Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]([CH2:7][C:6]1[CH:28]=[CH:29][C:3]([CH2:2][O:1][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:4][CH:5]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)(=[O:10])=[O:11])([O-:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CO)cc1)Cc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirring solution of N-(4-hydroxymethyl-benzyl)-2-nitro-N-pyridin-2-ylmethyl-benzenesulfonamide (Bridger, et al., U.S. Ser. No. 09/111,895) (0.2096 g, 0.51 mmol) in CH2Cl2 (5 mL) at 0° C. under Ar, was added Et3N (0.14 mL, 1.02 mmol) and MsCl (0.05 mL, 0.66 mmol). The mixture was stirred at 0° C. for 2 hours, then stirred at room temperature for 3 hours. Additional Et3N (0.30 mL, 2.16 mmol) and MsCl (0.10 mL, 1.32 mmol) were added, and stirred for 18 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide 0.2383 g (95%) of methanesulfonic acid 4-{[(2-nitro-benzenesulfonyl)-pyridin-2-ylmethyl-amino]-methyl}-benzyl ester as a yellow oil. 1H NMR (CDCl3) δ 3.14 (s, 3H), 4.51 (s, 2H), 4.60 (s, 4H), 7.02-7.24 (m, 6H), 7.54-7.57 (m, 2H), 7.66 (d, 2H, J=3.0 Hz), 7.94 (d, 1H, J=9.0 Hz), 8.41-8.43 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:16]/[C:15]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: CSc1ccc(/C=C/C(C)=O)cc1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(/C=C/C(=O)/C=C/C(=O)O)cc1

Procedure:
A solution of 10.5 g (54.6 mmol) of (E)-4-[4-(methylthio)phenyl]but-3-en-2-one and 5.02 g (54.6 mmol) of glyoxylic acid monohydrate in 15 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether yielded (E,E)-6-[4-(methylthio)-phenyl]-4-oxo-2,5-hexadienoic acid of melting point 160°-163°.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-:13].[K+]>CN(C)C=O>[F:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
18.6 g (0.1 mol) of 4-chloro-3-nitrobenzaldehyde and 6.4 g (0.11 mol) of potassium fluoride in 50 ml of dimethylformamide are stirred at 160° C. After 3 hours, 4-chloro-3-nitrobenzaldehyde is no longer detectable in the reaction mixture, according to gas chromatography. Instead, 4-fluoro-3-nitrobenzaldehyde has formed quantitatively.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([C:19](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69 %

Procedure:
A solution of 3-(1-benzyl4-(S)-phenylpyrrolidine-3-(R)-carbonyl)-4(S)-benzyl oxazolidin-2-one (from Step B) in 2.5 L of THF at 10° C. was treated with 1.18 L of 1.0 M lithium aluminum hydride solution in THF over a period of 2 h. The resulting mixture was warmed to rt and stirred for 20 h. The reaction was quenched by adding 40 mL of H2O, then 40 mL of 2.0 N NaOH, then 115 mL of H2O and then was stirred at rt for 1.5 h. The mixture was filtered and the filtrate was concentrated. Chromatography on 4 kg of silica using 4:1 hexanes/acetone (14 L), then 7:3 hexanes/acetone as the eluant to afford 108.4 g (69%) of the title compound: 1H NMR (400 MHz) δ2.38-2.46 (m, 2H), 2.78‥2.88 (3H), 3.20-3.26 (2H), 3.65 (dd, J=12.0, 4.0, 1H), 3.66 (app s, 2H), 3.74 (dd, J=12.0, 4.0, 1H), 7.18-7.34 (10H); ESI-MS 268 (M+H); HPLC A: 2.35 min.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(C)C.[OH-].[K+]>CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.3 %

