Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:73][O:72][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:24][C@@H:23]([O:25][C@@H]7O[C@H](CO[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)[C@@H](O[C@@H]8O[C@@H](C)[C@H](O)[C@@H](O)[C@H]8O)[C@H](O)[C@H]7O[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[CH2:22][CH2:21][C@:20]6([CH3:69])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:70])[C@H:7]3[C@@H:6]2[CH3:71])[CH2:4][CH2:3]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C@@H:2]1[CH2:73][O:72][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:69])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:70])[C@H:7]3[C@@H:6]2[CH3:71])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O[C@@H]6O[C@H](CO[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@@H](O[C@@H]7O[C@@H](C)[C@H](O)[C@@H](O)[C@H]7O)[C@H](O)[C@H]6O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Yield: 89.5 %

Procedure:
100 Parts of crude sarsasaponin is suspended in 255 parts of ethyl acetate and heated at reflux for 0.5 hour. The mixture is filtered hot and the filter cake washed with 89 parts ethyl acetate and dried. The dried residue is mixed with 1850 parts by volume of a 15% (v/v) solution of concentrated hydrochloric acid in water and heated at 95°-101° C. for 2 hours. The hot reaction mixture is then filtered to give a precipitate which is washed with water and dried to afford crude sarsasapogenin in an 89.5% yield. This crude material is treated with 50 parts alumina and 5 parts carbon in 440 parts toluene. Filtration affords a pale yellow solution, which upon standing, yields a solid. This solid is filtered, and recrystallized from hot n-hexane to give sarsasapogenin melting at about 200°-205° C. This compound exhibits an [α]D25 = -78.8° ±1.5 (c=0.996% in chloroform), an [α]36525 = -230.9° ±1.5 (c=0.996% in chloroform), and is represented by the following structural formula. ##STR1##
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][N:3]=1.C(N([CH2:26][CH3:27])CC)C.[CH2:28]([S:35](Cl)(=[O:37])=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>ClCCl>[CH2:8]([C:7]1[C:2]([N:1]([S:35]([CH2:28][C:27]2[CH:26]=[CH:31][CH:30]=[CH:29][CH:34]=2)(=[O:37])=[O:36])[S:35]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])=[N:3][CH:4]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(Cc1ccccc1)N(c1ncc(-c2ccccc2)nc1Cc1ccccc1)S(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 23.5 h

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-phenylpyrazine (c-41) (852 mg, 3.26 mmol) was dissolved in anhydrous dichloromethane (25 mL), and to this was added triethylamine (1.38 mL, 9.87 mmol), and cooled to 0° C. To this was added benzylsulfonyl chloride (1.87 g, 9.80 mmol) and stirred for 23.5 h after warming to room temperature. To this was added 2 M hydrochloric acid to stop the reaction and after separating the aqueous layer and organic layer, the organic layer was washed once with water and once with saturated hydrochloric acid and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (56 g, n-hexane/ethyl acetate=4/1) to give 3-benzyl-2-bis(benzylsulfonyl)amino-5-phenylpyrazine (c-42) as a reddish orange amorphous (1.27 g, 68.2%). Rf=0.70 (n-hexane/ethyl acetate=3/2). Mp. 71.5-74.5° C. UV (MeOH) λmax (log ε) 304 (4.20), 257 (4.15). UV (pH 7.4 PB) λmax (log ε) 331 (4.13), 269 (4.12). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 2H), 5.00 (s, 1H), 5.04 (s, 1H), 5.19 (s, 1H), 5.22 (s, 1H), 7.15 (d, J=7.0 Hz, 2H), 7.18-7.24 (m, 1H), 7.25-7.32 (m, 2H), 7.38-7.46 (m, 10H), 7.50-7.55 (m, 3H), 8.04-8.10 (m, 2H), 9.21 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6/CD3OD=2/1) δ 38.3, 61.7 (1C×2), 127.0, 127.5, 127.8 (1C×2), 128.8 (2C), 129.4 (2C×2), 129.7 (2C), 129.9 (2C), 130.2 (2C), 131.3, 132.2 (2C), 135.3, 138.3, 139.6, 142.0, 153.0, 156.5. IR (KBr, cm−1) 507, 538, 557, 611, 629, 694, 723, 748, 766, 779, 876, 920, 1144, 1163, 1252, 1354, 1375, 1427, 1454, 1495, 1530, 3032. HRMS (FAB+) m/z 570.1526 (M+H, C31H28N3O4S2 requires 570.1521).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1Cl
Yield: 65.6 %

