Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(Cl)c(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Methyl 4-chloro-3-(phenylmethoxy)benzoate (82b) (3.4 g, 11.9 mmol) was dissolved in 20 mL tetrahydrofuran (THF). The solution was cooled to 0° C. A 2M solution of lithium aluminum hydride in THF (5.9 mL, 11.9 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched at 0° C. using a small amount of water until hydrogen evolution ceased. The white precipitate was dissolved using 5% HCl and the solution diluted with ethyl acetate. The ethyl acetate layers were washed with water, brine, dried over sodium sulfate (Na2SO4) and concentrated to dryness to provide 2.74 g (93% yield) of the title compound (82c).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)([CH3:4])[CH3:3].S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:23][CH2:11][C:9]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(-c2ccc(CO)cc2C(C)(C)C)c1
Solvent: ClCCl
Product: COc1cccc(-c2ccc(CCl)cc2C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
A dry, round bottom flask containing 12.2 (0.82 g, 3.04 mmol) and DCM (8.5 mL) was cooled to 0° C. After 15 minutes, thionyl chloride (1.50 mL, 20.56 mmol) was carefully added dropwise at 0° C. Upon complete addition of thionyl chloride, the mixture was allowed to warm to room temperature and stirred overnight. After 25 hours, the reaction was concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-15% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 12.3 as a colorless oil (0.82, 93%). 1H NMR (500 MHz, CDCl3) δ ppm 7.53 (1H, d, J=1.7 Hz), 7.28 (3H, m), 7.03 (1H, d, J=7.8 Hz), 6.90 (3H, m), 4.65 (2H, s), 3.82 (3H, s), 1.23 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([F:28])[CH:27]=1)[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([F:28])[CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cc(F)cc(F)c4)cc3c2C1
Yield: 36.5 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 3,5-difluorobenzoyl chloride, 6.2 mg (36%) of the title compound were recovered as a beige solid.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[N:17]=[C:18]([NH:20]C(=O)C)[S:19][C:10]=4[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[N:17]=[C:18]([NH2:20])[S:19][C:10]=4[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3ccccc3)ncc1CC2
Agent: Cl
Product: Nc1nc2c(s1)-c1nc(-c3ccccc3)ncc1CC2

Procedure:
9.0 g (28 mmol) N-(8-phenyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamide (prepared analogously to Example 64) are refluxed for 2 hours in 130 ml semi-concentrated hydrochloric acid. After cooling the reaction mixture is made basic, the precipitate formed is suction filtered and dried. Yield: 7.3 g
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5]2.[C:29]([O:46][CH:47]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:48][S:49][CH2:50][CH2:51][C:52](O)=[O:53])(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].O>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:29]([O:46][CH:47]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:48][S:49][CH2:50][CH2:51][C:52]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5]2)=[O:53])(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CC(C)(C)OC(=O)CCC(C(=O)OC(C)(C)C)N1Cc2cc(N)ccc2C1=O
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: O
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc2c(c1)CN(C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2=O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of 5-amino-2-(1,3-bis-(t-butyloxycarbonyl)propyl)isoindolin-1-one (178 mg) in pyridine (2.3 ml), phosphorus trichloride (0.020 ml) was added, followed by stirring at room temperature for 2 hours. To this mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid (150 mg) was added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate =2:1) to yield the title compound (208 mg, yield 91%) as a wax-like substance.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:14]1([O:13][CH2:12][CH2:11][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:24])=[O:2])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccccc1OCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1ccccc1OCCOc1cccc2ccccc12
Yield: 77 %

