Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1[C:15]2[C:6](=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)C=CC=1>CO.C(O)C>[N:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Oc1cccc2ccc3cccnc3c12
Solvent: CO
Solvent: CCO
Product: c1ccc2ncccc2c1

Procedure:
To begin with, 1.53 g(7.84 mmol) of 10-hydroxybenzo [h] quinoline was dissolved in 40 ml of mixed solution of methanol and ethanol in a flask with heat to produce alcoholic quinoline solution; the ratio of methanol to ethanol was 1 : 1. Then, 0.69 g(3.92 mmol) of BeSo4.4H2O was dissolved in 100 ml of pure water in another flask to produce beryllium solution. Beryllium solution was gradually added to alcoholic quinoline solution while being stirred, then a substance emitting strong blue-green light appeared. To fully precipitate the substance, the pH of the solution was adjusted to mild alkaline from neutral by adding 1N NaOH solution. The precipitates were filtered off by suction and dried for 2 hours at 80° C. with heat, and sublimated by the train sublimation technique using a sublimation-purification unit. [For further information, see the paper of H. J. Wagner, R. O. Loutfy, C. K. Hsiao, J. Mater, Sci., 17, 2781(1982)] It is confirmed that the crystallites of the luminous material thus produced emit strong blue-green light having a peak wave length of 510 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:3]=1[C:4]([NH:6][C:7](=[O:25])[NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[Cl:1][C:2]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:3]=1[C:4]([NH:6][C:7](=[O:25])[NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[O:5]
Reactant: COC(=O)C=Cc1cc(C(=O)OC)ccc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=Cc1cc(C(=O)O)ccc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reaction time: 2 h
Yield: 9.1 %

Procedure:
0.22 g (0.5 mmol) of methyl 4-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-3-(2-methoxycarbonylvinyl)benzoate (example 11 c) were dissolved in 10 ml of THF, after which 10 ml of H2O and 0.06 g (2.4 mmol) of lithium hydroxide were added. After 2 hours, the mixture was made acid with 2 N hydrochloric acid; this was then followed by extraction with ethyl acetate and concentration. Following preparative HPLC (column: Waters Xterra ™MS C18, 5 μm, 30×100 mm, mobile phase: A: H2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B), 0.02 g (10%) of the desired product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccccc2Br)cc1
Yield: 70.3 %

Procedure:
A stirred mixture of 2-bromophenol (5.19 g), 4-methoxybenzyl chloride (4.70 g), potassium carbonate (4.15 g) and acetone (30 ml) is heated under reflux for 8 hours. The cool mixture is evaporated under reduced pressure, and the residue is mixed with water (60 ml) and ether (60 ml) and shaken. The aqueous layer is extracted with ether (2×60 ml), and the combined extracts washed with 2M sodium hydroxide solution (20 ml) and water (20 ml), dried (MgSO4) and evaporated to give a solid residue which is recrystallized from ethanol to give 6.18 g of 1-bromo-2-(4-methoxybenzyloxy)benzene, mp 87-90° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[OH-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1Cl)([O-:17])=[O:16]>O1CCCC1.COC(C)(C)C.[Pd](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1cc(F)c(F)c(F)c1
Temperature: 105 °C

Procedure:
A well-inertized pressure vessel was initially charged with a mixture of 49.6 g (0.113 mol) of a 40% solution of 3,4,5-trifluorophenylboronic acid in tetrahydrofuran from preliminary stage a) with 121.6 g (0.304 mol) of a 10% sodium hydroxide solution and 19.7 g (0.124 mol) of 2-nitrochlorobenzene. The particular ligand was then added at room temperature, the mixture was stirred and the palladium(II) chloride was finally added. Subsequently, the reaction mixture was heated to 105° C. This established a pressure of approx. 3-4 bar. After about 12 hours of reaction time, the pressure vessel was decompressed to standard pressure and cooled to 30° C., and the reaction mixture was discharged. For workup, the reaction mixture was taken up in tert-butyl methyl ether, the phases were separated and the aqueous phase re-extracted twice with tert-butyl methyl ether. The solvents were distilled off completely under reduced pressure, the final weight was determined and the content of the crude 3,4,5-trifluoro-2′-nitrobiphenyl was analyzed by means of quantitative HPLC. If desired, the crude 3,4,5-trifluoro-2′-nitrobiphenyl can be purified further, for example by crystallization from isobutanol.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[F:10][C:11]1[C:20]2[NH:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=3)[C:17]([CH3:34])([CH3:33])[CH2:16][C:15]=2[C:14]([C:35](O)=[O:36])=[CH:13][CH:12]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[C:20]2[NH:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:22]=3)[C:17]([CH3:33])([CH3:34])[CH2:16][C:15]=2[C:14]([C:35]([NH:9][S:6]([CH:3]2[CH2:5][CH2:4]2)(=[O:8])=[O:7])=[O:36])=[CH:13][CH:12]=1
Reactant: CC1(C)Cc2c(C(=O)O)ccc(F)c2NC1c1cccc(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(C(=O)NS(=O)(=O)C3CC3)ccc(F)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride (200 mg, 5.0 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (630 mg, 5.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (200 mg, 0.52 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-amide (100 mg, 40%) as a white solid: LC/MS m/e calcd for C25H30FN3O4S (M+H)+: 488.60, observed: 488.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14]C(C)C)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Cc1cccc(OC(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cccc(CC(=O)O)c1
Temperature: 66 °C
Yield: 97.5 %

