Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)(=O)C1C=CC=CC=1.[CH:26](OCC)=[O:27].Cl>C1COCC1>[CH:26]([CH:23]1[C:22](=[O:25])[CH2:21][CH2:20][NH:19][CH2:24]1)=[O:27]
Reactant: CCOC=O
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: O=CC1CNCCC1=O
Yield: 73 %

Procedure:
The following general procedure was used to synthesize compound IV (R2 ≠H): Into a dried, 3-neck flask fitted with a mechanical stirring device, an addition funnel and a low temperature thermometer was cannulated lithium hexamethyldisilazane (1.0 M in THF, 1.1 molar equiv). The solution was cooled via a dry ice/acetone bath. A solution of N-benzoyl-4piperidone (1.0 equiv) in THF (50 mL) was added dropwise, with stirring, over thirty minutes. The solution was stirred at -72° to -68° C. for thirty minutes. Ethyl formate (2 equiv) was added all at once and the solution stirred at -70° C. for ten minutes, then at room temperature for twenty eight hours. The solution was treated with 1N HCl (200 mL) and extracted (methylene chloride and brine). The extracts were dried (MgSO4) and concentrated to yield 3-formyl-4-piperidone as an orange oil (73%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[N:3]=1.O.[NH2:22][NH2:23]>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:5]=3)=[CH:15][CH:14]=2)[NH:23][N:22]=1
Reactant: CC(C)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
In a 25 mL sealable tube were combined 4-{2-amino-6-[(1-methylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (0.21 g, 0.54 mmol), hydrazine monohydrate (1.06 mL, 21.6 mmol), and EtOH (10 mL). The tube was sealed and the reaction mixture was stirred overnight at 95° C. The mixture was concentrated and to the resulting solid was added to EtOH (2 mL) followed by hexanes (15 mL). The mixture was sonicated and filtered. The solid was washed with hexanes to afford the title compound (167 mg, 99%) as an off-white solid. LC-MS (ES) m/z=284 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (d, J=6.6 Hz, 6H), 4.12 (bs, 1H), 5.36 (s, 2H), 5.94 (s, 2H), 6.24 (s, 1H), 6.71 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.82 (s, 1H), 11.50 (bs, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:15]2[CH3:25])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C
Reaction time: 2 h

Procedure:
To a stirred suspension of sodium hydride (0.27 g, 60% dispersion in mineral oil) in DMF (50 mL) under nitrogen at room temperature was added ethyl 4-benzyloxyindole-2-carboxylate (1.59 gm). Methyl iodide (0.5 mL) was added 10 min. later. After 2 hr. excess sodium hydride was quenched with acetic acid (0.4 mL) and the solvent evaporated under reduced pressure. The residue was taken into EtOAc, washed with water and brine, dried over MgSO4, and evaporated to dryness to give an oil which was triturated with hexane to precipitate 1.45 g of the title compound. Mp 89-90.5° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([NH:3][O:2][CH3:1])[CH3:20])=[CH:7][CH:8]=2)=[CH:18][CH:17]=1
Reactant: CON=C(C)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC(C)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 64.7 %

Procedure:
A solution of crude 1-[4-(4-chlorophenoxy)-phenyl]-propan-2-one O-methyl-oxime (6.0 g, 20.7 mmol) in acetic acid (50 ml) was treated at 10° C. with sodium cyanoborohydride (2.6 g, 41.4 mmol) added in small portions over 10 minutes and the resulting solution was stirred at 23° C. for 3.5 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) and the residue was slurried with water and pH was adjusted to 11 with 1M NaOH. The aqueous phase was extracted with dichloromethane (2×20 ml), washed with brine and dried over anhydrous Na2SO4. After removal of the solvent (100 mbar; 45° C.), the residue (7.17 g) was purified by flash chromatography over silica gel (eluent: c-hexane). 3.91 g (65.0% of theory) of N-{2-[4-(4-chloro-phenoxy)-phenyl]-1-methyl-ethyl}-O-methyl-hydroxylamine was obtained in form of a clear liquid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]1([CH2:7][CH2:8][S:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(SCCc2ccccc2)cc1
Yield: 66.8 %

