Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.[CH2:10](Br)[CH:11]=[CH2:12].[NH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=4[C:28](=[O:37])[N:27]4[CH2:38][CH2:39][C@H:26]4[C:25]=23)[N:17]=1>C(Cl)Cl>[CH2:10]([N:14]([CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=4[C:28](=[O:37])[N:27]4[CH2:38][CH2:39][CH:26]4[C:25]=23)[N:17]=1)[CH2:6][CH:4]=[CH2:5])[CH:11]=[CH2:12]
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2F)no1
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCBr
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2C2CCN2C(=O)c2c-3ccc(F)c2F)no1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.3 ml (13.5 mmol) of N-ethyldiisopropylamine and 0.66 ml (7.8 mmol) of allyl bromide were added to a solution of 700 mg (1.95 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 40 ml of methylene chloride and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with methylene chloride and washed three times with water. The organic phases were dried over magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol 19:1). There were obtained 400 mg (46%) of S)-1-[5-(diallylaminomethyl)-1,2,4-oxadiazol-3-yl]-7,8-difluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as a colourless foam, Rf=0.17 (silica gel, methylene chloride/methanol 19:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[CH3:11]
Reactant: CCN
Reactant: Cc1ccnc(C=O)c1
Solvent: C1CCOC1
Product: CCNCc1cc(C)ccn1

Procedure:
prepared by reaction of the commercially available 4-methyl-pyridin-2-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[O:22]1[CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23]1>>[OH:22][CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: CCCC1CO1
Product: CCCC(O)COc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 58 with 1,2-epoxypentane gave 2-(3-(3-(2-hydroxypentyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.93 g, 73%): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=6.0 Hz, 1H), 7.53-7.60 (m, 1H), 7.47-7.52 (m, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.14-7.19 (m, 1H), 6.78-6.83 (m, 2H), 6.73 (d, J=8.2 Hz, 1H), 3.81 (d, J=4.8 Hz, 2H), 3.73-3.79 (m, 1H), 3.18-3.24 (m, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.73-1.81 (m, 2H), 1.30-1.52 (m, 4H), 0.89 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=1[CH3:30])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=4[CH3:30])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 85.8 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (45.9 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days The precipitate was collected by vacuum filtration, washed with ethanol and dried, then washed with 1N HCl (3×), water (5×) and dried to give 88.8 mg (86%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.55 (br s, 1H, NH), 11.84 (br s, 1H, NH), 9.28 (s, 1H), 8.34 (s, 1H), 7.74 (m, 1H), 7.43 (m, 1H), 7.41 (s, 1H), 7.38 (t, J=9.1 Hz, 1H), 6.74 (d, J=2.15 Hz, 1H), 2.22 (s, 3H, CH3). MS 414 [M++1].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[N:17]=[C:16]1S(C)(=O)=O.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[N:15]([CH2:14][CH2:13][O:12][CH3:11])[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(Oc2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a stirred solution of 4-bromophenol (149 mg) in DMF (4 mL) was added NaH (60% in oil, 36.0 mg) at room temperature. The mixture was stirred at room temperature for 30 min. To the mixture was added 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (200 mg). The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (243 mg).
