Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][O:18][C:16]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (0.1 g, 0.5 mmol) was combined with methyl chloroformate (0.046 mL, 0.59 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, and then concentrated. The resulting residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give tert-butyl 4-[(methoxycarbonyl)amino]piperidine-1-carboxylate, LCMS [M+Na] 281.1. The later was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give crude product which was used directly in the next step. LCMS calculated for C7H15N2O2 (M+H)+: m/z=159.1; Found: 159.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:15]#[N:16])[C:7](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:8]#[N:9])[CH3:2].[S:18](=[O:22])(=[O:21])([OH:20])[OH:19].C(N(CC)CC)C>[OH-].[Pd+2].[OH-].[C].COCCOC>[S:18]([OH:22])([OH:21])(=[O:20])=[O:19].[CH2:13]([O:12][C:11]1[CH:10]=[C:7]2[C:6](=[C:5]([F:17])[C:4]=1[O:3][CH2:1][CH3:2])[C:15]([NH2:16])=[N:9][CH2:8]2)[CH3:14]
Reactant: CCOc1cc(C#N)c(C#N)c(F)c1OCC
Agent: [Pd+2]
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOc1cc2c(c(F)c1OCC)C(N)=NC2
Temperature: -23 °C
Reaction time: 29 h
Yield: 0 %

Procedure:
A mixture of 4,5-diethoxy-3-fluorophthalonitrile (2.34 g, 10 mol) prepared in Preparation Example 1, sulfuric acid (0.56 mL, 10 mol), 20% palladium hydroxide-carbon (0.59 g, 50% hydrate) (20% palladium-carbon powder, palladium hydroxide type (hydrate), N.E. Chemical Corporation) and 1,2-dimethoxyethane (23 mL) was stirred at −23° C. under hydrogen atmosphere (atmospheric pressure) for 29 hours. After insoluble matter in the reaction mixture was filtered off, the residue was washed with methanol (23 mL), and the combined filtrate was divided into five equal portions. To one of them, triethylamine (0.14 mL, 1 mol) was added, and the mixture was stirred at 60° C. for three hours and concentrated at 40° C. under reduced pressure. Methanol (2.3 mL) and 1,2-dimethoxyethane (6.9 mL) were added to the residue, then sulfuric acid (0.11 mL, 2 mol) was added on ice, and the mixture was stirred. Precipitated crystals were filtered, washed with a 5% methanol-1,2-dimethoxyethane solution, and dried at room temperature under reduced pressure to give 0.45 g of the title compound (yield: 72%) as grayish white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:10].CCN(C(C)C)C(C)C>C1COCC1>[N:1]1([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
Morpholine Compound 50b (1.41 mL, 16.2 mmol) was added dropwise to a solution of 2-bromo-1-(4-nitro-phenyl)-ethanone Compound 50a (4.15 g, 16.2 mmol) in THF (50 mL) and DIPEA (3.1 mL, 17.8 mmol). The reaction was stirred for 3 hours and then extracted from 0.5 M NaH2PO4 with EtOAc. The combined extracts were dried over MgSO4, filtered and evaporated down. The residue was recrystallized from EtOAc and hexanes to give 2-morpholin-4-yl-1-(4-nitro-phenyl)-ethanone Compound 50c (2.55 g) as a yellow solid. MS 251 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:27]=[C:26]([O:28]C)[CH:25]=[CH:24][C:12]=3[C:13]=2[C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:12]=3[C:13]=2[C:14](=[O:23])[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 10 °C
Reaction time: 24 h

Procedure:
A mixture of 53 g. of the product of Example 9 in dry chloroform was prepared. The mixture was cooled to 10° C., and 75 g. of boron tribromide were added. The mixture was stirred for 24 hours at room temperature. The mixture then was poured into water, the chloroform layer was separated, and the aqueous layer was extracted with additional chloroform which was added to the separated chloroform layer. The resulting chloroform mixture then was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in benzene, the benzene solution was filtered, concentrated to dryness, and the residue was chromatographed on silica using 10 percent ether in benzene as eluant. Those fractions containing material having the same Rf value were combined and rechromatographed on alumina using ether as solvent followed by a mixture of 10 percent methanol in ether. The title compound (5.8 g.) was obtained, melting point 138°-140° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].[Cl:15]N1C(=O)CCC1=O.C(OCC)(=O)C>C(#N)C>[Cl:15][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:11]([F:12])([F:13])[F:14])[C:7]=1[NH2:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 75 %

