Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][N:15]=1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C1COCC1.O>[Si:26]([C:18]1[C:17]([F:21])=[CH:16][N:15]=[C:14]([F:13])[C:19]=1[F:20])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1cnc(F)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
A solution of diisopropylamine (98.85 g, 136.9 mL, 976.9 mmol) in THF (1.350 L) was cooled to −65° C. n-BuLi (2.5 M in hexanes) (375.8 mL of 2.5 M, 939.4 mmol) was added dropwise via cannula over 1 h at such a rate as to maintain reaction temperature below −60° C. Once the addition was complete the cooling bath was removed and the reaction mixture was allowed to warm up to 0° C. The reaction mixture was stirred for 15 min at 0° C., then re-cooled to −78° C. 2,3,5-trifluoropyridine (100 g, 751.5 mmol) was added dropwise via cannula over 20 min at such a rate to maintain the reaction temperature below −69° C. The reaction mixture was stirred for 45 min at −78° C. during which time the solution turned orange brown. A solution of tert-butyl-chloro-dimethyl-silane (147.2 g, 976.9 mmol) in THF (150 mL) was then added via cannula over 30 min. The reaction mixture was stirred at −78° C. for 90 minutes during which time the solution darkened. Lc/Ms after this time indicated that the reaction was complete. A saturated ammonium chloride solution (300 ml) was then added and mixture was allowed to warm up to RT. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (1.5 L then 2×500 ml). The combined organics were washed with saturated NaHCO (500 ml) and brine (400 ml). The crude mixture was partially concentrated in vacuo, dried over magnesium sulfate, filtered and concentrated in vacuo to an oil. The crude was purified by flash chromatography (CombiFlash Companion XL, 1.5 kg column, 0-20% ethyl acetate in petroleum ether). This afforded the title compound as a colourless oil (136.2 g, 73%); 1H NMR (CDCl3) 0.34 (6H, s), 0.89 (9H, s), 7.73 (1H, s); MS ES(+) 248.25 (M+1).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C.CCCCCC>[C:1]1([S:7][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
Benzenethiol (500 mg, 4.54 mmol) was dissolved in 6 mL of DMF. K2CO3 (940 mg, 6.81 mmol) was added and the resulting mixture was stirred at room temperature for 10 mins. 4-Fluoro-benzaldehyde (675 mg, 5.44 mmol) was then added and the resulting mixture was stirred at 50° C. for 2 hours. The mixture was then stirred at 80° C. for 3 hours. Water was added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 5/95 EtOAc:hexane as the eluent) afforded 940 mg (96% yield) of 4-phenylsulfanyl-benzaldehyde. LC-MS purity: 91.3%
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]2=[O:24])(=O)=O)=CC=1.[H-].[Li+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>COCCOC>[N:28]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:18](=[O:24])[CH2:19][O:20][CH2:21][C:22]2=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Reactant: C1CCNCC1
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: O=C1COCC(=O)N1CCCCCCN1CCCCC1
Yield: 42.5 %

Procedure:
To a mixture of 3.63 grams (9.84 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate (prepared as described in Example IX) and 84.75 milligrams (10.7 millimoles) of lithium hydride in 10 milliliters of 1,2-dimethoxyethane was added 1.0 milliliter (10.0 millimoles) of piperidine in 10 milliliters of 1,2-dimethoxyethane. The mixture was heated under reflux for 22 hours, and the resulting heterogeneous mixture filtered to obtain a clear yellow filtrate. The filtrate was concentrated to an orange oil which after evaporative distillation (bath 120° C.; 0.05 torr.) produced 1.18 grams (42.5 percent yield) of 4-(6-piperidinohexyl)-3,5-dioxomorpholine base having infrared and nuclear magnetic resonance spectral characteristics appropriate for said compound. A 286.23 milligram (1.02 millimoles) sample of the free base, 4-(6-piperidinohexyl)-3,5-dioxomorpholine, was dissolved in 1.0 milliliter of 1N sodium hydroxide (1.0 millimole) and the mixture concentrated to produce 289.63 grams (90 percent yield) of sodium [2-(6-piperidinohexyl)-amino-2-oxoethoxy]acetate product with the following spectral characteristics:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12].[OH-].[Na+]>>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Product: ClCCCSc1ccccc1
Temperature: 0 °C
Yield: 70.3 %