Procedure:
A solution of 382 mg of p-[(trimethylsilyl)ethynyl]-phenol (prepared according to Example 10) in 15 ml of a 1:1 mixture of methanol and 1N aqueous potassium hydroxide solution was stirred at room temperature for 45 minutes in a round flask under argon gasification. Methanol was subsequently removed on a rotary evaporator and the residue, after the addition of 30 ml of 1N hydrochloric acid, was extracted three times with 30 ml of diethyl ether each time. The organic phases were washed twice with 30 ml of water each time and once with 30 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. There were obtained 207 mg (88%) of p-ethynylphenol as a colourless oil (decomposing rapidly in the pure state) which was taken up immediately in 50 ml of diethyl ether and treated with 436 mg of trans-4-pentylcyclohexanecarboxylic acid, 454 mg of N,N'-dicyclohexylcarbodiimide and 24.4 mg of 4-(dimethylamino)pyridine. This mixture was stirred at room temperature for 18 hours and subsequently filtered. The filtrate was treated with 50 ml of water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the residue (847 mg) on silica gel with 3% ethyl acetate petroleum ether gave 277 mg (46%) of trans-4-pentylcyclohexanecarboxylic acid p-ethynylphenyl ester as colourless crystals (purity 98.5%) which were recrystallized further from methanol (purity 99.1%); m.p. (C-N) 50.6° C., cl.p. (N-I) 78.5° C.
Reaction SMILES: [N+]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH2:16][CH:15]3[CH2:17][CH:11]([CH2:12][N:13]([C:18](=[O:26])[NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14]3)[CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[ClH:29]>>[C:20]1([NH:19][C:18]([N:13]2[CH2:14][CH:15]3[CH2:17][CH:11]([CH2:10][N:9]([CH2:8][C:7]4[CH:27]=[CH:28][C:4]([Cl:29])=[CH:5][CH:6]=4)[CH2:16]3)[CH2:12]2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl
Reactant: O=C(Nc1ccccc1)N1CC2CC(CN(Cc3ccc([N+](=O)[O-])cc3)C2)C1
Product: O=C(Nc1ccccc1)N1CC2CC(CN(Cc3ccc(Cl)cc3)C2)C1

Procedure:
7-(4-Nitrobenzyl)-3-(phenylcarbamyl)-3,7-diazabicyclo[3.3.1]nonane, mp.: 187° C. (×HCl)
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:5]=1.[Cl:24]C(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:24][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CN(C)C)c2cccnc21
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCl)c2cccnc21
Reaction time: 2 h

Procedure:
Into a round bottom flask was added compound 4 (500.0 mg, 1.51 mmol) and toluene (5.0 mL, 0.047 mol) under an atmosphere of nitrogen. Into the reaction mixture 1.0 M isopropyl chloroformate in toluene (1.6 mL) was added slowly at room temperature. The reaction mixture was stirred for another 2 hours to give desired compound 5 used for next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[CH3:23][N+:24](=[CH2:26])[CH3:25].O>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH2:26][C:7]1[CH:6]=[C:5]([CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:3][C:2]=1[OH:1])[CH3:25]
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Reactant: C=[N+](C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)Cc1ccc(O)c(CN(C)C)c1
Reaction time: 72 h

Procedure:
To a solution of ethyl 3-(4-hydroxyphenyl)-2-methylpropanoate (672) (150 mg, 0.72 mmol), potassium carbonate (149.3 mg, 1.08 mmol) in toluene (7 mL) was added N,N-dimethylmethylideneammonium iodide (173.2 mg, 0.94 mmol) and stirred for 72 hours. Water was added and the reaction was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%) to give ethyl 3-(3-((dimethylamino)methyl)-4-hydroxyphenyl)-2-methylpropanoate (673).
Reaction SMILES: C([O:8][C:9](=O)[CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][O:13][CH3:14])C1C=CC=CC=1.[Li+].[BH4-].C1COCC1>C(OCC)C>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:11]([CH2:12][O:13][CH3:14])[CH2:10][CH2:9][OH:8])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC[C@H](CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of (S)-3-tert-Butoxycarbonylamino-4-methoxy-butyric acid benzyl ester (10.4 g, 32.3 mmol) in dry diethylether (70 ml) cooled to 0° C. is treated slowly with a 2.0 M solution of LiBH4 in THF (32.2 ml, 64.4 mmol). The reaction mixture is allowed to warm to ambient temperature and then left to stir. After 6 hours the reaction mixture is quenched slowly with 0.5 M aqueous solution of citric acid and extracted with ether. The ether phase is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (elution with a gradient 3:7 to 6:4 ethylacetate/hexane) to afford ((S)-3-Hydroxy-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester as a clear oil. [M-BOC] 120.13
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-])=O.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].P.[OH-].[Na+]>Cl[Pd]Cl.O.C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[NH2:12]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: P
Solvent: O
Solvent: Cc1ccccc1C
Product: Nc1cc(C(F)(F)F)ccc1Cl