Procedure:
Dissolve isopropyl 2-(3-isopropoxyphenyl)acetate (4.2 g, 17.8 mmol) in tetrahydrofuran (35.6 mL). Add water (35.6 mL) and lithium hydroxide (6.05 g, 248.8 mmol). Heat the reaction mixture to 66° C. overnight. Concentrate under reduced pressure to remove the tetrahydrofuran. Dilute the reaction mixture with water and wash with diethyl ether. Acidify the water layer with 5N HCl to pH 1. Extract the water layer with diethyl ether. Wash the diethyl ether extract with water and brine, dry over sodium sulfate, filter and concentrate under reduced pressure to give the title compound (3.37 g, 17.35 mmol). MS (m/z): 195.0 (M+1), 212.0 (M+18).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:11][CH:10]2[C:12]([O:14]C)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:11][CH:10]2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1OC1c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1OC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of methyl (2RS,3SR)-3-(3,4-dichlorophenyl)oxirane-2-carboxylate (90.9 g) in methanol (500 ml) was added 4 N sodium hydroxide solution (138 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was filtered and washed with methanol. To the mother liquor was added 3 N hydrochloric acid (400 ml), and the mixture was stirred at room temperature for 1 hr. The resultant product was collected by filtration, and washed with distilled water to give the title compound (57.3 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][C@H:9]([NH2:28])[C:10](=[O:27])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[OH:40][C:41]1[N:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:44]=[C:43]([C:52](O)=[O:53])[CH:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][C@H:9]([NH:28][C:52]([C:43]1[CH:42]=[C:41]([OH:40])[N:45]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:44]=1)=[O:53])[C:10](=[O:27])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(O)n(-c2ccccc2)n1)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 84.8 %

Procedure:
To 2.2 g of (S)-4-Amino-5-oxo-5-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-pentanoic acid tert-butyl ester in 30 ml of DMF, 892 mg of HOBT, 1.08 g of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid 1.12 g EDC Hydrochlorid and 1.90 ml DIPEA was added. After 3 h at RT the mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution. Drying of the organic layer over sodium sulfate and evaporation under reduced pressure afforded a brownish powder that was purified by chromatography over silica gel eluting with ethyl acetate/heptane 1:1 to 100% ethyl acetate to give 2.7 g of the desired product. Yield: 2.7 g MS (ES+): m/e=416.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:20].Cl>O1CCCC1.CN(C)C=O>[C:3]([O:7][C:8]([N:10]([CH3:20])[C@@H:11]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.5 %

Procedure:
To a stirred suspension of sodium hydride (89 mg, 2.24 mmol) in tetrahydrofuran (10 mL) and dimethyl formamide (10 mL) cooled in an ice bath was added (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (427 mg, 1.86 mmol, WO2006/011035) and iodomethane (128 microL, 2.05 mmol). The mixture was allowed to warm to room temperature and stirred for 20 h. Sodium hydride (178 mg, 4.474 mmol) and idomethan (256 microL, 4.102 mmol) were added, and the reaction mixture was stirred at 20 h at room temperature. Reaction mixture was acidified to pH 3.5 with 1 mol/L hydrochloric acid and extracted with ethyl acetate. Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by column chromatography (50% ethyl acetate in hexane containing 1.5% acetic acid) to give the desired compound as a colorless solid (138.0 mg, 31%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@@H:8]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:9](N(OC)C)=[O:10])=[O:6])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.Cl>C(OCC)C>[CH3:3][C:2]([CH3:22])([O:4][C:5]([NH:7][C@@H:8]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH:9]=[O:10])=[O:6])[CH3:1]
Reactant: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCCCC1
Reaction time: 1.25 h