Procedure:
40 ml of an aqueous solution containing 6.0 g of thiophenol and 7.8 g of 3-bromo-1-chloropropane were subjected to reflux for 1 hour under heating. To the solution, 40 ml of aqueous solution of sodium hydroxide containing 2.4 g thereof were then fed dropwise. Then, the solution was further subjected to reflux for another 2 hours under heating, and the solution reacted was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer resulted was then washed with dilute aqueous alkaline solution and saturated saline solution in series, then dried with anhydrous magnesium sulfate. The solvent used was removed by distillation under reduced pressure, and the residue obtained was purified by using silica gel column chromatography, for which hexane was used for the developer, thereby affording 6.5 g of 1-chloro-3-phenylthio propane.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:12])[CH2:10][CH3:11].Cl>>[C:9]([O:7][C:6]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][CH:5]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)Cl
Reactant: Cc1ccccc1O
Agent: Cl
Product: CCC(=O)Oc1ccccc1C
Yield: 98 %

Procedure:
Into a spherical flask equipped with a condenser, a dropping funnel and containing 2 mols of o-cresol are introduced, in 15 minutes, 2.2 mols of propionyl chloride. The mixture as obtained is heated at 110° C. for about 2 hours, until the discharge of hydrochloric acid ceases. The o-cresol propionate which is obtained is distilled under vacuum:
Reaction SMILES: [CH:1]([CH:4]1[C:9](=O)[NH:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:3])[CH3:2].Br[C:19]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:20]=1[NH2:21].CN[C@@H]1CCCC[C@@H]1NC>CN1C(=O)CCC1.O>[CH:1]([CH:4]1[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7][N:8]2[C:19]3[CH:25]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:23]=[CH:22][C:20]=3[N:21]=[C:9]12)([CH3:3])[CH3:2]
Reactant: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(N)c(Br)c1
Agent: CN[C@H]1CCCC[C@H]1NC
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a solution of tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (200 mg, 0.83 mmol) in NMP (3 mL) was added 2-bromo-4-(methylsulfonyl)aniline (207 mg, 0.83 mmol), (1R,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (12.0 mg, 0.08 mmol), K3PO4.3H2O (660 mg, 2.48 mmol), Cul (16 mg, 0.08 mmol). The mixture was stirred at 150° C. for 1 h under microwave. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC with CH2Cl2/MeOH 35/1 to afford tert-butyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (110 mg, 34% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (4.00 g, 18.6 mmol), N,O-dimethylhydroxylamine hydrochloride (1.69 g, 17.4 mmol), and DIEA (7.5 mL, 41.8 mmol) in CH2Cl2 (80 mL) was added solid EDC.HCl (4.00 g, 20.9 mmol). The mixture was stirred at rt for 18 h and concentrated under reduced pressure. The residue was taken up in ether (175 mL), washed with 5% aq HCl (2×50 mL) and satd aq NaHCO3 (50 mL), and dried over MgSO4. Removal of the solvent left tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (3.16 g, 65%) as an oil.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>[OH-].[Na+]>[CH2:13]([O:12][C:10]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
L-Proline 5 (100 gms, 0.87 moles) was dissolved in 2N sodium hydroxide (430 mL) and cooled in an ice bath. A further 220 mL of 4N sodium hydroxide was added simultaneously with benzyl chloroformate (155 gms, 0.90 moles) over 2 hrs. The reaction was then allowed to warm to room temperature overnight.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)([O-])=O.CCO.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:16]([N:13]1[CH2:12][CH2:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added 1-(2-nitrophenyl)-4-benzylpiperazine (42 g, 160 mmol), EtOH (300 mL), and SnCl2.2H2O (Aldrich) (141 g, 624 mmol), and the reaction mixture was warmed to 60° C. for 5 h. The reaction mixture was treated with 1N NaOH (30 mL) and CH2Cl2. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). All organic fractions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the amine as a light yellow oil (34 g). MS (ESI, pos. Ion) m/z: 268 (M+H); MS (ESI, neg. Ion) m/z: 266 (M−H). Calc'd for C17H21N3: 267.17.
Reaction SMILES: [CH2:1]([CH:4]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7]Br)[CH2:2][CH3:3].CC([O-])(C)C.[K+].O>C1C=CC=CC=1.CS(C)=O>[CH2:5]([CH:4]([CH2:9][CH2:10][CH3:11])[CH2:1][CH:2]=[CH2:3])[CH2:6][CH3:7]
Reactant: CCCC(CCC)CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: C=CCC(CCC)CCC
Reaction time: 2 h