Reaction SMILES: C(OC([NH:8][CH:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C@@H:13]1[C:38](=[O:39])[N:15]2[C@@H:16]([C:22]([O:24]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:23])[C@@:17]([Cl:21])([CH3:20])[CH2:18][S:19][C@H:14]12)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[NH2:8][CH:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C@@H:13]1[C:38](=[O:39])[N:15]2[C@@H:16]([C:22]([OH:24])=[O:23])[C@@:17]([Cl:21])([CH3:20])[CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)C(N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
A mixture of benzhydryl 7β-(α-tert.-butoxycarbonylamino-α-phenylacetamido)-3β-chloro-3α-methylcepham-4α-carboxylate (150 mg), trifluoroacetic acid (4 ml), and anisole (1 ml) is stirred at room temperature for 30 minutes, then evaporated in vacuo, The residue is treated with ether to remove soluble material. The insoluble material is 7β-(α-aminophenylacetamido)- 3β-chloro-3α-methylcepham-4α-carboxylic acid trifluoroacetate. The material is mixed with water (1.5 ml) and 25% Amberlite LA-1R is methyl isobutyl ketone (1.5 ml), and stirred for 2 hours to give an insoluble material which is collected by filtration. The solid is washed with water, methyl isobutyl ketone, and ethyl acetate, and dried to give 7β-(α-aminophenylacetamido)-3β-chloro-3α-methylcepham-4α-carboxylic acid (35 mg). Yield: 40%. IR: νmaxNujol 5.8, 5.7, 5.7μ.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](C(C)=O)=[CH:5][CH:4]=1.N1[CH2:17][CH2:16][O:15]CC1.[S].[OH-:19].[Na+]>O>[CH2:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:17][C:16]([OH:15])=[O:19])=[CH:5][CH:4]=1)[CH3:1]
Reactant: [OH-]
Reactant: CCc1ccc(C(C)=O)cc1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [S]
Solvent: O
Product: CCc1ccc(CC(=O)O)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A 300 ml 3-neck flask equipped with a mechanical stirrer, condenser, dropping funnel, and Dean-Stark trap was charged with 66.9 grams (0.45 mol) 4-ethylacetophenone, 62.1 grams (0.71 mol) morpholine, and 22.8 grams (0.71 mol) sulfur. The contents were heated to 135°-140° C. under nitrogen, in some cases with removal of water. After 3 hours, the mixture was cooled to about 40° C. and about 120 grams of a 20% aqueous sodium hydroxide solution was added with stirring. This mixture was then heated to reflux and stirred for about 9 hours. After the reaction mixture was cooled some of the morpholine and water were distilled off at 90-100 Torr. To the residue at 60° C. was added slowly with stirring 50 ml of concentrated hydrochloric acid brought to boiling and the hot reaction mass was stirred for about 1 hour. The solid, which is a mixture mainly of the formed acid and sulfur, was collected after cooling by filtration and subsequently extracted with a 15% aqueous solution of sodium bicarbonate. The filtrate then was heated to boiling, decolorized with carbon, filtered, and the procedure repeated with the filtrate. The solid was washed with hot water, and the combined filtrates were acidified with concentrated hydrochloric acid to precipitate the free 4-ethylbenzeneacetic acid which was collected by filtration. Comparison of experiments performed with and without water removal during the morpholine-sulfur stage is shown in Table 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH:18][C:19](OC)=[O:20])=[CH:14][CH:15]=2)[CH:10]=[C:9]1C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH:18][CH2:19][OH:20])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=Cc1ccc2c(c1)cc(C)n2C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2cc(C=CCO)ccc21
Temperature: -5 °C
Yield: 69.1 %

Procedure:
To a solution of methyl 5-(2-methoxycarbonyl-vinyl)-indole-1-carboxylic acid tert-butyl ester (4.64 g, 15.3 mmol, 1.0 eq.) in THF (87 mL) at −30° C. was added LiAlH4 (1 N in THF, 18.6 mL, 1.2 eq.) by syringe pump over 20 min and the resulting mixture was stirred and warmed to −5° C. After cooling back to −30° C., the reaction was then quenched by slow addition of acetone (10 mL) keeping temperature below −15° C., poured into Rochelle salt at 0° C., stirred for 1 h and the separated aqueous layer was extracted with EtOAc. The combunede organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purification by column chromatography (methylene chloride to 2% acetone/methylene chloride) to give 5-(3-hydroxy-propenyl)-indole-1-carboxylic acid tert-butyl ester (2.89 g, 70%) or similarly 6-(3-hydroxy-propenyl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:23]=1[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:14]=2)[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cccc1COc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 85 °C

Procedure:
