Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)=[O:4].[Se](=O)=[O:20]>O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH:17]=[O:20])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)=[O:4]
Reactant: Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Reactant: O=[Se]=O
Solvent: O
Product: O=Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Yield: 18 %

Procedure:
In a 25 ml. round-bottomed flask equipped with a magnetic bar, water-cooled reflux condenser, and argon-filled balloon, 7-chloroacetamido-2-methylquinoline-5,8-dione (28) (prepared as described in Example 28) (0.529 g., 2 mmol), selenium dioxide (0.255 g., 2.3 mmol), 12 ml of dried, distilled 1,4-dioxane, and 0.25 ml. of water were stirred and slowly heated to reflux over a two-hour period. The reaction was monitored by TLC and allowed to go to completion (29.5 hours). The selenium was allowed to settle, and the supernatant solution was pipetted off and filtered. 1,4-Dioxane (10 ml.) was added to the residue, stirred and refluxed for five minutes. The entire mixture was filtered and the selenium was washed with dichloromethane (10 ml.). All filtrates were combined and stored at 4 EC overnight. Solid precipitate from the chilled mixture was filtered yielding 0.0985 9. of crude product (yield of 18%). This was purified by recrystallization from ethyl acetate/dichloromethane. The original remaining filtrate was diluted with 50 ml of dichloromethane and washed with 3% sodium bicarbonate solution (2×50 ml.). The aqueous layer was then extracted with dichloromethane (2×20 ml.) The organic layers were dried with magnesium sulfate and rotoevaporated to give a dark orange solid. The product was dried under vacuum overnight and 0.2941 g. of product was obtained (yield of 52%, total 70%). This product could be further purified by flash chromatography and recrystallization from ethyl acetate/dichloromethane: mp 190-192 EC; 1H NMR (CDCl3)*4.26 (2H, s, C—7NHCOCH2Cl), 8.04 (1H, s, C—6H), 8.33 (1H, d, J=8.1 Hz, C—3H), 8.62 (1H, d, J=8.1 Hz, C—4H), 9.54 (1H, br. s, C—7NH), 10.28 (1H, s, C—2CHO); IR (KBr) vmax 3310, 3089, 2950, 2852, 1731, 1720, 1678, 1644, 1521, 1118 cm−1; EIMS, m/e (relative intensity) 278/280 (M+, 2.7/1, 95), 243 (33), 229 (33), 215 (55), 202 (base), 175 (61), 146 (17); HRMS, m/e for C14H9ClN2O3 calculated 278.009435, found 278.008764; analysis for C14H9ClN2O3 calculated C, 51.72; H, 2.53; Cl, 12.72; N, 10.05; Found C, 51.81; H, 2.9; Cl, 12.79; N, 9.86.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Br:16][C:17]([CH2:19]Br)=[CH2:18].[H-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:16][C:17](=[CH2:18])[CH2:19][CH2:2][C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(Br)CCC(=O)NC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred mixture of diethyl acetamidomalonate (217 g, 1.0 mol) and 2,3-dibromopropene (240 g, 1.2 mol) in anhydrous tetrahydrofuran (2.50 L), under nitrogen, was added sodium hydride (26.4 g, 1.1 mol) in several portions. The reaction mixture was stirred at ambient temperature for 30 minutes, then heated to reflux. After heating for 18 hours, the resultant slurry was cooled to ambient temperature and suction filtered through a short pad of silica gel. The solid residue was washed with tetrahydrofuran (2×50 mL), and the filtrates were combined and concentrated. The residue obtained was dissolved in ethyl acetate (2.0 L), washed with water and brine, and then was dried over magnesium sulfate. Filtration and concentration gave a yellow oil which solidified upon drying. The resultant solid was recrystallized from a mixture of hot ethyl acetate/hexane to give 301 g (89%) of the desired product: m.p. 85°-87° C. 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=7.4 Hz, 6H), 2.04 (s, 3H), 3.57 (s, 2H), 4.27 (m, 4H), 5.55 (bs, 1H), 5.61 (bs, 1H) , 6.82 (broad, 1H); IR (KBr) 1745, 1635 cm-1. Anal calcd for C12H18BrNO5 : C, 42.87; H, 5.40; Br, 23.77; N, 4.12. Found: C, 43.25; H, 5.56; Br, 22.97; N, 4.12.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1.CCN(CC)CC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Br)cc1)CCNC2
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1sc2c(c1C(=O)c1ccc(Br)cc1)CCN(C(=O)Nc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-(4-bromobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine) (1.02 mmol) in dry CH2Cl2 (20 mL), Et3N (1.2 eq) and phenylisocyanate (1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, then was concentrated at reduced pressure and the residue puri fied by flash chromatography (EtOAc/light petroleum 3/7) to afford the desired compound as a solid (mp 89-90 ° C.).