Procedure:
A mixture of 2-phenylethylmercaptan (72.3 mmol, 10.0 g), 4-bromobenzaldehyde (79.6 mmol, 14.7 g) and potassium carbonate (116 mmol, 16 g) were stirred in dimethylformamide (100 ml) at 110° C. for 48 hours. The solution was cooled and diluted with water (200 ml). The aqueous was extracted with ether (3×200 ml) and the combined ether layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica gel using hexane:ethyl acetate (9:1) as eluant to afford 11.7 g (67%) of present title product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH2:26]([NH:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:27]>>[CH2:26]([NH:28][CH2:29][CH:30]1[CH2:31][N:32]([C:16]2[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=2[F:21])[CH2:33][CH2:34][O:35]1)[CH3:27]
Reactant: CCNCC1CNCCO1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Product: CCNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
By the use of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(ethylaminomethyl)morpholine, the reaction is similarly carried out as Example 26 to give 7-[2-(ethylaminomethyl)morpholino]-1(2,4-difluorophenyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 226°-229° C. with decomposition. Examle 28
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cnnn2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (Example H15) according to the general procedure K. Obtained as a light yellow solid (159 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Cl:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCCl
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCCCl)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
4-Amino-piperidine-1-carboxylic acid benzyl ester (12.0 g) in dichloromethane (100 mL) was added to pyridine (7.2 mL). The solution was cooled to 0° C. then 5-chlorovaleryl chloride (7.3 g) was added drop wise to the reaction. The reaction was warmed to room temperature. After 5 hours the reaction was diluted with dichloromethane and washed with water (1×), saturated aqueous copper sulfate (2×), and water (1×). The organic extracts were dried and evaporated. The resulting solids were suspended in ether, filtered, and then placed under high vacuum to give the title compound as a white solid (15.6 g). Rf=0.60 in ethyl acetate.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:4][N:3]=1.[F:41][C:42]1[CH:43]=[C:44]([NH2:50])[CH:45]=[N:46][C:47]=1[O:48][CH3:49].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:41][C:42]1[CH:43]=[C:44]([NH:50][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:4][N:3]=2)[CH:45]=[N:46][C:47]=1[O:48][CH3:49]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -20 °C
Yield: 15.5 %

Procedure:
A mixture of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.500 g, 0.918 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.261 g, 1.836 mmol) in THF (20 mL) was cooled to −20° C. and treated with a 1.0 M solution of lithium bis(trimethylsilyl)amide (3.21 mL, 3.21 mmol) added dropwise. The mixture was allowed to slowly warm to ambient temperature over 1 h. The reaction mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give the crude product as a tan solid. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica-gel column (80 gram) eluting with a gradient of 0% to 100% EtOAc in hexane over 30 min to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.095 g) as a tan oil. This was treated with trifluoroacetic acid (1.8 mL, 23.36 mmol) and trifluoromethanesulfonic acid (0.2 mL, 2.252 mmol) and heated at 70° C. for 20 min. The mixture was cooled to ambient temperature and concentrated to give a tan oil. This was dissolved in DCM (10 mL) and allowed to stir for 5 min, then sodium carbonate (1.6 g) was slowly added to the mixture and stirred vigorously for 20 min. The mixture was filtered and concentrated. The mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was diluted with diethyl ether (20 mL) and placed in a sonicator for 2 min. The precipitate was collected by filtration. The solid was recrystallized from hot ethyl acetate to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.025 g, 0.059 mmol, 6.39% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 11.94 (s, 1H); 8.72 (s, 1H); 8.41 (s, 1H); 8.36 (d, J=12.91 Hz, 1H); 8.24 (s, 1H); 7.90 (s, 1H); 7.75 (s, 1H); 3.93 (s, 3H); 3.57 (s, 4H); 3.43 (s, 2H); 2.44 (s, 7H). m/z (ESI, +ve ion) 427 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[C:23]3[CH2:25][O:26][C:27]4[CH:52]=[C:51]5[C:30]([CH2:31][CH2:32][C:33]6[N:37]=[C:36]([C@@H:38]7[CH2:42][CH2:41][C@H:40]([CH3:43])[N:39]7[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[NH:35][C:34]=65)=[CH:29][C:28]=4[C:22]3=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:47]([O:46][C:44]([N:39]1[C@@H:40]([CH3:43])[CH2:41][CH2:42][C@H:38]1[C:36]1[NH:35][C:34]2[C:51]3[C:30]([CH:31]=[CH:32][C:33]=2[N:37]=1)=[CH:29][C:28]1[C:22]2[C:23]([CH2:25][O:26][C:27]=1[CH:52]=3)=[CH:24][C:19]([C:16]1[NH:15][C:14]([C@@H:9]3[CH2:10][CH2:11][C@H:12]([CH3:13])[N:8]3[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[N:18][CH:17]=1)=[CH:20][CH:21]=2)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(cc3-4)CCc3nc([C@@H]4CC[C@H](C)N4C(=O)OC(C)(C)C)[nH]c3-5)[nH]2)N1C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)OC(C)(C)C)[nH]c65)cc3-4)[nH]2)N1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
Tert-butyl (2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (393 mg, 0.55 mmol) was suspended in DCM (7 mL) and activated MnO2 (1.45 g, 16.7 mmol) was added in a single portion. The reaction mixture was heated to 40° C. After stirring for 2.5 h, the mixture was cooled to rt and the slurry was filtered over celite. The filter cake was washed with copious CH2Cl2 and MeOH and the filtrate was concentrated under reduced pressure. The crude material was taken on to the next step without further purification to afford tert-butyl (2S,5S)-2-(5-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (328 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH3:13])[CH:10]=[C:11](I)[C:3]=12.[N:14]1([C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH3:13])[CH:10]=[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[CH:20]=3)[C:3]=12
Reactant: OB(O)c1cccc(N2CCCC2)c1
Reactant: Cc1cc(Cl)c2c(I)cn(C)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)c2c(-c3cccc(N4CCCC4)c3)cn(C)c2n1
Temperature: 65 °C
Yield: 25.4 %

