Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](Cl)=[O:9].[CH3:22][NH:23][CH3:24]>O1CCCC1.O>[CH3:22][N:23]([CH3:24])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=2[F:1])[CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (2.2 g) in tetrahydrofuran (8 ml) was added dropwise to a stirred solution of dimethylamine (50% in water; 2 ml) in water (10 ml) at 5° C. The mixture was stirred for 30 minutes at 5° C. and for 1 hour at room temperature. The mixture was concentrated and extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure. The residue (2.4 g) was solidified with a mixture of hexane and ethanol to give pale brown powder of N,N-dimethyl-3-(2,4-difluorophenoxy)-4-nitrobenzamide (2.0 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:13]1[N:14](C=C)[CH:15]=[CH:16][N:17]=1)[OH:12])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[Mn]([O-])(=O)(=O)=O>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cn1ccnc1C(O)(c1ccccc1)c1ccccc1C(C)(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1C(O)(c1ccccc1)c1ncc[nH]1

Procedure:
To a solution of 10.0 g. (0.03 mol) of α-(o-tert.-butylphenyl)-α-phenyl-1-vinylimidazole-2-methanol in 180 ml. of pyridine and 180 ml. of 0.5 N methanolic sodium hydroxide, 360 ml. of a 4% aqueous potassium permanganate solution were added drop-wise at 20° to 30° C. After the addition was completed, 4.8 g. of solid potassium permanganate were added (total permanganate 0.12 mol). The manganese dioxide was filtered off. The filtrate was treated with active charcoal, concentrated almost to complete dryness and poured into water. The solid substance was filtered off, dissolved in warm acetone, decolorised with active charcoal and precipitated by addition of water. The precipitate was recrystallised from a mixture of acetone and water. α-(o-tert.-Butylphenyl)-α-phenylimidazole-2-methanol was obtained. Melting point 185°-186° C.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:31]([CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:13]3[CH:14]=[C:15]([C:18]([N:20]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1)[CH3:3]>C(Cl)(Cl)Cl.ClCCl.[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:31]([CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:13]3[CH:14]=[C:15]([C:18]([N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:19])[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:8][CH:9]=1)(=[O:1])[CH3:3]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3ccc(C(C)O)cc3)c(CCCN3CCCCC3)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2nn3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3c2CCCN2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 0.05 h

Procedure:
To a solution of 2-(4-(1-hydroxyethyl)phenyl)-N,N-diisopentyl-3-(3-(piperidin-1-yl)propyl)pyrazolo[1,5-a]pyridine-5-carboxamide (35 mg, 0.053 mmol) in chloroform (1 mL) was added activated manganese dioxide (92 mg, 1.06 mmol,) and the mixture was heated to 50° C. for 24 h. The reaction mixture was then diluted with dichloromethane and filtered through a 0.45 um filter, concentrated and then purified by preparative HPLC on a reverse-phase Zorbax SB-C18 column 21.2×100 mm eluted with MeOH-water-0.1% TFA. Isocratic 30% for 3 minutes then Gradient: 30% to 100% MeOH over 14 minutes. LCMS m/z 545.4 (M+H)+, ret. time=2.45 min.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([N:45]3[CH2:46][CH2:47][CH:42]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:43][CH2:44]3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)[CH:9]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(N4CCC(c5ccccc5)CC4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure R using 4-phenylpiperidine (162 mg, 1 mmol) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:13][C:3]1[C:2]([C:18]2[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=2)=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)cc(-c2cc(C=O)c([N+](=O)[O-])cc2F)c1
Temperature: 90 °C
Yield: 73.7 %