Reaction SMILES: C[O-].[Na+].[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[NH:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.[C:20]([O:24][C:25]([CH2:27][O:28][C:29]1[C:36]([Cl:37])=[CH:35][C:34]([Cl:38])=[CH:33][C:30]=1[CH:31]=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[NH3:4].[C:20]([O:24][C:25]([CH2:27][O:28][C:29]1[C:36]([Cl:37])=[CH:35][C:34]([Cl:38])=[CH:33][C:30]=1[CH2:31][NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[NH:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: NCCCNc1cc(=O)c2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)COc1c(Cl)cc(Cl)cc1C=O
Agent: C[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(Cl)cc1CNCCCNc1cc(=O)c2ccccc2[nH]1
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 158 %

Procedure:
To a solution of the compound prepared as in Example 1b (0.13 g, 0.45 mmol) in methanol (1 ml) and acetic acid (0.2 ml) was added sodium methoxide (0.5 M in methanol, 1.8 ml, 0.9 mmol). An aliquot of this solution (1.34 ml; 0.2 mmol 2-(3-aminoprop-1-ylamino)-1H-quinolin-4-one) was added to 2-tert-butoxycarbonylmethoxy-3,5-dichlorobenzaldehyde (0.061 g, 0.2 mmol) followed by sodium cyanoborohydride (0.02 g, 0.32 mmol) in methanol (0.6 ml). The mixture was stirred at room temperature under argon for 1 h. The product was purified by chromatography on a SCX cartridge, eluting with methanol and then 0.2M NH3 in methanol to give the title compound as a colourless gum (0.08 g, 79%); δH (CD3OD) 1.39 (9H, s), 1.8 (2H, m), 2.62 (2H, t), 3.33 (2H, t), 3.82 (2H, s), 4.52 (2H, s), 5.57 (1H, s), 7.1-7.5 (5H, m), and 7.99 (1H, dd): MS (ES+) 506, 508, 510 (12, 10, 3%, MH+), 450, 452 (10, 8%) and 201 (80).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:46][C@@H:47](O)[CH2:48][CH:49]=[CH2:50].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1.CCOCC>[CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[O:33][C@H:49]([CH2:48][CH:47]=[CH2:46])[CH3:50])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O)c4)cn23)CC1
Reactant: C=CC[C@@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-hydroxy-5′-methyl-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (51 mg, 0.083 mmol, 1 equiv), (R)-pent-4-en-2-ol (22 mg, 0.250 mmol, 3 equiv), and PPh3 (44 mg, 0.167 mmol, 2 equiv) in THF (0.8 mL) was added DEAD (0.066 mL of a 40% solution in toluene, 0.167 mmol, 2 equiv). After stirring 18 h, the yellow solution was diluted with ether, washed with water, dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (53 mg, 94%) as a colorless film. LCMS (ESI, M+1): 680.45.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li][CH2:12][CH2:13][CH2:14][CH3:15].[N:16]1[CH:21]=[CH:20][CH:19]=C[C:17]=1[C:22]([OH:24])=[O:23].C(=O)CC>C1COCC1>[CH2:14]([CH:13]1[C:12]2[C:17](=[N:16][CH:21]=[CH:20][CH:19]=2)[C:22](=[O:23])[O:24]1)[CH3:15]
Reactant: O=C(O)c1ccccn1
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: CCC=O
Product: CCC1OC(=O)c2ncccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 11 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (20.3 ml, 120 mmol) in a 250 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 60 ml of dry THF is added. The reaction mixture is cooled to −78° C. The cooled reaction mixture is treated dropwise with nBuLi solution (64 mL of a 2.5 M solution in hexanes, 160 mmol) and the reaction is let stir at −78° C. for 5 min. A solution of picolinic acid (4.92 g, 40 mmol) in THF (60 mL) is added dropwise to the reaction at −78° C. The reaction is stirred at −78° C. for 1 h and is then warmed to −20° C. for 30 min. The reaction mixture is treated with propionaldehyde (7.2 ml, 100 mmol, 2.5 eq) dropwise at −50° C. The reaction is stirred at −20° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated and the residue is dissolved in water and ether. The aqueous layer is collected and extracted with dichloromethane and ether (6×50 ml). The aqueous phase is concentrated and the residue is dissolved in EtOH (30 mL) and acetic acid (2 mL) and heated at reflux overnight under argon. The reaction mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel) to give the title compound (0.70 g, 11%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:43][C:26]([CH3:42])([CH3:25])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]5=[O:23])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:24]=2)[CH:30]=[N:29]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)cn1