Procedure:
4-Nitro-2-trifluoromethyl-phenylamine (5.6 g) and N-chlorosuccinimide (4.0 g) were suspended in acetonitrile (15 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. Ethyl acetate (80 mL) was added and the organic phase was washed with 5% aqueous NaOH (2×50 mL), water (2×50 mL) and brine (2×50 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 4.9 g (75% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, CDCl3): 5.35 (b, 2H), 8.35 (b, 1H), 8.37 (b, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=O.[C:14](#[N:17])[CH:15]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH:4]=[CH:15][C:14]#[N:17]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: Cc1ccc([N+](=O)[O-])cc1C=CC#N

Procedure:
0.336 g (1.5 millimols) of palladium acetate, 29.93 g (150 millimols) of 2-methyl-5-nitrobenzoyl chloride, 9.94 g (187.5 millimols) of acrylonitrile and 27.80 g (150 millimols) of tri-n-butylamine, in 150 ml of p-xylene, are stirred for 80 minutes at 130°. The mixture is then extracted, and dried, as described in Example 68. The crude product is chromatographed on silica gel in toluene and is then recrystallised from carbon tetrachloride/cyclohexane. 6.3 g (22% of theory) of white crystals, of melting point 115.6° C., are obtained. Analysis for C10H8N2O2 : calculated C 63.83%, H 4.29%, N 14.89%; found C 63.8%, H 4.2%, N 15.1%.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:14][CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17].O>C1CCCCC1>[Cl:14][C:15]1[C:16]([OH:17])=[N:4][C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[N:5][C:21]=1[CH3:23]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCCCC1
Product: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of 30.0 g (0.18 mole) trichloroacetamidine, 25.2 g (0.18 mole) potassium carbonate, 30.3 g (0.18 mole) ethyl 2-chloroacetoacetate, and 300 ml water was stirred 18 hours. The aqueous solution was decanted from heavier tars and acidified with hydrochloric acid. The precipitate that was formed was filtered, washed, and dried to give 14.7 g (31% yield; mp 130°-145° C.) of crude product. An analytical sample was prepared by recrystallization from cyclohexane (mp 156°-157° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [OH:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:22][S:23]([CH2:26][C:27]([NH2:35])([CH3:34])[C:28]1[N:32]=[C:31]([CH3:33])[O:30][N:29]=1)(=[O:25])=[O:24]>>[OH:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:19])([F:20])[F:18])=[CH:8][C:9]([C:12]([NH:35][C:27]([C:28]3[N:32]=[C:31]([CH3:33])[O:30][N:29]=3)([CH3:34])[CH2:26][S:23]([CH3:22])(=[O:25])=[O:24])=[O:14])=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(O)CCC1)C(F)(F)F
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(O)CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-hydroxycyclobutyl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (Example 126d) and 2-Methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 109d) as starting materials and isolated (28 mg, 42%); MS (ESI, m/z): 507.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[C:11]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]([CH3:17])=[CH:13][C:14]=2[CH3:16])[NH:9][CH2:8]1)=[O:4].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CCOC(C)=O>CN(C=O)C>[CH2:26]([N:9]1[C:10]2[C:15](=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:8]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCI
Reactant: COC(=O)CCC1CNc2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CC(CCC(=O)OC)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 40 °C
Reaction time: 10 h
Yield: 82.2 %

Procedure:
N-[3-(2-Methoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (1.0 g) was dissolved in DMF (10 ml) and 1-iodooctane (1.44 g) and K2 CO3 (830 g) were added, which was followed by stirring at 40° C. for 10 hr. AcOEt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=20/1−5/1) to give 1.1 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[F-].[Cs+]>C(#N)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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 81.7 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (3.70 g, 24.3 mmol), 1-chloro-4-nitrobenzene (3.84 g, 24.3 mmol) and cesium fluoride (7.40 g, 48.7 mmol) in 150 mL of 2:1 acetonitrile-water was degassed under vacuum for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (844.0 mg, 0.73 mmol) was added and the reaction refluxed for 3 h. The solvent was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic phase was separated, dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue on silica gel using 5% ethyl acetate hexanes as the eluent gave 4′-methoxy-4-nitro-biphenyl (4.55 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>>[OH:9][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Temperature: 24 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
Molten 2,4-dichlorophenol (82.13 g) was added to 166 ml of ClSO3H at 37°-40° C. over a 1 hour period. After a 20 minute hold period at 37°-40° C. the mixture was cooled to 24° C. and held an additional 1 hour. The reaction mixture was then cautiously poured onto 1100 g of ice with constant agitation. Filtration, washing and drying afforded 104 g of 97.6% pure 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride (C) (77% yield), mp 79°-82° C.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]#[N:4].S(=O)(=O)(O)[OH:10]>>[NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]([NH2:4])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C)(N)C#N
Product: CC(C)C(C)(N)C(N)=O