Procedure:
A mixture of 5-bromo-4-fluoro-2-nitrobenzaldehyde (10.0 g, 40.0 mmol), 3,5-dimethoxyphenylboronic acid (7.3 g, 40.0 mmol), bis(triphenylphosphino) palladium(II) chloride (1.4 g, 2.0 mmol) and cesium carbonate (32.6 g, 100.0 mmol) in dioxane/water (550 mL, v/v=10/1) was degassed with nitrogen for three times and heated at 90° C. for 3 hours. The mixture was cooled to room temperature, concentrated, diluted with ethyl acetate (1000 mL), and washed by water (500 mL) and brine (500 mL). The organic layer was dried, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8/1 to 5/1) to afford the title compound (9 g, 61%) as a yellow solid. MS (ES+) C15H12FNO5 requires: 305, found: 306 [M+H]+.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1.COC1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)C>[F:15][C:16]1[N:17]=[CH:18][C:19]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:20][CH:21]=1
Reactant: Fc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(F)nc1
Temperature: 80 °C
Yield: 32.1 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.300 g, 1.01 mmol), prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), in anhydrous toluene (30 ml) was treated with 2-fluoro-5-iodopyridine (0.34 g, 1.52 mmol), available as described in (U.S. Pat. No. 5,733,912), Pd2(dba)3 (0.028 g, 0.03 mmol), (S)-(−)-2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl (0.028 g, 0.06 mmol), available from Strem Chemicals, and sodium tert-butoxide (0.248 g, 2.58 mmol). The reaction mixture was heated at 80° C. for 5 hours. The reaction mixture was poured into diethyl ether (100 mL), washed with brine (100 ml), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (3% MeOH/CH2Cl2) to provide the title compound (0.095 g, 21% yield) as a yellow oil. MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6](=O)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])[CH3:4].[CH3:20][NH:21]N>C(O)(=O)C>[CH3:20][N:21]1[C:6]([C:7]2[C:8]([CH3:17])=[N:9][C:10]([O:15][CH3:16])=[C:11]([CH2:13][CH3:14])[CH:12]=2)=[N:5][C:3]([CH3:4])=[N:2]1
Reactant: CCc1cc(C(=O)N=C(C)N(C)C)c(C)nc1OC
Reactant: CNN
Solvent: CC(=O)O
Product: CCc1cc(-c2nc(C)nn2C)c(C)nc1OC
Temperature: 90 °C
Reaction time: 12 h
Yield: 57.3 %

Procedure:
In a round bottom flask under a nitrogen atmosphere N-(1-dimethylaminoethylidene)-5-ethyl-6-methoxy-2-methyl-nicotinamide (synthesized on 0.567 mmol scale) prepared in accordance with the procedures of Step 1, Example 19 is treated with glacial acetic acid (1 mL), followed by methylhydrazine (50 μL, 0.94 mmol). The resulting mixture is stirred at 90° C. for 12 hr. The reaction mixture is evaporated to dryness and the residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (99:1). Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (199:1). Fractions containing the product are combined and the solvent evaporated to give 3-(2,5-dimethyl-2H-1,2,4-triazol-3-yl)-5-ethyl-6-methoxy-2-methyl-pyridine (80 mg, 57% yield). MS: m/e 247 (M+H); 1H NMR (CDCl3, δ, ppm): 7.29 (1H, s), 3.98 (3H, s), 3.66 (3H, s), 2.58 (2H, q), 2.42 (3H, s), 2.31 (3H, s), 1.19 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Br.[C-:11]#[N:12].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:11]#[N:12]
Reactant: Clc1ccc(CBr)c(Br)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Cl)cc1Br
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
A mixture of 2-bromo-1-(bromomethyl)-4-chlorobenzene (9.8 g; 34.5 mmol) and sodium cyanide (2.0 g; 41.4 mmol) in 15 mL of 95% ethanol and 2.5 mL water was stirred and heated to reflux. After 30 minutes, the solvent was evaporated and the residue was partitioned between 100 mL ether and 50 mL water. The organic layer was dried over sodium sulfate and evaporated. The residual solid was washed out of the flask with hexane and collected by filtration, washed with hexane, and air-dried on the filter to give 4.82 g of 2-(2-bromo-4-chlorophenyl)acetonitrile as a light yellow solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=O)[CH:4]=1)[NH2:2].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[NH2:15][C:14]1[N:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=[C:12]([C:11]([CH3:18])([CH3:17])[CH3:10])[CH:13]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1cc[nH]c(=O)c1
Product: CC(C)(C)c1cc(N)n(-c2ccncc2)n1
Yield: 33 %

Procedure:
Following the procedure for Example 282A Step 1, 4-hydrazinylpyridin-2(1H)-one was heated at 80° C. overnight with 4,4-dimethyl-3-oxopentanenitrile. The reaction mixture was concentrated, triturated with DCM, and purified using silica gel chromatography eluting with a MeOH/DCM gradient (2-10%) to afford 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H-one (307 mg, 33% yield). 1H NMR (300 MHz, DMSO d6) δ 1.18 (s, 9H), 5.43 (s, 1H), 5.47 (s, 2H), 6.55 (s, 1H), 6.66 (m, 1H), 7.37 (d, 1H), 11.40 (s, 1H); LC-MS (ESI) m/z 233 (M+H)+
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C([NH:43][C:44]1C=C[C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1)=O>>[O:50]1[CH2:48][CH2:47][CH2:46][C@H:45]1[CH2:44][NH:43][C:29]([C:26]1[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: O=C(NC[C@@H]1CCCO1)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting (S)-(tetrahydrofuran-2-yl)methamine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.85 (t, J=6.1 Hz, 1H), 8.32 (d, J=9.3 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 7.41-7.28 (m, 4H), 5.04-4.72 (m, 4H), 4.04 (p, J=6.2 Hz, 1H), 3.85-3.74 (m, 1H), 3.69-3.58 (m, 1H), 3.38 (dd, J=11.2, 5.0 Hz, 2H), 2.01-1.74 (m, 3H), 1.71-1.54 (m, 1H); MS (ESI(+)) m/e 368 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]([CH2:16][CH2:17][NH:18][C:19](=O)[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>O.C(O)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]3[CH2:16][CH2:17][N:18]=[C:19]([CH3:20])[C:13]3=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cccn2CCNC(C)=O)cc1OC
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc3n2CCN=C3C)cc1OC
Reaction time: 1 h