13-(Quinolin-2-ylmethoxy)-phenol (5.2 g, 21 mmol, example 3), methyl 2-bromomethyl-6-methyl-benzoate (example 2) (5.0 g, 21 mmol) and potassium carbonate (4.4 g, 32 mmol) are combined in DMF (50 mL) and heated at 85° C. for 3 h. The reaction is poured into ethyl acetate (500 mL) and washed with water (4×120 mL) and brine (100 mL). The solution is dried over magnesium sulfate, filtered and concentrated in vacuo to provide a residue which is purified by column chromatography (silica, 10 to 20% ethyl acetate in hexane) to provide the title compound. MS (ESI) 414 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C@H:5]([CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)[NH2:6].[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([NH:21][C:22]([NH2:6])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:2][O:3][C:4](=[O:13])[C@H:5]([CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)[NH2:6]
Reactant: O=C=NCc1ccccc1
Agent: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of histidine methyl ester hydrochloride (2.0 g, 4.3 mmol) in methylene chloride, at 0° C., was added benzyl isocyanate (0.58 mL, 0.63 g, 4.7 nmol) and triethylamine (1.32 mL, 9.5 mmol), and the solution was stirred overnight at room temperature. The solution was concentrated and the residue taken up in ethyl acetate. The solution was washed with water, saturated NaHCO3, brine, dried over MgSO4, and concentrated. The product was obtained as a white foam (1.09 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33](Cl)[CH:32]=1)[OH:30]>>[OH:30][C@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][S:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)(=[O:10])=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Agent: Cl
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccccc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-methoxy-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloride (which was obtained in Example 1) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55-1.75 (m, 2H), 2.05-2.15 (m, 2H), 2.50-3.10 (m, 5H), 3.50-3.70 (m, 2H), 3.79 (s, 3H), 4.90-5.05 (m, 1H), 6.10-6.20 (m, 1H), 6.79 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 7.05 (d, J=11.8 Hz, 2H), 7.25-7.50 (m, 5H), 7.60 (d, J=11.8 Hz, 2H), 9.70 (brs, 1H); MS (ES) m/z: 482.2 (MH+); HRMS Calcd. for C26H32N3O4S(MH+): 482.2114. Found: 482.2120.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11]Br.[Mg]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4](=[O:5])[CH3:11]
Reactant: O=Cc1cc(F)ccc1F
Reactant: CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 2,5-difluorobenzaldehyde (24.6 g) in tetrahydrofuran (100 ml) was added dropwise to an ice-cooled solution (207 ml) of 0.92N magnesium methylbromide in tetrahydrofuran. The resulting solution was stirred at room temperature for 1.5 hours, and the organic phase was washed in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to subsequently distill off the solvents under reduced pressure. To the residue were added anhydrous dichloromethane (500 ml), sodium acetate (14.2 g) and pyridinium chlorochromate (55.94 g), prior to stirring at room temperature for 10 hours. To the resulting mixture was added an aqueous saturated sodium hydrogen carbonate solution, prior to extraction in ethyl acetate three times. The organic phase was washed in water and in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=85:15), to recover 2′,5′-difluoroacetophenone (22.73 g; yield of 84%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: C([O:4][CH:5]1[C:10]([OH:14])([CH2:11][CH2:12][CH3:13])[CH:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]1[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)C=C.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>C(O)C>[CH2:16]([O:15][CH:9]1[CH:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:5]([OH:4])[C:10]1([OH:14])[CH2:11][CH2:12][CH3:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCOC1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1(O)CCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1(O)C(O)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reaction time: 288 h
Yield: 79.2 %

Procedure:
20 (0.30 g, 0.48 mmol) was dissolved in 20 mL aqueous ethanol (90%). 93 mg (0.101 mmol) Wilkinson catalyst and 50 μL diisopropylethyl amine were added and the mixture was heated to reflux for 12 hours. After cooling to room temperature 30 μL triflouro acetic acid was added and the solution was allowed to stir for 12 days by when the starting material had disappeared. The solution was dried in high vacuum and the residue was dissolved in t-butylmethyl ether and washed with 0.5 M phosphate buffer pH=7 and brine. The organic phase was filtered after being dried over Na2SO4 and the filtrate was dried under reduced pressure. Further purification was accomplished by preparative HPLC (89% MeOH, 40 m/min, tRet=21.40 min) to give 220 mg of 21 (0.38 mmol, 78.4% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.CN(C)C(=O)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>O>[CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])(=[O:16])=[O:17])=[CH:11][CH:10]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=C(C)C(=O)NS(=O)(=O)c1ccc(NC(=O)OCC(C)C)cc1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a