) and the mixture held at 65° C. for 30 min. The mixture was cooled to ˜5° C. overnight and the product was isolated by filtration, washing the solids with cold 10% IPA in water (1 L), then dried in a vacuum oven to give the title compound (529 g);
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C[CH2:26][O:27][C:28]([CH2:30]Br)=[O:29]>CC(C)=O>[CH3:26][O:27][C:28](=[O:29])[CH2:30][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(=O)c(-c3ccccc3)coc2c1
Yield: 72.3 %

Procedure:
To a mixture of 7-Hydroxy isoflavone (35 grams, 147 mmol), anhydrous K2CO3 (84 grams, 608 mmol) in anhydrous acetone (500 mL) was added ethyl bromo acetate (29 grams, 174 mmol) and refluxed for 8 hours. Acetone was distilled and water (500 mL) was added. Crude 49 was filtered, dried, and recrystallized from toluene to give pure 49 (33 grams, 72.4%) as a white shining powder. The melting point was found to be 105-106.5° C. The structure was confirmed with IR and NMR. IHNMR (CDCl3) δ 1.31 (t, 3H, OCH2, CH3), 4.30 (q, 2H, OCH2, CH3), 4.70 (s, 2H, OCH2), 6.84 (d, 1H, Ar), 7.05 (dd, 1H, Ar), 7.41 (m, 3H, Ar), 7.57 (m, 2H, Ar), 7.97 (s, 1H, Pyran), 8.24 (d, 1H, Ar).
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])=[O:5].[ClH:19].N([O-])=O.[Na+]>O>[Cl:19][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])=[O:5]
Reactant: Nc1ccccc1C(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccccc1Cl)c1ccccc1[N+](=O)[O-]

Procedure:
A stirred solution of 75 g. of 2-amino-2'- nitrobenzophenone in 700 ml. of hot concentrated hydrochloric acid is cooled to 0° and a solution of 21.5 g. of sodium nitrite in 50 ml. of water is added in the course of 3 hours. The temperature of the suspension is kept at 2-7° during the addition. The resulting clear solution is poured into a stirred solution of 37 g. of cuprous chloride in 350 ml. of hydrochloric acid 1:1. The solid which has formed after a few minutes is filtered off, washed with water and recrystallized from ethanol. Crystals of 2-chloro-2'-nitrobenzophenone melting at 76-79° are obtained.
Reaction SMILES: [H-].[K+:2].[H-].[Na+].CC1C=CC(N)=CC=1.[CH3:13][C:14]1[CH2:18][C:17]([CH3:19])=[C:16]([CH3:20])[C:15]=1[CH3:21]>O1CCCC1>[CH3:13][C:14]1[CH:18]([K:2])[C:17]([CH3:19])=[C:16]([CH3:20])[C:15]=1[CH3:21]
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: [K+]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccc(N)cc1
Product: CC1=C(C)C([K])C(C)=C1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium hydride (containing mineral oil; the content of sodium hydride: 35%) (3.00 g) was suspended in tetrahydrofuran (18 ml), and then 4-methylaniline (0.056 g) was dropwise added to the suspension at 10° C., followed by stirring for 10 minutes. Thereafter, the solution of tetramethylcyclopentadiene (1.22 g) dissolved in tetrahydrofuran (6 ml) was dropwise added to the suspension, and heated to 25° C., followed by stirring for one hour. Thus, tetramethylcyclopentadienylpotassium was obtained. To this solution, the solution of (2-allyloxy-3-tert.-butyl-5-methylphenyl)chlorodimethylsilane (3.99 g; purity: 70.7%; pure compound: 2.82 g) dissolved in tetrahydrofuran (3 ml) was dropwise added, followed by stirring for one hour.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[Cl:18][C:19]1[N:24]=[C:23]([C:25](Cl)=[O:26])[CH:22]=[C:21]([Cl:28])[N:20]=1>C(Cl)Cl>[Cl:18][C:19]1[N:24]=[C:23]([C:25]([NH:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[O:26])[CH:22]=[C:21]([Cl:28])[N:20]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)c1cc(Cl)nc(Cl)n1
Yield: 33.2 %