Procedure:
To 100 g of 4-propylheptyl bromide in 400 ml of benzene was added 90 g of t-BuOK in 300 ml of DMSO. The temperature was kept below 50° C. during the addition. The mixture was stirred for 2 hrs and 600 ml of water was added. The organic phase was separated and the aqueous phase extracted with petroleumether (b.p. 40°-60°). The combined organic phases were washed with water and brine. After drying with Na2SO4 and evaporation the residue was distilled. Yield: 23.2 g (b.p. 56°-59° C. /75 Torr). 1H-NMR(CDCl3): δ0.9(6H,CH3), 1.2(9H,CH2,CH), 2.0(2H,CH2C=C), 4.8-5.1(2H,CH2 =C), 5.5-6.0(1H,CH=C)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 370.3 %

Procedure:
3,5-Dichlorophenol (500 mg, 3.07 mmol) was dissolved in dimethylacetamide (8.0 mL), and 4-fluorobenzaldehyde (0.390 mL, 0.368 mmol) and cesium carbonate (1.50 g, 3.69 mmol) were sequentially added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 150° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 85:15 (v/v)), whereby the objective title compound was obtained as a white solid (364 mg, yield: 44%).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1>>[Cl:3][C:2]1[N:4]=[C:5]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:7]=[C:8]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cccc(C)c1
Product: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3C)n2)c(C)c1

Procedure:
The reaction of cyanuric chloride with 1,3-xylene under Friedel-Crafts conditions to give 2-chloro-4,6-bis(2,4-dimethylphenyl)-s-triazine is known, e.g. from DE-A-1 169 947 and Helv. Chim. Acta 55, 1589 (1972). However, the product can also be obtained using an appropriate Grignard reagent, such as described in Helv. Chim. Acta 33, 1365 (1950) and U.S. Pat. No. 4,092,466.
Reaction SMILES: [Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1Br.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1[O:23][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Br
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Oc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
To a solution of 2,3-dibromo-6-methoxybenzo[b]thiophene 1,1-dioxide (12.5 g, 35.3 mmol) in THF (175 mL) at room temperature was added 4-bromophenol (6.49 g, 37.1 mmol) and Cs2CO3 (34.5 g, 106 mmol). The resulting suspension was warmed to 50° C. and the reaction turned faintly yellowish green after a few minutes and then subsequently faintly pink, the mixture remained a suspension. After 4 h at 50° C. the mixture was cooled to room temperature, diluted with water (175 mL), and stirred for 15 min. The solution was transferred to a separator funnel and the phases were separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were then washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (14.7 g, 33.0 mmol, 93% yield) as a faintly pink solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm==3.83 (s, 3H), 6.92-7.03 (m, 3H), 7.25-7.35 (m, 2H), 7.39-7.50 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[CH2:7][O:8][C:4]=2[CH:3]=1.C1(P(=[CH:31][C:32]([O:34][CH3:35])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:35][O:34][C:32](=[O:33])[CH2:31][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1coc2cc(O)ccc12
Temperature: 120 °C
Yield: 23.3 %

Procedure:
To a suspension of 6-hydroxy-benzofuran-3-one (5.0 g, 33.3 mmol) in xylene (100 mL) was added methyl (triphenylphosphoranylidene)acetate (11.1 g, 33.3 mmol) and the resulting reaction mixture was heated (120° C., 24 h). The reaction mixture was concentrated in vacuo and the residue was treated with 1 M HCl adjusting the pH to 3. The organic layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-70%) to provide the title compound as a clear oil (1.6 g, 23%). MS (ESI): mass calcd. for C10H10NO4, 206.2; m/z found, 207.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.03-7.07 (m, 1H), 7.37 (d, J=8.4, 1H), 6.93 (d, J=2.2, 1H), 6.77 (dd, J=8.4, 2.2, 1H), 5.20 (br s, 1H), 3.74 (s, 3H), 3.67 (s, 2H).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]N(C)C=O>[Cl-].[Na+].O>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([CH3:32])[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Nc2ccccc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN1c2ccccc2CN(C(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21