mixture of 54.4 g of p-isobutyloxycarbonylaminophenyl sulfonamide, 40 g of triethylamine, 2 g of N,N-dimethylaminopyridine and 150 ml of N,N-dimethylacetamide was then added dropwise 22.8 g of methacrylic chloride under cooling with ice. After the completion of the dropwise addition, the reaction mixture was stirred for 2 hours. The reaction product was then poured into water. The resulting crystal was then withdrawn by filtration. The crystal was then recrystallized from a 3/7 (by volume) mixture of toluene and ethyl acetate to obtain 40 g of N-(p-isobutyloxycarbonylaminophenylsulfonyl)methacrylamide in the form of white crystal (m.p. 194°-196° C.).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)[CH3:3].CC(C)=O.S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].O>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2occ(C#N)c(=O)c2c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc2occ(C#N)c(=O)c2c1

Procedure:
To a solution of 0.645 part of 6-(1-hydroxyethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile in 20 parts by volume of acetone under stirring at room temperature is added dropwise over a period of 1 hour 1.0 part by volume of a solution which is prepared from chromium trioxide, 97% sulfuric acid and water in a ratio of 6.0 parts: 3.6 parts by volume: 18 parts by volume. The dark-green resins precipitated in the flask bottom is separated from the reaction mixture by decantation, and the solution is concentrated at room temperature to a one-third volume and then admixed with water to give precipitates. The precipitates collected by filtration is washed with water and recrystallized from ethyl acetate. The procedure yields 0.440 part of 6-acetyl-4-oxo-4H-1-benzopyran-3-carbonitrile as colorless crystals. Melting point: 170°-172° C
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)CC1CCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)CC1CCC(O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Twenty-seven g (0.129M) of 4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-ylacetamide is dissolved in absolute ethanol (270 ml) and treated with sodium borohydride (4.9 g, 0.129 M). The mixture is stirred at room temperature overnight, water (250 ml) is added and stirring continued for 2 hours. The bulk of the ethanol is evaporated and the precipitated solid is filtered off, washed twice with water (total 50 ml) and air dried to afford the title compound (13.73 g, 50.4% yield) as an off white solid, m.p 175° C. to 179° C. dec.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.CN([C:25]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)=[O:26])OC.[Cl-].[NH4+]>C1COCC1>[CH:8]([N:7]([CH2:6][C:5]1[CH:14]=[CH:15][C:2]([C:25]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:31][CH2:32]2)=[O:26])=[CH:3][CH:4]=1)[CH:11]([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CON(C)C(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)N(Cc1ccc(Br)cc1)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)N(Cc1ccc(C(=O)C2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)cc1)C(C)C
Reaction time: 0.5 h
Yield: 253.6 %

Procedure:
To a solution of N-(4-bromobenzyl)-N,N-diisopropylamine (2.3 g) in THF (10 ml) was added dropwise at −78° C. n-BuLi (1.6 mmol/ml hexane solution, 3.8 ml). Ten minutes later, N,O-dimethyl-N-(1-trityl-piperidine-4-carbonyl)hydroxylamine (1.5 g) in THF (20 ml) was added dropwise to the mixture, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to give the title compound (5.0 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH:7]=[CH:8]1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C.C[Li].[C:25]([O-])(O)=O.[Na+]>C(#N)C.CCOCC>[N:20]([CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]([OH:1])([CH3:25])[CH2:8]1)=[N+:21]=[N-:22]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CC1(O)CC(N=[N+]=[N-])CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (Z)-tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (15 g, 71.1 mmol) in acetonitrile (25 mL) was added trimethylsilylazide (28.2 mL, 213 mmol) followed by Amberlite IRA 900F resin (loading: 2-3 mmol/g, 18 g) and the mixture was heated at 60° C. for 4 hr. After standing at room temperature for 16 hr, the resin was filtered off, washed with acetonitrile and the solvent removed under reduced pressure to give a yellow oil. To a solution of this oil (813 mg, 3.2 mmol) in dry Et2O (20 ml) cooled in an ice-salt bath was added a solution of methyl lithium (1.6 M in Et2O, 2.1 mL, 3.36 mmol) dropwise over 10 mins. After stirring for a further 1.5 hr, saturated NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to afford a green oil (0.8 g, 81% over four steps). 1H NMR (400 MHz, CDCl3) δ 4.00-2.65 (m, 6H), 2.30-1.60 (m, 4H), 1.55-1.20 (m, 12H).