Procedure:
(S)-α-[[(1,1-Dimethylethoxy)carbonyl]amino]-N-methoxy-N -methylcyclohexanepropanamide (55.3 g., 175.9 mmole, 1 eq.) was dissolved in diethyl ether (1760 ml., 0.1M) and cooled in an ice bath. A solution of lithium aluminum hydride in tetrahydrofuran (193 ml., 193 mmole, 1.1 eq., 1M in tetrahydrofuran) was added dropwise over 90 minutes. After 75 minutes, a 1N HCl solution (1 l.) was added cautiously and slowly. The cooling bath was removed and the mixture was stirred for 2 hours. The layers were separated and the aqueous layer was reextracted with ether (2×400 ml.). The combined ether layers were dried (MgSO4) and freed of solvent in vacuo leaving a viscous oil (46.47 g.). This was chromatographed on silica gel (500 g., Merck) which was packed in hexane. The aldehyde was eluted with ether:hexane (1:1) to give (S)-α-[[(1,1dimethylethoxy)carbonyl]amino]cyclohexanepropanal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:33])[N:9]=1)=[CH:17][C:16]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=1)=[CH:15][CH:14]=3.O.NN>CO.[Ni]>[NH2:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:22][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]1[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][C:10]([CH3:33])=[C:11]1[C:20]([CH3:21])=[N:19]2
Reactant: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(OCc3cccc([N+](=O)[O-])c3)ccc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(OCc3cccc(N)c3)ccc12
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
2.0 g 1-(2-Chlorophenyl)-3,4-dimethyl-7-(3-nitrobenzyloxy)-imidazo(1,5-a)quinoxaline was dissolved in 50 mL methanol, 0.4 g Raney Nickel was added followed by dropwise addition of 2.1 mL hydrazine hydrate. The reaction mixture was stirred 1 h at 40° C. and 10 min at reflux. After cooling the catalyst was filtered off, the solvent was removed by distillation and the residue was re-crystallised from 2-propanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([NH2:20])=[O:19].N1C=CC=CC=1.[CH3:27][O:28][CH2:29][C:30](Cl)=O.[OH-].[Na+]>C1COCC1>[CH3:27][O:28][CH2:29][C:30]1[NH:20][C:18](=[O:19])[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=3)=[N:7][C:2]=2[N:1]=1
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)nc1N
Reactant: COCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid amide (0.564 g, 2.0 mmol) in anhydrous THF (10 mL) under N2 atmosphere. Add dropwise pyridine (0.325 mL, 4.0 mmol) and methoxyacetyl chloride (0.365 mL, 4.0 mmol) to the reaction mixture and stir at room temperature overnight. Add 10% aq. NaOH (10 mL) and stir at 50° C. for 3 hours. Concentrate in vacuum, adjust the pH to 6.0 using AcOH, collect the solid by filtration and purify by column chromatography to give 2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)=[C:4]([CH3:19])[CH:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:27][CH2:19][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8]([CH3:17])([CH3:18])[CH2:9][C@:10]1([C:13]([F:16])([F:14])[F:15])[CH2:12][O:11]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)ccc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccc(F)cc1CBr
Temperature: 80 °C
Yield: 105.6 %