Procedure:
To a mixture of (S)-methyl 2-aminopropanoate hydrochloride (1.397 g, 10.01 mmol) in DCM (80 mL) was added iPr2NEt (4.35 mL, 24.97 mmol). The mixture was stirred for a few minutes and a solution of the 2,6-dichloropyrimidine-4-carbonyl chloride (2.107 g, 9.97 mmol) in DCM (20 mL) was added over a period of 1 minute. After stirring overnight, the reaction was concentrated in vacuo to a residue. The residue was chromatographed over silica gel using 10-40% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 2-(2,6-dichloropyrimidine-4-carboxamido)propanoate as a yellow oil (0.921 g, 3.31 mmol, 33% yield). LC/MS: m/z=278.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:15])[NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:30][CH2:31]2)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1C(c2cccnc2)SC[C@H]1C(=O)O
Agent: CCP(=O)(C#N)CC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(c2cccnc2)SC[C@H]1C(=O)NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 500 mg (1.61 mmole) of 3-t-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4(R)-carboxylic acid, 500 mg (1.61 mmole) of 1-(3-aminopropyl)-4-(diphenylmethyl) piperazine (prepared as described in Preparation 16'), 263 mg (1.61 mmole) of diethylphosphoryl cyanide, 163 mg (1.61 mmole) of triethylamine and 10 ml of tetrahydrofuran was stirred at room temperature overnight. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, diluted with water and extracted with methylene chloride. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was subjected to column chromatography through alumina, using ethyl acetate as the eluent, to afford 840 mg (yield 89%) of the title compound as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:9]=[C:10]([CH3:37])[N:11]([CH2:14][C:15]2[S:30][C:18]3[N:19]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:20](=[O:25])[N:21]([CH3:24])[C:22](=[O:23])[C:17]=3[C:16]=2[C:31]([N:33]([O:35]C)[CH3:34])=[O:32])[C:12]=1[Cl:13].CN(C)C=O>ClCCl>[Cl:7][C:8]1[N:9]=[C:10]([CH3:37])[N:11]([CH2:14][C:15]2[S:30][C:18]3[N:19]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:20](=[O:25])[N:21]([CH3:24])[C:22](=[O:23])[C:17]=3[C:16]=2[C:31]([N:33]([OH:35])[CH3:34])=[O:32])[C:12]=1[Cl:13]
Reactant: CON(C)C(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(Cl)n1Cc1sc2c(c1C(=O)N(C)O)c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.1 62 ml) was added to a stirred solution of the product of example 1 part d) (415 mg) and dimethylformamide (0.01 ml) in dichloromethane (4 ml). After 1 h the solution was evaporated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (3 ml) and 1 ml of the solution was added to a stirred solution of N-methylhydroxylamine hydrochloride (129 mg) in saturated aqueous sodium bicarbonate solution (2 ml). After 1 h, the mixture was diluted with water (10 ml) and extracted with ethyl acetate (3×10 ml). Organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound (129 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 68 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (3 ml) with heat, 4-methoxyphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and washed with toluene to obtain 54 mg of the title compound (yield: 68%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([F:16])=[CH:6][C:7]2[O:12][CH:11]([CH3:13])[C:10](=[O:14])[NH:9][C:8]=2[CH:15]=1.[CH2:17](Br)[C:18]#[CH:19].O>CN(C)C=O>[NH2:3][C:4]1[C:5]([F:16])=[CH:6][C:7]2[O:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH2:19][C:18]#[CH:17])[C:8]=2[CH:15]=1
Reactant: CC1Oc2cc(F)c(N)cc2NC1=O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(C)Oc2cc(F)c(N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
While kept under N2, 0.30 g (7.4 mmol) of sodium hydride (60% dispersion in oil) was washed with 1 ml pentanes and then suspended in 2 ml anhydrous dimethylformamide. A solution of 1.36 g (6.9 mmol) of 6-amino-7-fluoro-2-methyl-2H-1,4-benzoxazin-3(4H)-one in 10 ml of dimethylformamide was added to the sodium hydride slurry slowly by syringe with ice cooling and the reaction mixture was stirred at room temperature for 0.5 hr. There was then added 0.77 ml (8.6 mmol) of propargyl bromide by syringe with ice bath cooling. The reaction mixture was allowed to warm to room temperature, stirred for 84 hours and then poured into 50 ml of water. The resulting mixture was extracted with EtOAc (2×50 ml) and the organic layers were combined and washed with water (3×50 ml), dried over MgSO4 and filtered. The solvent was removed in vacuo to yield a golden solid which was recrystallized from chloroform to yield 0.66 g of 6-amino-7-fluoro-2-methyl-4-propargyl-2H-1,4-benzoxazin-3(4H)-one as a brown solid, m.p. 142°-145° C.
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[CH3:23][CH2:24][CH2:25][CH2-:26].[C:27]1([N:33]2CCC(=O)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:23]=[C:24]1[CH2:35][CH2:34][N:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: O=C1CCN(c2ccccc2)CC1
Reactant: [CH2-]CCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL round bottom flask, methyltriphenylphosphonium iodide (1.384 g, 3.42 mmol) was suspended in THF (10.0 mL) and cooled to 0° C. N-Butyllithium (1.370 mL, 3.42 mmol) was added drop-wise and the resulting yellow suspension was stirred at 0° C. for 30 min. A solution of 1-phenylpiperidin-4-one (0.500 g, 2.85 mmol) in THF (5.0 mL) was added drop-wise and the orange, yellow suspension was then allowed to slowly warm to 23° C. over 2 hr. The reaction mixture was quenched with sat. NH4Cl (30 mL), the aq. layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude yellow oil was purified by flash chromatography (EtOAc:Hex, 1:9 isocratic) affording the title compound as a clear, light yellow oil (0.0906 g, 18.33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14-2.39 (m, 4H) 3.12-3.29 (m, 4 H) 4.74 (s, 2H) 6.64-6.85 (m, 1H) 6.87-7.07 (m, 2H) 7.08-7.29 (m, 2H). ESI-MS: m/z 174.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([S:47][CH2:48][CH:49]([CH2:53][C:54]1[C:62]([Cl:63])=[CH:61][C:57]2[O:58][CH2:59][O:60][C:56]=2[CH:55]=1)[C:50](O)=[O:51])(=O)C>C(Cl)Cl.C(N(CC)CC)C>[Cl:63][C:62]1[C:54]([CH2:53][CH:49]([CH2:48][SH:47])[C:50]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:51])=[CH:55][C:56]2[O:60][CH2:59][O:58][C:57]=2[CH:61]=1
Reactant: CC(=O)SCC(Cc1cc2c(cc1Cl)OCO2)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(CS)Cc1cc2c(cc1Cl)OCO2
Yield: 63.9 %