Procedure:
N-[2-[2-(3,4-Dimethoxyphenyl)pyrrol-1-yl]-ethyl]-acetamide (2.6 g) was treated with 20 ml of phosphorus oxychloride under argon and boiled for 1 hour while stirring. The reaction mixture was hydrolyzed at 0° C. with 100 ml of 2N sodium hydroxide solution and 100 ml of 28% sodium hydroxide solution, diluted with 1200 ml of water and extracted with methylene chloride (1×200 ml, 2×100 ml). The organic extracts were combined, dried with MgSO4 and freed from solvent. 1.4 g of a total of 2.7 g of crude product were chromatographed on 30 g of silica gel with methylene chloride/methanol (19:1) as the eluent. The product, 0.8 g of brown oil, was dissolved in a 40-fold amount of ethanol, treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol and concentrated to a volume of 10 ml. There was obtained 0.8 g of 6-(3,4-dimethoxyphenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1.3); m.pt.: 158°-160° C. (dec.). A sample was recrystallized from a 40-fold amount of ethanol and yielded the (1:1) fumarate which melted at 160°-161° C. with decomposition.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53]Br)=[N:51][CH:52]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:51][CH:52]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrCc1ccc(OCc2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCc2ccccc2)cn1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a solution of 360 mg of di-tert-butyl (5S)-2-(benzyloxycarbonyl)-5-[(tert-butoxy-carbonyl)amino]hexanedioate (0.71 mmol; see example 12f) in N,N-dimethyl formamide (10 mL) was added under argon atmosphere 26 mg of sodium hydride (60% in oil, 0.64 mmol). The resulting mixture was stirred at room temperature for 30 minutes. A solution of 197 mg 5-(benzyloxy)-2-(bromomethyl)pyridine (prepared according to example 17a; 0.71 mmol) in N,N-dimethylformamide (5 mL) was added, and the mixture was stirred at 60° C. for one hour. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was purified by preparative HPLC (method A) to give 327 mg of the title compound (65% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C([Sn](CCCC)(CCCC)[C:17]1[O:18][C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:21]=1)CCC>O1CCOCC1>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:19]1[O:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])=[CH:21][CH:20]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([Sn](CCCC)(CCCC)CCCC)o1
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1-c1ccc(-c2ccc([N+](=O)[O-])cc2C)o1
Temperature: 97.5 °C
Yield: 84.8 %