Procedure:
To a solution of 17.7 g (R)-2-[2-(4-fluoro-2-methylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (0.064 mol) in 250 mL of CCl4 was added 14.8 g (0.083 mol) of NBS followed by 1.5 g (0.006 mol) benzoyl peroxide and heated to 80° C. for 2 hours. The mixture was cooled to room temperature, diluted with 1800 mL of hexanes, filtered through a pad of CELITE® filter aid, and concentrated in vacuo. The crude mixture was chromatographed on silica gel using 0-5% ethyl acetate/hexanes to afford 24 g (69%) (R)-2-[2-(2-bromomethyl-4-fluorophenyl)-2-methylpropyl]-2-trifluoromethyloxirane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.Cl.[CH3:17][N:18]([CH3:26])[C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([N:18]([CH3:26])[CH3:17])[CH2:20][CH2:21]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (250 mg, 0.880 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine hydrochloride (280 mg, 1.32 mmol) to afford the desired product (63 mg, 18%): ESI MS m/z 390 [C19H24BrN3O+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31](O)=[O:32])(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:31](=[O:32])[CH2:30][C@H:29]([O:28][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Solvent: CI
Solvent: ClCCCl
Product: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 89.4 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-dodecanoyloxytetradecanoic acid (935 mg, 2.2 mmol) in the presence of EDC·MeI (745 mg, 2.5 mmol) in CH2C2 to afford 1.08 g (90%) of N-[(R)-3-dodecanoyloxytetradecanoyl]-L-serine benzyl ester: mp 53-54° C. 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.5 Hz), 1.1-1.6 (m, 46H), 2.30 (t, 2H, J=7.7 Hz), 2.50 (d, 2H, 5.6 Hz), 2.62 (t, 1H, J=6.2 Hz), 3.97 (m, 2H), 4.65 (m, 1H), 5.19 (m, 3H), 6.63 (d, 1H, J=6.8 Hz), 7.35 (br s, 5H).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:4]=1[CH:5]([C:15]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[OH-].[K+].C(=O)(O)[O-].[Na+]>O>[CH3:34][N:2]([CH3:1])[C:3]1[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:4]=1[C:5]1([C:6]2[CH:7]=[CH:8][C:9]([N:12]([CH3:13])[CH3:14])=[CH:10][CH:11]=2)[C:15]2[C:16](=[CH:20][C:21]([N:24]([CH3:25])[CH3:26])=[CH:22][CH:23]=2)[C:17](=[O:19])[O:18]1
Reactant: CN(C)c1ccc(C(c2ccc(N(C)C)cc2C(=O)O)c2ccc(N(C)C)cc2N(C)C)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc(N(C)C)ccc32)cc1
Yield: 79.6 %

Procedure:
A solution of 29.78 g of 2-[2,4,4'-tris(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid prepared as described in part B above, 450.0 g of water and 16.2 g of flake potassium hydroxide was prepared and the pH adjusted to 10.0 by the gradual addition of sodium bicarbonate. The solution was then heated at approximately 75° C. under an atmosphere of oxygen at 60-65 psi for approximately six hours in an agitated stainless steel autoclave. The solid which separated was collected by filtration at ambient temperature, washed with water until alkali free when tested with Brilliant Yellow test paper and dried. The dried solid was slurried with hexane at room temperature, filtered and dried to obtain 23.6 g of 3-(2,4-bis[dimethylamino]phenyl)-3-(4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula I: R=CH3 ; X=H; Y=4-(CH3)2NC6H4 ; Z=2,4-[(CH3)2N]2C6H3) a pale blue-colored solid melting at 171°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[C:6]2O.P(Br)(Br)[Br:18]>CN(C=O)C>[Br:18][C:6]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: COc1ccc2ncc([N+](=O)[O-])c(O)c2n1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: COc1ccc2ncc([N+](=O)[O-])c(Br)c2n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
The compound of Example 2 (132.3 g, 1 eq.) was suspended in DMF (1200 mL) at 20° C. and PBr3 (68 mL, 1.2 eq.) was added over a period of 15 min. The mixture was stirred at 65° C. for 60 min, cooled to 20° C., poured on ice (800 g) and filtered. The product was slurried in ethanol (500 mL), filtered and dried on a rotary evaporator at 65° C., affording a yellow solid (155.8 g; 92% yield).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>O1CCCC1>[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=[CH:2][O:3][CH3:4]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.7 %

Procedure:
To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (10 g, 28 mmol) in tetrahydrofuran (46 mL) cooled at −15° C. was added potassium tert-butoxide (3.7 g, 31 mmol) as a solid in one portion. After 5 minutes, 2-chlorobenzaldehyde (2.0 g, 14 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for two hours. The reaction was quenched with saturated aqueous ammonium chloride solution (5 mL), tetrahydrofuran evaporated in vacuo, and the resulting residue was diluted with diethyl ether (100 mL) and water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 80 g, ISCO, 0-10% ethyl acetate in heptane) to afford the title compound as a colorless oil (2.4 g, 100%), which was used in the next step without further purification.