Procedure:
A solution of ethyl 4-hydroxy-6,7,8-trifluoroquinoline-3-carboxylate (59.0 g) and POCl3 (500 ml) was refluxed for 8 h. Excess POCl3 was distilled off, the residue was removed into the mixture of ice and water. Solid NaHCO3 was added into the mixture to pH 7˜8 and the precipitated solid was isolated by filtration. The crude was recrystallized by toluene to afford the title compound (41.3 g, 65.6% yield), mp: 110-112° C.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH2:21]>CN(C=O)C.CC(N(C)C)=O>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Reactant: Nc1ccc(Cl)c(Br)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Fc1cc2c(Nc3ccc(Cl)c(Br)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.6 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.50 g, 9.09 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 3 h to give a homogeneous mixture. It was evaporated under reduced pressure at 40° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-bromo-4-chloroaniline (2.07 g, 10.0 mmol) in dry DMA (15 mL). The residue of 3-bromo-4-chloroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 19 h. It was poured into water (200 mL). The pH was adjusted to ca. 8 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether. The solid was collected by filtration and washed with water (4×20 mL). It was dried in vacuum over silica gel/KOH overnight to give N-(3-bromo-4-chlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (205) (3.20 g, 99%) as a yellow/orange solid, mp 271-275° C.; 1H NMR δ [(CD3)2SO] 10.15 (s, 1H), 8.99 (s, 1H), 8.79 (s, 1H), 8.45 (d, J=2.5 Hz, 1H), 8.26 (br s, 1H), 7.98 (dd, J=8.8, 2.5 Hz, 1H), 7.69 (d, J=8.8 Hz, 11-1). Anal. Calcd for C13N7BrClFN4: C, 44.16; H, 2.00; N, 15.85. Found C, 44.21; H, 1.87; N, 15.98.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8]C(C#N)(O[Si](C)(C)C)[C:6]=2[CH:18]=1.[C:19]([OH:22])(=[O:21])[CH3:20]>>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:6][C:5]2[O:10][CH2:9][CH2:8][CH:20]([C:19]([OH:22])=[O:21])[C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: C[Si](C)(C)OC1(C#N)CCOc2ccc(Cl)cc21
Product: Cl
Product: O=C(O)C1CCOc2ccc(Cl)cc21

Procedure:
Following the procedure of Example 2, 6-chloro-4-cyano-4-trimethylsilyloxy-3,4-dihydro-2H-1-benzopyran (6.0 g.) and stannous chloride dihydrate (30 g.) were reacted in glacial acetic acid (25 ml.) and concentrated hydrochloric acid (25 ml.) to form 6-chloro-3,4-dihydro-2H-1-benzopyran-4-carboxylic acid. Filtration and chromatography over silica gel (300 ml.) eluted with chloroform:hexane (1:1) yielded 2.91 g. of product, m.p. 90°-90.5° C. (sublimed).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:15]=[C:16]([OH:18])[CH:17]=1>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:41])([CH3:42])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:15]=[C:16]([OH:18])[CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Trifluoroacetic acid (0.12 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-5-hydroxy-2′-methyl-biphenyl-3-yl]-acetic acid methyl ester (Example 165-(2); 15.9 mg, 0.0247 mmol) in dichloromethane (0.60 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (11.5 mg, 88%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[C:28]([CH3:33])=[CH:29][O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[C:28]([CH3:33])=[CH:29][O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: Cc1coc2cc(O)ccc2c1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Cc1coc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 0.23 ml of trifluoromethansulfonic anhydride was added at 0° C. to 3 ml solution of pyridine with 120 mg of 7-hydroxy-3-methyl-4H-chromen-4-one, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and then dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified with silicagel chromatography (hexane/ethyl acetate=10/1) to obtain 183 mg of the above compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[C:30]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[C:40]([OH:42])[CH:39]=[C:38]([Br:43])[CH:37]=1)([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O.O.Cl>[C:30]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[C:40]([O:42][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:29])[C:10]=2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:39]=[C:38]([Br:43])[CH:37]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)c1cc(O)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)OC(C)(C)C)c2)c1CCC(=O)OCC
Temperature: 70 °C
Yield: 98.8 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (9.48 g, 20.1 mmol), 3-bromo-5-hydroxy-benzoic acid tert-butyl ester (5.0 g, 18.3 mmol) in N,N-dimethylformamide (100 mL) and acetone (200 mL) was added potassium carbonate (25.3 g, 183 mmol) at room temperature. The resulting suspension was heated to 70° C. for 24 h. Then, the reaction mixture was cooled to room temperature and diluted with water and 10% aq. HCl. The organic compound was extracted into ethyl acetate and the combined organic extracts were washed with water and brine solution. The organic layers were dried over anhydrous sodium sulfate and removal of the solvent under reduced pressure gave the crude product which was purified on a silica gel column eluting with 0-20% ethyl acetate in hexanes to afford the title compound (12 g, 99%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[S:4][N:3]=1.Cl[C:19]1[CH:20]=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[CH:26][C:25]([O:29][CH3:30])=[CH:24]2.CC(O)CC.N>CO>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([NH:17][CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[CH:6]=5)[CH:8]=[CH:9][C:10]4=[N:15][N:14]=3)=[CH:20][CH:21]=[N:22]2)=[N:27][CH:26]=1
Reactant: Cc1cc(-c2ccc3nnc(CN)n3n2)sn1
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: N
Solvent: CCC(C)O
Solvent: CO
Product: COc1cnc2c(NCc3nnc4ccc(-c5cc(C)ns5)nn34)ccnc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (548 mg, 2225 μmol) and 8-chloro-3-methoxy-1,5-naphthyridine (576 mg, 2959 μmol) were charged in a microwave vial. 2-butanol (7 mL) was added and the reaction mixture was stirred at 120° C. under micro-waves irradiation for 8 h. 2M NH3 in MeOH was added. Purification by MPLC (DCM/MeOH+1% NH4OH: 100/0 to 90/10) afforded the title compound (720 mg, 80% yield). MS m/z=405.1 [M+H]+. Calc'd for C19H16N8OS: 404.46
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>C1(C)C=CC=CC=1.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:30]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[O:31])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)c2cnc3[nH]ccc3c2)cc1OC
Temperature: 100 °C
Reaction time: 22 h
Yield: 3.5 %