Procedure:
In a similar way hydrolysis of the (±)-2-amino-2,3-dimetylbutyronitrile with sulfuric acid yields (±)-2-amino-2,3-dimethylbutyramide, mp 74.5°-76° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[OH2:12]>>[Cl:3][C:4]1[C:5]([CH2:6][OH:12])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: ClCc1cccnc1Cl
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cccnc1Cl

Procedure:
In 100 ml of cold water was dissolved 8.98 g of sodium borohydride and with ice-cooling and stirring, 11.7 g (0.0665 mole) of 2-chloronicotinyl chloride was added in small portions. The mixture was further stirred at the same temperature for 30 minutes and, then, extracted with Et2O (100 ml×3). The extract was dried over MgSO4 and distilled to remove Et2O. The procedure gave 8.75 g of (2-chloro-3-pyridyl)methanol as a pale yellow oil. When left standing at room temperature, this product solidified thoroughly.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[CH3:4][N:5]([CH3:11])[C:6](=[NH:10])[N:7]([CH3:9])[CH3:8]>C(Cl)Cl>[CH:1]([O-:3])=[O:2].[CH3:4][N:5]([CH3:11])[C:6](=[NH2+:10])[N:7]([CH3:9])[CH3:8]
Reactant: CN(C)C(=N)N(C)C
Reactant: O=CO
Solvent: ClCCl
Product: CN(C)C(=[NH2+])N(C)C
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
A solution of tetramethylguanidinium formate in methylene chloride was prepared by combining at room temperature 0.064 g of formic acid with 0.159 g of tetramethylguanidine in 15 ml of methylene chloride. The solution was stirred at room temperature for 5 minutes and a solution of 0.311 g, 1 eq., of 2,2,2-trichloroethyl 7-acetamido-2-chloromethylidene-3-methyl-3-cephem-4-carboxylate sulfoxide in about 25 ml of methylene chloride was added. The reaction mixture was stirred at room temperature for 5 minutes during which time the color of the solution changed from yellow to brown. The reaction mixture was washed with water and an aqueous solution of sodium chloride, was dried, and evaporated to dryness. The 2-formyloxymethylidene ester sulfoxide was obtained as a yellow froth weighing 0.308 g (97% yield).
Reaction SMILES: [Li]CCCC.CN(C)CCN(C)C.[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2.[C:23](=[O:25])=[O:24]>CCCCCC.O>[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:15]1=2
Reactant: O=C=O
Reactant: c1ccc2c(c1)CCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a solution of n-BuLi (1.7M, 123 ml, 0.21 mol) in 400 ml of hexane at room temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA), followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol). The mixture was stirred under argon at room temperature for 4 hours, and then poured into dry ice (pre-washing with anhydrous ether). After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated. The aqueous layer was acidified with conc. HCl to pH 1, cooled and the precipitate collected on a filter. This was recrystallized from CH2Cl2 to give 15a (9.43 g, 54.7%) as a white solid, mp 167°-169.5° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH3:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[C:43](O)(=[O:54])[CH2:44][C:45](CC(O)=O)([C:47](O)=[O:48])O>C1COCC1.C(Cl)Cl>[CH:11]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:9]=1[O:10][C:43](=[O:54])[CH2:44][CH2:45][C:47]([NH:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:48])([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: NCCN1CCCC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)CCC(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of propofol hemisuccinate (2.0 g, 7.2 mmol) in THF—CH2Cl2 (1:1, 60 mL) was added EDCI (1.72 g, 9 mmol) followed by HOBt (1.37 g, 9 mmol). The reaction mixture was stirred at ambient temperature for 15 min and 1-(2-aminoethyl)pyrrolidine (0.912 g, 8 mmol) was added and stirring was maintained overnight. 10% aqueous citric acid (50 ml) was added and the mixture was extracted with CH2Cl2 (100 ml×2). The organic layer was washed with brine and dried over anhydrous MgSO4. The solvent was removed and the product was purified by silica gel column chromatography using acetone with 1% Et3N. Removal of the solvent gave the product as an oil. Yield: 2.47 gram (92%)
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.CC1N=C(C)OC=1.[C:14]([C:17]1[O:21][C:20]([CH3:22])=[N:19][C:18]=1[CH3:23])(=[O:16])[CH3:15]>>[CH3:22][C:20]1[O:21][C:17]([C:14]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:16])[CH3:15])=[C:18]([CH3:23])[N:19]=1
Reactant: CC(=O)c1oc(C)nc1C
Reactant: Brc1ccsc1
Agent: Cc1coc(C)n1
Product: Cc1nc(C)c(C(C)(O)c2ccsc2)o1