Yield: 12 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki conditions to give 485. Yield 12% MS(ESI+): 468.2. 1H NMR (400 MHz, DMSO) δ 11.86 (s, 1H), 8.16 (t, J=8.8, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.38 (dd, J=8.2, 1.8, 1H), 7.24 (d, J=1.8, 1H), 4.73 (s, 1H), 4.33 (t, J=4.9, 2H), 4.03 (s, 2H), 3.25 (t, J=5.0, 2H), 1.78 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH2:15]([O:18][NH2:19])[CH:16]=[CH2:17]>>[CH2:15]([O:18][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])[CH:16]=[CH2:17]
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Reactant: C=CCON
Agent: Cl
Product: C=CCON=C(C(=O)O)c1ccc(O)c(Cl)c1
Yield: 98.1 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2 g.) and O-allylhydroxylamine hydrochloride (1.1 g.) were reacted according to a similar manner to that of Preparation 5-(2)(a) to give oil of 2-allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.5 g.).
Reaction SMILES: C(NC(C)C)(C)C.[Li].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].[F:21]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>O1CCCC1>[F:21][C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)([CH3:20])[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(C)c1ccccn1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(F)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a stirred, cooled (−78° C.) solution of 5.00 mL (10.0 mmol) of a 2.0 M solution of lithium diisopropylamine in tetrahydrofuran under an atmosphere of nitrogen was added a solution of 1.5 g (9.1 mmol) of methyl 2-pyridin-2-yl-propanoate in 4.0 mL of anhydrous THF. The reaction mixture was allowed to stir for 10 min then warmed to 0° C. over 30 min. The mixture was then re-cooled to −78° C. and a solution of 3.70 g (11.8 mmol) of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide in 4.0 mL THF was added. The resulting mixture was allowed to warm to ambient temperature and stir for 2 h. The reaction was quenched with 50 mL of a saturated ammonium chloride solution and then extracted with diethyl ether (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 0-40% ethyl acetate in hexanes gradient to afford the title compound as a dark oil (1.3 g, 78%). LC-MS: m/z (E/S) 184 (MH)+.
Reaction SMILES: C(OC([N:8]1[C:20]2[CH2:19][CH:18]([C:21]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])([C:23]([O:25][CH3:26])=[O:24])[CH3:22])[CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([N:36]([CH3:38])[CH3:37])[CH:13]=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:26][O:25][C:23](=[O:24])[C:21]([S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH:18]1[CH2:17][CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([N:36]([CH3:37])[CH3:38])[CH:13]=3)[NH:8][C:20]=2[CH2:19]1)[CH3:22]
Reactant: COC(=O)C(C)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(N(C)C)cc23)C1)S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C1CCc2c([nH]c3ccc(N(C)C)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 4.6 %

Procedure:
To 42 mg (9.3 mmol) of (RS,SR)-2-(-1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-6-dimethylamino-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester in 1 ml of CH2Cl2 were added 0.06 ml of TFA at 0° C. The solution was stirred at RT for 5 h, a NaHCO3 solution was added, and the inorganic phase was extracted with CH2Cl2, washed with brine and dried over Na2SO4. Column chromatography on ISOLUTE Flash NH2 (Separtis, aminopropyl-modified silicagel) with EtOAc/heptane 2:1, followed by tituration with ether/heptane yielded 190 mg (56%) of (RS,SR)-2-benzenesulfonyl-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester as light green amorphous material, MS: 441 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[C:10](=[O:20])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:41](O)[CH2:42][OH:43]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]2([O:43][CH2:42][CH2:41][O:20]2)[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(=O)c2c1[nH]c1ccccc21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC2(OCCO2)c2c1[nH]c1ccccc21

Procedure:
A mixture of 3-(4-fluorobenzoyl)-1-oxo-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (39 mg, 10.1 mmol) and TsOH (10 mg) and ethylene glycol (0.2 mL) in toluene (10 mL) was heated to reflux overnight under nitrogen. After cooling, the reaction was diluted with DCM. It was then washed with saturated aqueous NaHCO3 and water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluted with MeOH-DCM (2:98) to give the title compound (7.5 mg); 1H-NMR (CDCl3): δ 9.68 (1H, s), 8.24 (1H, d), 7.08 (2H, m), 7.57 (1H, s), 7.41 (2H, m), 7.12 (2H, m), 4.77 (2H, m), 4.55 (2H, m), 4.46 (2H, q), 1.46 (3H, t). MS (ES): 437 (MH+).