Procedure:
A degassed solution of 40 mmol of 2-chloro-5-trifluoromethylnitrobenzene (starting material) and 40 ml of xylene are placed in an autoclave (volume: 200 ml). 5.0 mmol of TPPTS (in the form of 9.2 g of an aqueous solution containing 0.546 mol of TPPTS/kg of solution) as phosphine and 2.4 g (60 mmol) of NaOH, 23.8 ml of H2O and 1.0 mmol of PdCl2 are added. The pH is from 10.5 to 11.0.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:1]([O-:4])=[O:2])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
40.8 g of 100% nitric acid were added dropwise at from 0 to 5° C. to a solution of 118.9 g of 3-chloro-2-(4-fluorophenyl)-5-trifluoromethylpyridine in 563 ml of 96% sulfuric acid, and the mixture was then stirred at from 0 to 5° C. for 11/2 hours. For work-up, the reaction mixture was poured into 2 l of ice water, and the product was then extracted with ethyl acetate (3×300 ml). The combined organic phases were washed twice with 100 ml of water in each case, dried over sodium sulfate and then evaporated. Yield: 134.5 g (97%) of a colorless oil which crystallized slowly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][CH:16]([CH2:18]Cl)[CH3:17]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:16]([Cl:15])=[CH2:17])=[CH:4][CH:3]=1
Reactant: CC(Cl)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cl)COc1ccc(Cl)cc1
Yield: 92.5 %

Procedure:
To a mixture of 4-chlorophenol (6.1 g, 47.4 mmol) and potassium carbonate (13.1 g, 94.7 mmol) in acetone (200 mL), 2,3-dichloropropane (6.6 mL, 71 mmol) was added. After heating to reflux the reaction mixture for 48 hours, the reaction mixture was cooled and filtered. The residue was washed with more acetone and the combined filtrates were concentrated in vacuo. The crude pale brown liquid (11.5 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 85/15) to give 1-(4-chlorophenoxy)-2-chloro-2-propene (8.9 g, 98%) as a white liquid: Anal. Calc'd. for C9H8OCl2: C, 53.23; H, 3.97. Found: C, 53.09; H, 3.95.
Reaction SMILES: C[O:2][C:3]([C:5]1([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]>CO.C1COCC1.[OH-].[Na+]>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:5]2([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)(=[O:14])=[O:15])=[CH:21][CH:20]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)OC)CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)O)CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of methyl1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)-amino]cyclohexanecarboxylate (4.6 g, 12.1 mmol) in methanol:THF (4:1, 100 ml), 10 N sodium hydroxide (15 ml) was added at room temperature. The reaction was stirred for 16 h and evaporated to dryness in vacuo and the residue was dissolved in 100 mL water. The pH was adjusted to 1 with 5N hydrochloric acid solution and the mixture was extracted with chloroform, washed with water, dried and concentrated to give 1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohexanecarboxylic acid as a yellow solid. Yield: 4 g(88%); mp 124-6° C. Electrospray Mass Spec 364(M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:18]([O-])=O.Cl.[OH-].[Na+]>CCO>[NH2:18][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:11][C:12]=2[C:2]=1[Cl:1]
Reactant: CCOC(=O)N1CCc2ccc([N+](=O)[O-])c(Cl)c2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc(N)c(Cl)c2CC1
Yield: 99.3 %

Procedure:
To 6.431 g of ethyl 6-chloro-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate was added 120 ml of EtOH, followed by stirring at 60° C. for dissolution, and 12.15 g of reduced iron and 60 ml of 1 M hydrochloric acid were added thereto, followed by heating and refluxing for 1 hour. The reaction mixture was alkalified by the addition of a 1 M aqueous sodium hydroxide solution and then filtered through celite, and then the organic solvent was evaporated under reduced pressure. The residue was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain 5.743 g of ethyl 7-amino-6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a reddish orange viscous substance.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:20]C([N-]C(C)C)C.C1CCCCC1.CI>C1COCC1>[CH3:20][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
A solution of Example 532A (2.1 g, 8.1 mmol) in THF (81 mL) at −78° C. was treated dropwise with 1.5M LDA in cyclohexane (6.0 mL, 8.9 mmol), stirred for 30 minutes, treated dropwise with methyl iodide (0.76 mL, 12.1 mmol), stirred for 2.5 hours, quenched with saturated NH4Cl, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated to provide the desired product. MS (DCI) m/e 272 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]3([CH3:16])[O:15][CH:9]3[C:8]=2[CH:17]=1)([O-:3])=[O:2].[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[O:24].O.C(OCC)(=O)C>C(O)C.O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([OH:15])[CH:9]([N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]3=[O:24])[C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: O=c1cccc[nH]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C2OC21C
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)C1(C)O
Yield: 25.3 %