Procedure:
A solution of 1.6 g (3.15 mmol) of 3,5-bis[2-[2-(naphthalenyloxy) ethoxy]benzoic acid methyl ester and 15 mL (15 mmol) of 1N NaOH in 45 mL of methanol and 20 mL of dioxane was stirred at reflux for 2 hours. The usual workup followed by recrystallization from THF-ethyl acetate gave 1.2 g (77% yield, mp 205°-207°) of 3,5-bis[2-[2-(naphthalenyloxy)ethoxy]benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH2:21](O)[CH3:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([O:16][CH2:21][CH3:22])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)C1CCN(c2ccc(Br)cc2)CC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-bromophenyl)piperidine-4-carboxylic acid (1.56 g, 5.5 mmol) in absolute ethanol (30 mL) was cooled to 0° C. and SOCl2 (1.18 g, 10 mmol) added drop-wise. The mixture was stirred to room temperature and heated to reflux for 3 hours. The reaction mixture was evaporated in vacuo and the residue dissolved in saturated aqueous solution of NaHCO3 (50 mL). The aqueous solution was extracted with EtOAc (3×30 mL). The organic extracts was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane=1:1) to yield the title compound pale brown oil 1.08 g. MS (m/z): 314 (M+2)+
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CCNCC1
Solvent: O
Product: CC(=O)N1CCC(C(=O)O)CC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Isonipecotic acid (129.2 g, 1.00 mol) was dissolved in water (390 mL), and acetic anhydride (153.1 g, 1.50 mol) was added dropwise under ice-cooling for about 10 min. (dropwise addition at 15-18° C. for about 10 min.). After stirring at 55±5° C. for 2 hrs., the mixture was allowed to cool to room temperature and stirred under ice-cooling for 1 hr. The precipitated crystals were collected by filtration, washed with cold diisopropyl ether (125 mL×2) and dried under reduced pressure at 40° C. for 8 hrs. to give the title compound (129.1 g, yield 75.4%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[Mg].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:41])[CH:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH3:34])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:2]2[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=2)([OH:41])[CH:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH3:34])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: CCC(C(=O)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(c1ccccc1)C(O)(c1ccc(OCc2ccccc2)cc1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 19.32 g of (4-bromophenoxy)-tert-butyldimethylsilane in 50 ml of tetrahydrofuran is added in drops to a suspension of 1.58 g of magnesium chips in 100 ml of tetrahydrofuran at 80° C. bath temperature, and it is refluxed for 1 hour. Then, it is cooled to 0° C., and 6.0 g of 1-(4-benzyloxyphenyl)-2-phenyl-butan-1-one [D. W. Robertson; J. A. Katzenellenbogen; D. -J. Ellen; A. Rorke; B. S. Katzenellenbogen, J. Steroid Biochem., 1982, 16, 1-13] is added, and it is stirred for 24 more hours at room temperature. For working-up, 60 ml of saturated ammonium chloride solution is added, diluted with ethyl acetate, washed neutral with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 9.1 g of 1-(4-benzyloxyphenyl)-1-(4-tert-butyldimethylsiloxy-phenyl)-2-phenyl-butan-1-ol is obtained as oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](O)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:51][CH2:52][CH2:53][C:54]#[N:55]>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](=[O:25])[NH:55][CH2:54][CH2:53][C:52]#[N:51])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: N#CCCN
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)NCCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
Next, to a solution of (R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl ester (200 mg, 0.522 mmol) in THF (10 mL) at room temperature is added EDC HCl (120 mg, 0.626 mmol) and HOBT (96 mg, 0.626 mmol). The reaction is stirred at room temperature for 10 minutes then added 3-aminopropionitrile (0.046 ml, 0.626 mmol) and TEA (0.087 ml, 0.626 mmol). After 1 hour, 0.5 equivalent of EDC HCl, HOBT, and 3-aminopropionitrile are added and stirred for 16 hours. The reaction mixture is quenched by brine and is extracted with ethylacetate. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 2% to 5% EtOH/DCM) to give (R)-4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-butyric acid ethyl ester (218 mg, 96% yield). HPLC retention time=0.77 minutes (condition E); MS=436 (m+1).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:28]C(C)(CC(C)C)C(O)=O>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:20]3[CH:27]=[CH:26][C:23]([CH2:24][NH2:28])=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reactant: CC(C)CC(C)(N)C(=O)O
Solvent: CN(C)C=O
Product: NCc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Temperature: 150 °C