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.O[N:9]=[C:10]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[S:12][C:11]1=[CH:20][C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1>N1C=CC=CC=1>[C:5]([O:4][N:9]=[C:10]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[S:12][C:11]1=[CH:20][C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)(=[O:7])[CH3:6]
Reactant: ON=C1Nc2ccccc2SC1=Cc1ccc[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)ON=C1Nc2ccccc2SC1=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (1.3 ml, 13.78 mmol) was added to a solution of 3-hydroxyimino-2-[(pyrrol-2-yl)methylene]-2H-1,4-benzothiazine (0.27 g, 1.05 mmol) (Compound 273) in dry pyridine (1.5 ml). The reaction mixture was stirred for 30 minutes at room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with 10% HCl and brine, dried over magnesium sulfate and brought to dryness in vacuo. The residue was purified by silica gel chromatography using (9:1) dichloromethane:ethanol as the mobile phase.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].O>C1COCC1>[CH2:29]([O:28][C:26]([NH:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc([N+](=O)[O-])c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 0° C. solution of methyl 5-amino-2-methyl-3-nitrobenzoate (1 g, 4.76 mmol, prepared according to the procedure described in J.Med.Chem. 1984, 27, 386) and diisopropylethylamine (0.91 mL, 5.24 mmol) in THF (24 mL) was treated with benzyl chloroformate (0.65 mL, 5.34 mmol), stirred at 0° C. for 30 minutes, warmed to room temperature for 2 hours, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to give 1.7 g of the desired product. MS (ESI(−)) m/e 343 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]=[CH2:12])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[OH-].[K+].I[CH3:16]>CS(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH3:12])[CH:5]=[C:6]([CH3:9])[C:7]=1[O:8][CH3:16]
Reactant: C=CCc1cc(C)c(O)c(C)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC=Cc1cc(C)c(OC)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(3,5-Dimethyl-4-hydroxyphenyl)-1-propene (5.0 g) is added to a mixture of powdered potassium hydroxide (7.98 g) in dimethylsulfoxide (50 ml) at 15°. Iodomethane (8.8 ) is then added and stirred below 20° for 0.5 hr. The reaction mixture is poured into ice/water and the product is extracted with ether (2×). The ether extracts are washed with water (3×), saline, dried over sodium sulfate and concentrated under reduced pressure to give 3-(3,5-dimethyl-4-methoxyphenyl-1-propene. The "propene" is transformed to the corresponding "propanol" with borane-dimethylsulfide by the general procedure of PREPARATION NA-19 to give the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(OCC)(=O)C.CCCCCCC>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CCCCCCCCCCCC(=O)NS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: CCCCCCCCCCCC(=O)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 120.2 %

Procedure:
At 80° C., N-bromosuccinimide (1.43 g, 8.06 mmol) and dibenzoylperoxide (62 mg, 0.25 mmol) were added successively to a solution of N-dodecanoyl-4-methylbenzenesulfonamide (3 g, 8.48 mmol) in tetrachloromethane (75 ml). The reaction mixture was heated for 1 h to 80° C. Another portion of dibenzoylperoxide (100 mg, 0.41 mmol) was added. The reaction mixture was heated another 2 h to 80° C. It was cooled to room temperature and left for 16 h. Ethyl acetate (100 ml) and heptane (100 ml) were added. The solid was removed by filtration. The solvent was removed from the filtrate to give 4.19 g of crude 4-bromomethyl-N-(dodecanoyl)benzenesulfonamide, which was used for the next step, without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]2[N:43]=[C:42](C(Cl)(Cl)Cl)[O:41][N:40]=2)=[CH:29][CH:28]=1.C(=O)([O-])[O-:49].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][C:42](=[O:49])[O:41][N:40]=3)=[CH:29][CH:28]=2)[C:7]1=[O:18]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (1.43 g), potassium carbonate (0.8 g) and acetonitrile (40 mL) was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (8 mL) and methanol (8 mL). 1N Aqueous sodium hydroxide solution (8 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.74 g, 45%).