Procedure:
Starting with 3-bromothiophene and 5-acetyl-2,4-dimethyloxazole dimethyloxazole and following the general method of Example 4 the title compound was prepared. M.p. 132°-133° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=1>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[C:26]([O:28][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:27]=[C:18]([C:17]([O:16][CH3:15])=[O:29])[CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 25 °C
Yield: 105.1 %

Procedure:
K2CO3 (21 g, 153 mmol, 2 equiv) and benzyl bromide (11 ml, 92 mmol, 1.2 equiv) were added to a solution of 5-hydroxy-isophthalic acid dimethyl ester (D42) (16.1 g, 76.7 mmol, 1 equiv) in acetone (400 ml) at room temperature. The resulting solution was refluxed for 18 h, cooled to room temperature and concentrated in vacuo. The residue was partitioned between H2O and AcOEt. The aqueous phase was extracted with AcOEt and the combined organic layers were washed with 2N aqueous NaOH solution and brine, dried over MgSO4 and concentrated in vacuo to give 5-benzyloxy-isophthalic acid dimethyl ester (D44) (24.2 g, 105%) as a white solid. [M+H]+=301.0, RT=3.50 min
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[OH-].[Na+].Cl[C:11]1[N:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13](OCC)=[O:14]>COCCOC>[OH:14][C:13]1[C:12]2[C:11](=[N:21][CH:20]=[CH:19][CH:18]=2)[O:3][C:2]=1[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CCOC(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CCOC(=O)c1oc2ncccc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Ethyl glycolate (35.5 mL, 375 mmol) is slowly added (over 20 minutes) to a slurry of NaOH (15.8 g, 394 mmol) in 1,2-dimethoxyethane (400 mL) under N2 with the flask being in an ice bath. The mixture is allowed to warm to rt, is stirred for 30 min, and ethyl 2-chloronicotinate (27.84 g, 150 mmol) in 1,2-dimethoxyethane (50 mL) is added over 10 minutes. The reaction is warmed to 65° C. for 15 h in an oil bath. The mixture is concentrated to dryness, the residue is dissolved in H2O (500 mL), washed with hexane (500 mL), acidified to pH 3 with 5% HCl, and extracted with CHCl3 (4×400 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated to a yellow solid. The solid is suspended in ether (200 mL) and heated on a steam bath until concentrated to a volume of 40 mL. The material is allowed to crystallize overnight, then filtered to afford ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate (C40) as a pale orange solid (41% yield). Additional material is obtained by concentrating the filtrate. Recrystallization in ether a second time afforded (C40) as a pale yellow solid (7.3% yield). MS (EI) for C10H9NO4, m/z: 207 (M)+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Br:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>ClCCCl>[Br:15][C:16]1[N:21]=[C:20]([CH2:22][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=[CH:18][CH:17]=1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Brc1cccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
NaBH(OAc)3 (68.5 g, 0.323 mol) was added to a solution of 6-bromopicolinaldehyde 66 (40 g, 0.22 mol) and morpholine 67 (20.9 g, 0.24 mol) in 1,2-dichloroethane (500 mL). The mixture was stirred at room temperature for 16 h. Saturated NaHCO3 (500 mL) was added and the mixture was extracted with EtOAc, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether:ethyl acetate (10:1) to give 68 (38 g, 68% yield).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]#[N:24]>C(#N)C>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:22][C:23]#[N:24])=[CH:3][CH:2]=1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1cccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.7 %

Procedure:
To a mixture of 9H-carbazol-4-ol (1.1 g, 6.0 mmol) in acetonitrile (100 mL) is added potassium carbonate (1.66 g, 12 mmol) and bromoacetonitrile (0.42 mL, 6.0 mmol). The mixture is stirred at room temperature for 20 h. The mixture is partitioned between water and CH2Cl2. The layers are separated and the organic layer dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography, silica gel (100 mL), using CH2Cl2 as eluent gave 1.13 g (85%) of the title compound; 1H NMR (DMSO-d6) δ5.4, 6.81, 7.18, 7.36, 7.46, 8.09; Anal. Calcd for C14H10N2O: C, 75.66; H, 4.53; N, 12.60. Found: C, 75.18; H, 4.56; N, 12.54.