Procedure:
A suspension of 4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzaldehyde (4-2, 0.80 g, 2.3 mmol) and 2-amino-2,4-dimethylpentanoic acid (3-7, 0.340 g, 2.3 mmol) in DMF (10 mL) was heated at 150° C. for 30 min. The reaction mixture cooled and the solvent was removed in vacuo. The crude residue was dissolved in 3N HCl (8 mL) and was heated at 100° C. for 30 min. The mixture was cooled and purified via reverse phase HPLC (5-65% acetonitrile/water over 15 min) to give, upon evaporation of the solvents, the title compound as a yellow solid. 1H-NMR (CD3OD) δ 9.60 (s, 1H), 8.98 (s, 1H), 8.73 (d, 1H), 7.75 (d, 1H), 7.60 (d, 2H), 7.46 (d, 2H), 7.39-7.36 (m, 5H), 4.15 (s, 2H).
Reaction SMILES: S(C1SC2=C[N+]([O-])=CC=C2C=1)(=O)(=[O:3])N.[S:15]([C:19]1[S:27][C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[CH:20]=1)(=[O:18])(=[O:17])[NH2:16].S(C1SC2=CN=CC=C2C=1)(=O)(=O)N>>[S:15]([C:19]1[S:27][C:26]2[CH:25]=[CH:24][N+:23]([O-:3])=[CH:22][C:21]=2[CH:20]=1)(=[O:17])(=[O:18])[NH2:16]
Reactant: NS(=O)(=O)c1cc2cc[n+]([O-])cc2s1
Reactant: NS(=O)(=O)c1cc2cnccc2s1
Agent: NS(=O)(=O)c1cc2ccncc2s1
Product: NS(=O)(=O)c1cc2c[n+]([O-])ccc2s1

Procedure:
The title compound was prepared according to the procedure described for 2-sulfamoylthieno[2,3-c]pyridine-6-oxide (Example 3) except 2-sulfamoylthieno[3,2-c]pyridine was substituted for 2-sulfamoylthieno[2,3-c]pyridine. The title compound was obtained in 69% yield; m.p. 252°-254° C., after recrystallization from dimethyl sulfoxide/ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](O)=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:21].P(Cl)(Cl)(Cl)=O>CCCCCC>[Cl:21][C:8]1[C:7]2[C:12](=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([N+:17]([O-:19])=[O:18])[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:14]#[N:15]
Reactant: CCOc1cc2ncc(C#N)c(O)c2cc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Yield: 58.2 %

Procedure:
A mixture of 3.45 g (13 mmol) of 7-Ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 5.55 g (26 mmol) of phosphorous pentachloride, and 10 ml of phosphorous oxychloride was refluxed for 3 hours. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in 500 ml of ethyl acetate and washed with cold diluted sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed giving 2.1 g of beige solid: mass spectrum (electrospray, m/e) M+H 277.7.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([NH:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([N+:20]([O-:22])=[O:21])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C)cccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a mixture of 0.72 g of 2-acetylamino-3-methylbenzoic acid and 8 ml of concentrated sulfuric acid was added dropwise 1.6 g of fuming nitric acid at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water. A deposited precipitate was collected by filtration to obtain 0.45 g of 2-acetylamino-3-methyl-5-nitrobenzoic acid of the formula:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]#[N:21])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.CO.[Pt]=O>[NH2:21][CH2:20][CH2:19][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH:10]1[OH:22]
Reactant: CCOC(=O)C1(CC#N)CCN(Cc2ccccc2)CC1=O
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1(CCN)CCN(Cc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 10000-mL 4-necked round-bottom flask was placed a solution of ethyl 1-benzyl-4-(cyanomethyl)-3-oxopiperidine-4-carboxylate (180 g, 599.30 mmol) in acetic acid/methanol (1:1, 5.4 L) and platinum oxide (27 g, 118.90 mmol). The flask was then flushed and charged with hydrogen and stirred overnight at room temperature. After filtration under nitrogen through CELITE®, the filtrate was concentrated under vacuum to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=1.[C:14]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[C:14]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[CH:13]=[CH:12][C:7]4[N:8]=[CH:9][S:10](=[O:11])[C:6]=4[CH:5]=3)[CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=S1C=Nc2ccc(CCBr)cc21
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=S1C=Nc2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc21