Procedure:
To the crude pinacol ester 44 (310 mg, 1.27 mmol) in dry toluene (25 mL) was sequentially added cesium carbonate (2.07 g, 6.35 mmol), tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.06 mmol) and 3,4-dimethoxybenzoyl chloride (510 mg, 2.54 mmol). The mixture was heated at 100° C. in the dark. After 28 h a further portion of tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) was added. Following another 22 h the mixture was allowed to cool to ambient temperature and diluted with EtOAc and water and partitioned. The organic layer was washed with saturated sodium hydrogen carbonate, saturated brine, dried (MgSO4), filtered and concentrated. The crude residue was purified by preparative LCMS (column LUNA 10μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford ketone 45 [12.6 mg, 3.6% (2 steps)] as a white solid. 1H NMR (400 MHz; CDCl3) δ 3.99 (s, 3H), 4.00 (s, 3H), 6.54 (dd, J=2.0 and 3.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 7.38 (dd, J=2.5 and 3.5 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.81 (dd, J=0.7 and 2.5 Hz, 1H), 7.93 (dd, J=2.0 and 8.5 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H) and 8.90 (brs, NH).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C=O.[BH3-][C:27]#N.[Na+]>CC(O)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH3:27])[C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C)CO3
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(C)[C@H](C)CO3
Yield: 66.1 %

Procedure:
Compound 102 was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (12 mg, 0.04 mmol), 37% formaldehyde solution (0.010 mL, 0.2 mmol, 5 equiv) and NaCNBH3 (10 mg, 0.2 mmol, 5 equiv) in 1 mL AcOH (0.04 M) to afford 9 mg (ca. 70%) of (R)-3,4-dihydro-8-isopropoxy-3,4-dimethyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (9 mg, 0.03 mmol) was taken on directly according to General Method 4 (EXAMPLE 1) by treatment with 3 mL acetic acid and 3 mL concentrated HCl and heated at 90° C. for 4 h to afford 7 mg (89%) of Compound 102 after flash chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 11.90 (bs, 1H), 7.12 (s, 1H), 7.01 (d, J=9.3, 1H), 6.96 (d, J=9.3, 1H), 4.19 (dd, J=10.7, 2.9, 1H), 4.11 (dd, J=10.7, 3.7, 1H), 3.43 (m, 1H), 2.93 (s, 3H), 1.21 (d, J=6.8, 3H)
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH2:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH:35]=[CH:34]1>C1(C)C=CC=CC=1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)/C=C\C(=O)O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 81.3 %