Procedure:
[1,1′-Biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone of Example 6 (0.97 g) was added to sodium hydride (2 equivalents, 60% in oil, washed with hexane) and N,N-dimethylformamide (25 mL). lodomethane (0.45 g) was added and after overnight stirring, the mixture was poured into brine. The precipitate was collected, redissolved in dichloromethane and the solution filtered through a short column of Magnesol®. The column was rinsed with several volumes of dichloromethane, and the combined eluate refluxed with the gradual addition of hexane until incipient crystallization. Cooling and filtration provided the title compound (0.89 g), m.p. 198–201° C.
Reaction SMILES: COC1C=CC=CC=1N1CC[N:12]([C:15]([C:17]2[O:18][C:19]3[C:24]([C:25](=[O:27])[CH:26]=2)=[CH:23][CH:22]=[CH:21][C:20]=3[N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:16])CC1.CN([C:38]([O:42]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.ON1C2C=CC=CC=2N=N1.[N:67]1([C:73]2[CH:79]=[CH:78][C:76](N)=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>CN(C)C1C=CN=CC=1.CN(C)C=O.C(N(CC)CC)C>[N:67]1([C:73]2[CH:79]=[CH:78][C:76]([NH:12][C:15]([C:17]3[O:18][C:19]4[C:24]([C:25](=[O:27])[CH:26]=3)=[CH:23][C:22]([O:42][CH3:38])=[CH:21][C:20]=4[N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)=[O:16])=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1
Reactant: COc1ccccc1N1CCN(C(=O)c2cc(=O)c3cccc(N4CCN(C)CC4)c3o2)CC1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
6-Methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) (3.0 g, 8.5 mmol), TBTU (5.5 g, 17 mmol), 1-hydroxybenztriazole (2.6 g, 17 mmol), 4-dimethylaminopyridine (0.05 g, catalytic) and commercially available 4-morpholin-4-yl-aniline (1.66 g, 9.3 mmol) were dissolved in dimethylformamide (100 mL). Triethylamine (3.5 mL, 25 mmol was added and this mixture stirred at room temperature for 17 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between chloroform (400 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated, dried (Na2SO4), vacuum-filtered and concentrated under vacuum. The residue was purified by chromatography on silica eluted with 2-5% methanol in chloroform and then triturated with ether to yield a yellow powder. (1.6 g=39%) LCMS−m/z=479.5 mp=234-236° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH2:15]([OH:19])[CH2:16]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[O:19][CH2:15][CH2:16][O:4]1
Reactant: CCCCO
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: c1ccccc1
Product: BrCC1(c2ccc3ccccc3c2)OCCO1
Reaction time: 8 h

Procedure:
To a stirred solution of 74.4 parts of 2-bromo-1-(2-naphthalenyl)-1-ethanone in 240 parts of a butanol are added successively 3 parts of 4-methylbenzenesulfonic acid and 270 parts of benzene. Then there are added dropwise 28 parts of 1,2-ethanediol. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated. The residue is dissolved in 2,2'-oxybispropane and the solution is stirred with a diluted sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with 2,2'-oxybispropane. The extra ct is neutralized with water, dried, filtered and evaporated. The oily residue is crystallized from methanol. The product is filtered off and recrystallized from methanol, yielding 41 parts of 2-(bromomethyl)-2-(2-naphthalenyl)-1,3-dioxolane; mp. 64° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(OC)(OC)OC.[CH2:20](O)[CH2:21][OH:22]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:21]1[O:22][C:7]2([CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH2:8]2)[O:12][CH2:20]1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: ClCCl
Product: Brc1ccc2c(c1)CCC1(C2)OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
A mixture of 6-bromo-2-tetralone (8.80 g, 39 mmol), trimethyl orthoformate (17.2 ml, 157 mmol), ethylene glycol (16.2 ml, 290 mmol) and p-toluenesulfonic acid (0.07 g, 0.37 mmol) in dry dichloromethane (200 ml) was stirred at room temperature for 18 h, then partitioned between saturated aqueous NaHCO3 (100 ml) and dichloromethane (2×50 ml). The combined organic extracts were dried (Na2SO4) then evaporated in vacuo to give an oil. Column chromatography on silica with 0-10% diethyl ether-hexane gradient elution gave 6-bromo-2-tetralone ethylene ketal as a yellow oil (8.84 g, 84%).