Procedure:
To a solution of 2-bromo-5-nitrotoluene (4.32 g, 20 mmol) and tetrakis(triphenylphospine)palladium (0) (0.40 g) in anhydrous 1,4-dioxane (50 ml) was added 2,5-bis(tri-n-butylstannyl)furan (6.46 g, 10 mmol) and the mixture was heated overnight under nitrogen at 95-100° C. The resulting orange suspension was diluted with hexanes (15 ml), cooled to room-temperature, and filtered to give, after rinsing with hexanes, an orange solid (3.10 g), mp 241-243° C. The product was recrystallized from DMF (100 ml) to give a bright orange fluffy solid (2.87 g, 85%), mp 242-243° C. 1H NMR (DMSO-d6): 2.69 (s, 6H), 7.31 (s, 2H), 8.12 (m, 4H), 8.23 (s, 2H). Anal. Calcd. for C18H14N2O5 (338.31): C, H, N.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:32][C:33]3[CH:34]=[C:35]([O:44][CH3:45])[CH:36]=[C:37]4[C:42]=3[N:41]=[CH:40][CH:39]=[C:38]4[CH3:43])=O)[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].[OH-].[Na+]>O1CCCC1.O>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:32][C:33]3[CH:34]=[C:35]([O:44][CH3:45])[CH:36]=[C:37]4[C:42]=3[N:41]=[CH:40][CH:39]=[C:38]4[CH3:43])[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: COc1cc(NC(=O)CCCCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)c2nccc(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NCCCCCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)c2nccc(C)c2c1
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A cold (-40°) slurry of 0.9 g (0.007 mole) of anhydrous aluminum chloride in 20 ml of dry tetrahydrofuran was added to a cold (-30°) slurry of 0.75 g (0.02 mole) of lithium aluminum hydride in 30 ml of tetrahydrofuran. To the stirred mixture, which had been allowed to warm up to -20°, was added dropwise a solution of 2.7 g (0.0052 mole) of 4-(3,4-dichlorophenyl)-N-(6-methoxy-4-methyl-8-quinolinyl)-1-piperazinehexanamide in 30 ml of tetrahydrofuran. The mixture was stirred at -20° -0° for 3 hr, and then treated with 3.3 ml of 30% sodium hydroxide and enough water to clarify the supernatant. The supernatant was decanted from the soft white precipitate which was then washed with additional tetrahydrofuran. The decanted solvent and wash were combined, concentrated in vacuo to remove the tetrahydrofuran, and then combined with water and ether. The ether was washed, dried and concentrated to dryness in vacuo to afford 2.3 g of white solid. Recrystallization from 2-propanol afforded 2.1 g (81%) of the title compound, mp 92°-94°.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21]Br>O>[Br:19][CH2:20][CH2:21][N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: BrCCBr
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1CCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.9 g of succinimide and 50 ml of N,N-dimethylformamide were put into a 200-ml three-necked flask equipped with a stirrer and a thermometer. 14 g of potassium carbonate was added to the mixture. The admixture was then stirred at room temperature for 30 minutes. 39.6 g of 1,2-dibromoethane was added to the admixture. The admixture was allowed to react at a temperature of 40° to 50° C. for 2 hours. The reaction mixture was poured into water. The aqueous mixture was then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized with hexane. The resulting crystal was filtered off and then air-dried. Yield: 16.7 g (81%); m.p. 55° to 56° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([C:28]([OH:30])=[O:29])=[CH:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[CH2:31](O)[CH3:32]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:20]3)[CH2:18][CH2:19]1)=[O:13])[CH2:8]2
Reactant: O=C(O)C1=CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Reactant: CCO
Product: CCOC(=O)C1=CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21

Procedure:
A procedure analogous to that described Example 4 was followed using 1′-((2-adamantyl)carbamoyl)spiro[indene-1,4′-piperidine]-3-carboxylic acid and ethanol. 1H NMR (CD3OD) δ=1.40 (m, 5H), 1.63 (m, 2H), 1.84 (m, 8H), 1.98 (m, 5H), 2.11 (m, 2H), 3.25 (m, 2H), 3.89 (m, 1H), 4.15 (m, 2H), 4.36 (m, 2H0, 7.26 (m, 2H), 7.39 (m, 1H), 7.84 (s, 1H), 7.91 (m, 1H); LC-MS (4 min) tR=2.19 min, m/z=435.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([OH:25])=[CH:23][C:12]2[CH2:13][C:14](=[O:22])[N:15]([CH2:18][CH2:19][CH2:20]Cl)[CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1>>[CH2:1]([O:8][C:9]1[C:24]([OH:25])=[CH:23][C:12]2[CH2:13][C:14](=[O:22])[N:15]([CH2:18][CH2:19][CH2:20][N:27]([CH3:26])[CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)[CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: O=C1Cc2cc(O)c(OCc3ccccc3)cc2CCN1CCCCl
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OCc4ccccc4)c(O)cc3CC2=O)cc1OC

Procedure:
This compound was prepared analogous to Example 5(b) by reacting 1-(7-benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5]([O:6][CH2:7][CH3:8])[CH:4]=1.[CH2:13]([O:16][CH2:17][CH2:18]Cl)[CH2:14][CH3:15].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[CH2:7]([O:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:9]=1[O:10][CH2:18][CH2:17][O:16][CH2:13][CH2:14][CH3:15])[CH:2]=[O:1])[CH3:8]
Reactant: CCCOCCCl
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(C=O)cc1OCC
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl vanillin (5.0 g), 2-chloroethyl propyl ether (4.6 ml), sodium iodide (5.46 g), potassium carbonate (6.23 g) and DMF (50 ml) was stirred at 90° C. for 3 days. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain 3-ethoxy-4-(2-propoxyethoxy)benzaldehyde (7.34 g) as a light yellow, oily substance.