Procedure:
To a 100 ml round-bottomed flask with condenser and nitrogen inlet were added 1.0 gram (3.88 mmol) of 6-(2-bromoethyl)benzothiazolone, 822 mg (3.88 mmol) N-(1-naphthyl)piperazine, 410 mg (3.88 mmol) sodium carbonate, and 50 ml methylisobutlyketone. The reaction was refluxed for 24 hours, cooled, and evaporated. The residue was taken up in ethyl acetate, wawshed with water and brine, dried over sodium sulfate, and evaporated. The resulting solid was treated with hot ethyl acetate to afford a white solid, m.p. 198°-220° C., 540 mg (36%).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:45])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:35](=[O:44])[NH:36][C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)[CH2:26][CH2:27][N:28]2[CH2:33][C@@H:32]3[CH2:34][C@H:29]2[CH2:30][O:31]3)=[CH:21][CH:20]=1)(C)(C)C.C([O-])(O)=O.[Na+]>CO>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([CH:25]([CH2:26][CH2:27][N:28]2[CH2:33][C@@H:32]3[CH2:34][C@H:29]2[CH2:30][O:31]3)[C:35]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)=[O:44])=[CH:23][CH:24]=1)=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCN2C[C@@H]3C[C@H]2CO3)C(=O)Nc2ccc(Br)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCN2C[C@@H]3C[C@H]2CO3)C(=O)Nc2ccc(Br)cc2)cc1
Reaction time: 4 h

Procedure:
Hydrochloric acid in methanol (1.25 M, 5 mL) was added to the (E)-[2-(3-{4-[1-(4-bromo-phenylcarbamoyl)-3-({1S,4S}-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-propyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester residue, the mixture was stirred for about 4 h, and then NaHCO3 was added to the reaction system. After filtration of solids, the crude mixture was purified by preparative HPLC to obtain light yellow solid. MS: calc'd 575 (MH+), exp 575 (MH+). 1H NMR (d6-DMSO, 400 MHz), 10.25 (d, 1H, J=8.8 Hz), 9.40 (s, 1H), 7.59-7.45 (broad m, 9H), 7.39 (d, 1H, J=8.0 Hz), 6.94-6.85 (m, 2H), 6.75 (d, 1H, J=8.0 Hz), 6.58 (t, 1H, J=8.0 Hz), 4.95 (s, 1H), 4.31 (s, 1H), 3.85-3.78 (broad m, 2H), 3.47-3.42 (broad m, 2H), 2.78 (broad s, 1H), 2.43-2.20 (broad m, 3H), 1.78-1.54 (broad m, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1C=CC=CC=1>[C:38]([O:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2)(=[O:40])[CH3:39]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
0.725 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione was dissolved in 4 ml of benzene; 400 mg of dry pyridine were added; 0.2 g of acetic anhydride was added dropwise under a nitrogen stream at 5°-10° C.; and the mixture was reacted for 2 days at room temperature. The resulting white crystals were separated by filtration, washed with benzene and vacuum-dried for 30 minutes at 90° C., giving 0.74 g of the benzene mono adduct of 5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione. This substance was liquefied at 98°-100° C., solidified and again liquefied at 176°-178° C.
Reaction SMILES: Br[CH2:2][CH:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].O1C=CCCC1>C(Cl)Cl.CCOCC.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>[O:10]1[CH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCC(O)CBr
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: OCCCCCC1CO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 225.1 %

Procedure:
A solution of 4 (123 mg, 0.58 mmol) and dihydropyran (0.22 mL, 2.33 mmol) in methylene chloride (2 mL) containing pyridinium tosylate (25 mg, 0.1 mmol) was stirred at room temperature for 20 hours. It was diluted with ether and washed with saturated aqueous sodium chloride. The separated aqueous layer was extracted once with ether and the combined ether layer was dried over magnesium sulfate. The crude product was purified on a silica gel column to give 170 mg of 7-bromo-1,6-bistetrahydropyranyl heptanyl ether (6). PMR (CDCl3): δ4.86-4.48 (m, 2H), 4.00-3.41 (m, 9H), 1.93-1.18 (m, 20H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:12][CH2:13][C:14]([O:16]CC1C=CC(OC)=CC=1)=[O:15])[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]([O:4][CH:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)C(CCC(=O)OCc1ccc(OC)cc1)OC(C)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)C(CCC(=O)O)OC(C)=O
Yield: 116.4 %

Procedure:
According to a similar procedure to that described in Example 1-(11), allyl 2-acetoxy-5-[(4-methoxybenzyl)oxy]-5-oxopentanoate (1.36 g, 3.88 mmol) obtained from Example 2-(3), anisole (1.50 g, 13.87 mmol), and trifluoroacetic acid (3 ml) were reacted, and the reaction mixture was worked up to afford the title compound (1.04 g, quantitative yield).