Procedure:
2.0 g (4.7 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) and 0.61 g (6.2 mmol) of maleic anhydride were dissolved in 50 ml of toluene. Some molecular sieves were added and the reaction mixture was refluxed for 5 hours. After cooling, the reaction mixture was evaporated in vacuo to dryness, dissolved in CH2Cl2 and washed with sat. sol. NaCl, 20% citric acid, sat. sol. NaCl. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of i-Pr2O/EtOAc 70:30 containing 0.5% of 85% formic acid, and then triturated with i-Pr2O to yield 2.0 g of the title compound.
Reaction SMILES: ClN1C(=O)CCC1=O.[I-:9].[Na+].[CH3:11][O:12][C:13]([C:15]1[NH:19][C:18]2[C:20]([Br:23])=[CH:21][S:22][C:17]=2[CH:16]=1)=[O:14].[O-]S([O-])=O.[Na+].[Na+]>CC(C)=O>[CH3:11][O:12][C:13]([C:15]1[NH:19][C:18]2[C:20]([Br:23])=[CH:21][S:22][C:17]=2[C:16]=1[I:9])=[O:14]
Reactant: COC(=O)c1cc2scc(Br)c2[nH]1
Reactant: [I-]
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1[nH]c2c(Br)csc2c1I
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of N-chlorosuccinimide (12 mmol) in acetone (25 mL) was added dropwise a solution of sodium iodide (12 mmol) in acetone (80 mL). 3-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester (10 mmol) in acetone (80 mL) was then added portionwise into the reaction mixture. After 1 hr of stirring, the reaction was poured into a solution of Na2SO3 10% and extracted with AcOEt. Organic phases were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography to give compound 69 as a yellowish solid in 68% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 3.96 (s, 3H), 7.26 (s, 1H), 9.22 (s, 1H).
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][NH:6][S:5]1(=[O:15])=[O:14].[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1.N1C=CC=CC=1.B.[OH-].[Na+]>CO.O>[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][N:4]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[CH:7]=[N:6][S:5]4(=[O:15])=[O:14])[CH2:28][CH:27]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: O=CCN1c2ccccc2CNS1(=O)=O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: O=S1(=O)N=Cc2ccccc2N1CCN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Reaction time: 8 h

Procedure:
To a dry 100 ml round bottomed flask containing powdered molecular sieves 4A (1.5 g) was added 3,4-dihydro-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (0.8 g, 3.54 mmol) in methanol (30 ml)and 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (0.76 g) dissolved in methanol (10 ml). Borane-pyridine (1 ml) was added after 1 hour and the solution stirred overnight. 5 MHCl (10 ml) was added followed by 50% sodium hydroxide solution(5 ml) and water(5 ml). Solution was filtered through celite and ethyl acetate(3×50 ml) added. The organics were collected, washed with water, dried, filtered and the solvent removed in vacuo. Column chromatography through flash silica eluting with ethyl acetate/hexane gave product, 3,4-dihydro-(1-(2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 183-185° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C1COCC1>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:7]2[C:6]([CH:9]=[O:10])=[CH:5][C:4]([Br:3])=[CH:8]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)cc2C=O)cc1
Reaction time: 1 h
Yield: 68.6 %

Procedure:
Following a reported procedure,18 a stirred suspension of NaH (865 mg, 36.0 mmol) in THF (200 mL) was treated with 6 (5.22 g, 30.0 mmol) at room temperature. When the evolution of gas had ceased, the mixture was stirred for 1 h before treating with p-toluenesulfonyl chloride (6.30 g, 33.0 mmol). After 16 h, the conversion was complete as monitored by TLC. The reaction mixture was quenched by adding aqueous NH4Cl. Ethyl acetate was added and the organic layer was separated. The organic layer was washed with water, brine and dried (Na2SO4). Concentration followed by crystallization (ethyl acetate/hexanes) afforded pale yellow crystals (6.75 g, 68%): mp 83-85° C.; 1H NMR δ 2.43 (s, 3H), 7.09 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.57 (d, J=2.0 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 9.94 (s, 1H); 13C NMR δ 22.0, 101.8, 125.4, 127.8, 127.9, 130.6, 133.5, 134.7, 146.7, 178.5. Anal. Calcd or C12H10BrNO3S: C, 43.92; H, 3.07; N, 4.27; S, 9.77. Found: C, 43.92; H, 3.02; N, 4.26; S, 9.84.