Procedure:
A solution of 6-nitro-2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran (9.93 g, 0.0422 mol), 2(1H)-pyridinone (8.04 g, 0.0845 mol) and Triton B (40% in ethanol, 2.5 ml) in dioxan (100 ml) was heated at reflux for twenty hours. Water and ethyl acetate were added to the cooled solution, the organic phase separated and the solvent removed under reduced pressure. The residue was washed with diethyl ether and pentane, to give 3.53 g of 6-nitro-2,2,3-trimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-3,4-dihydro-3-hydroxy-2H-1-benzopyran, m.p. 214° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5]([NH2:7])=[O:6].O=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([OH:13])=[O:12].C(OC)(=O)CC(C)C>O>[CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5]([NH:7]/[C:10](=[CH:14]\[CH2:15][CH2:16][C:17]([OH:19])=[O:18])/[C:11]([OH:13])=[O:12])=[O:6]
Reactant: CC1(C)CC1C(N)=O
Reactant: O=C(O)CCCC(=O)C(=O)O
Agent: COC(=O)CC(C)C
Solvent: O
Product: CC1(C)CC1C(=O)N/C(=C\CCC(=O)O)C(=O)O
Reaction time: 8 h

Procedure:
A mixture of 1.0 g. of 2,2-dimethylcyclopropanecarboxamide, 2.4 g. of 2-ketoadipic acid and 25 ml. of methyl isovalerate was heated under reflux for 4 hrs, with removal of H2O by a modified Dean-Stark trap containing molecular sieves (4A). After standing at room temperature overnight, the crystalline precipitate was filtered, washed with ether and recrystallized from ethyl acetate to give 0.23 g. of product, m.p. 163°-165°. The NMR spectrum was consistent with the desired structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:3]=2)=[CH:28][CH:27]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: Oc1ccc(F)cc1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2ccc(F)cc2)n1

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-fluorophenol in analogy to example 3. It was purified by column chromatography on silica gel using ethyl acetate as eluent to give the title compound as a yellowish solid in 52% yield.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:21][NH:22]CC2C=CC=CC=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.[C:38]([OH:41])(=[O:40])[CH3:39]>CO>[C:38]([OH:41])(=[O:40])[CH3:39].[NH2:22][CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
8-Benzyloxy-5-[(R)-2-(N-benzylamino)-1-(tert-butyldimethylsilanyloxy)ethyl]-1H-quinolin-2-one (100 g, 194 mmol) and acetic acid (17.5 mL, 291 mmol) were dissolved in methanol (1 L). The clear solution was purged with nitrogen and then palladium hydroxide on carbon (20 g, 20 wt. % Pd (dry basis), wet (about 50% water)) was added. Hydrogen gas was bubbled through the stirred solution at room temperature for 6 hours during which time a thick slurry developed. The reaction mixture was then purged with nitrogen and methanol (1 L) was added. The resulting mixture was stirred for about 30 minutes (to dissolve the product) and then the mixture was filtered through a pad of Celite. The filterate was concentrated under reduced pressure to a volume of about 500 mL and, to the resulting slurry, was added ethanol (500 mL). The resulting mixture was again concentrated under reduced pressure to a volume of about 500 mL and the resulting precipitate was collected by filtration and dried to provide the title compound as a yellow-white solid (65 g, 85% yield, >98% purity).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([C:23]#[N:24])[CH3:22])[C:12]([CH2:26][CH3:27])=[CH:11][C:10]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pt]=O>[CH2:26]([C:12]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([CH3:22])[CH2:23][NH2:24])=[CH:14][C:9]([OH:8])=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:11]=1)[CH3:27]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCCCC(C)(C)CN
Reaction time: 20 h
Yield: 120.5 %

Procedure:
1-(benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(6-methyl-6-cyanoheptyl)oxy]-benzene (485 mg) was dissolved in ethanol (15 mL) and added to a solution of platinum oxide (20 mg) in 10 mL ethanol in a Parr bottle. The bottle was pressurized to 55 psi with hydrogen and shaken for 20 hours. Additional catalyst (120 mg) was added and bottle shaken at 55 psi of hydrogen for an additional 18 hours. The solution was filtered through Celite and concentrated under vacuum to afford crude 4-ethyl-2-(4-fluorophenyl)-5-[(6,6-dimethyl-7-aminoheptyl)oxy]phenol (475 mg) as an oil. It was purified by chromatography on silica gel with chloroform/methanol eluant. The product fractions were combined and concentrated under vacuum (120 mg). NMR (CDCl3): 1.00, s, (6H); 1.15, t (3H); 1.33, m (2H); 1.44, m (2H); 1.77, m (2H); 2.55, q (2H); 2.74, s (2H); 3.92, t (2H); 6.52, s (1H); 6.96, s (1H); 7.11, d of d (2H); 7.43, d of d (2H). Mass Spec (EI), m/e=374.3 (M+H).