Procedure:
The operation is carried out as in Stage 5 of Example 1, starting with 121 mg of L-Tryptophan in the form of the hydrochloride, 2 ml of anhydrous methylene chloride, 0.13 ml of triethylamine, 199 mg of BOP and 143 mg of the product obtained in Stage 5 above, dissolved in 3 ml of anhydrous methylene chloride. Purification is carried out by chromatography on silica with chloroform-ethyl acetate: 90-10 as eluant. In this way 133 mg of expected product (yellow gum) is obtained.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4](=O)[CH2:5][Br:6].[NH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:11]=1[NH2:18]>>[Br:1][CH2:2][C:3]1[C:4]([CH2:5][Br:6])=[N:9][C:10]2[C:11](=[CH:12][C:13]([Cl:17])=[C:14]([Cl:16])[CH:15]=2)[N:18]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(CBr)C(=O)CBr
Product: Clc1cc2nc(CBr)c(CBr)nc2cc1Cl

Procedure:
Following the procedure of Example 1, condensation of 1,4-dibromo-2,3-butanedione with 1,2-diamino-4,5-dichlorobenzene yielded 2,3-bis(bromomethyl)-6,7-dichloro-quinoxaline, m.p. 154°-156° C.; 1H NMR (CDCl3, 200 MHz): δ4.86 (s, 4H, CH2), 8.18 (s, 2H, ArH).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[Br:26])[CH:13]=[CH2:14].[C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])#[N:28].N1CCCCC1>C(O)C.O>[CH2:33]([O:32][C:30]([C:29]1[CH:20]([C:19]2[CH:22]=[C:23]([O:24][CH3:25])[C:16]([O:15][CH2:12][CH:13]=[CH2:14])=[C:17]([Br:26])[CH:18]=2)[C:2]2[C:1](=[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=2)[O:11][C:27]=1[NH2:28])=[O:31])[CH3:34]
Reactant: C=CCOc1c(Br)cc(C=O)cc1OC
Reactant: CCOC(=O)CC#N
Reactant: Oc1cccc2ccccc12
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: C=CCOc1c(Br)cc(C2C(C(=O)OCC)=C(N)Oc3c2ccc2ccccc32)cc1OC
Temperature: 80 °C

Procedure:
1-Naphthol (170 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μL) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (270 mg, 0.58 mmol, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:61]=[CH:60][C:54]([O:55][CH2:56][CH2:57]CO)=[CH:53][CH:52]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:57][CH2:56][O:55][C:54]2[CH:60]=[CH:61][C:51]([O:50][CH3:49])=[CH:52][CH:53]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(OCCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCOC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (82 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (122 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-methoxyphenoxy)-1-propanol (75 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (92 mg, yield 62%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)=[CH:20][C:6]=2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:10]1)[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
In toluene/ethanol/water (=10/1/1, 41 ml) was dissolved methyl 7-bromo-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.90 g). To the solution were added 4-(2-propoxyethoxy)phenyl borate (0.72 g) and potassium carbonate (0.81 g) and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (123 mg) and the mixture was heated to reflux for 14 hours. After cooling to room temperature, the solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give methyl 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.79 g).