Procedure:
A mixture of 4-chloro-3-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (D13) (500 mg, 1.631 mmol), (3-(pyrrolidin-1-yl)phenyl)boronic acid (374 mg, 1.957 mmol), bis(triphenylphosphine)palladium(II) chloride (114 mg, 0.163 mmol) and sodium carbonate (2M aq. solution) (8 mL, 16.00 mmol) was heated at 65° C. for 1 hour. The mixture was transferred to a separatory funnel with ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL×3). The organics were combined, dried over magnesium sulfate and concentrated. The crude was purified over normal phase chromatography eluting with ethyl acetate and cyclohexane (0-30%) to give the title compound (135 mg). LCMS (A): m/z (M+H)+ 326, C19H20ClN3 requires 325 (acidic).
Reaction SMILES: [OH-:1].[Na+].F[C:4]1[CH:5]=[C:6]([O:21][CH3:22])[C:7]([N+:18]([O-:20])=[O:19])=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1>CS(C)=O.Cl>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]([OH:1])[CH:5]=[C:6]([O:21][CH3:22])[C:7]=1[N+:18]([O-:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: COc1cc(F)cc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Yield: 26.9 %

Procedure:
In 10N NaOH (5.8 ml, 58.0 mmol) and DMSO (20 ml), benzyl 5-fluoro-3-methoxy-2-nitrophenyl ether (5.35 g, 19.3 mmol) was stirred for 15 hours. The reaction mixture was poured in 1N HCl (100 ml), followed by extraction with ether (300 ml). The extract was washed with saturated brine (2×100 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (4:1) eluate fractions, the title compound (1.43 g, 27%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[C:9](=[O:13])[NH:10]2)=[CH:5][C:4]=1[C:20]([O:22][CH3:23])=[O:21].N1C=CC=CC=1.[O:30](S(C(F)(F)F)(=O)=O)[S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[C:9]([O:13][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:30])=[N:10]2)=[CH:5][C:4]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(=O)[nH]c2cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(OS(=O)(=O)C(F)(F)F)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 7-methoxy-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, 3.15 mmol) in dichloromethane (80 ml) was added pyridine (990 mg, 12.52 mmol) and Tf2O (1.69 g, 5.99 mmol), and the reaction was stirred overnight under an atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (200 ml), extracted with dichloromethane (3×30 mL), the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford (S)-methyl 7-methoxy-3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (1.20 g, crude), which was used in the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[CH2:4][C:5]1[NH:9][CH:8]=[N:7][CH:6]=1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:28])=CC=1>C1COCC1.O>[Cl:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[NH:9][C:8](=[S:28])[NH:7][CH:6]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Clc1cccc(Cl)c1Cc1cnc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: S=c1[nH]cc(Cc2c(Cl)cccc2Cl)[nH]1
Reaction time: 3 h

Procedure:
A solution of 5-(2,6-dichloro-benzyl)-1H-imidazole (Intermediate A4) (0.34 g, 1.5 mmol) in THF (6 mL) and water (6 mL) was treated with NaHCO3 (1.2 g) at rt for 10 m. Phenyl chlorothionoformate (0.60 mL, ˜4.3 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (4×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (6 mL) and treated with NEt3 (0.6 mL) for 18 h. The solvent was removed under vacuum and the product was washed on a glass frit with CH2Cl2 to give a white solid 4-(2,6-dichloro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 1) in ˜50% yield.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH:8]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C1CC=CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC=CCCNC1
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a solution of ethyl N-(tert-butoxycarbonyl)-1,2,3,6,7,8-hexahydroazocine-7-carboxylate (167 mg, 0.59 mmol) in ethyl acetate (4 mL) was added 4N solution of HCl in ethyl acetate (2 mL). After the mixture was stirred for 3 hours, the solvent was evaporated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate, then the mixture was adjusted to pH 9 with a saturated aqueous K2CO3 solution. The organic layer was separated and dried over Na2SO4, and evaporated in vacuo to give ethyl 1,2,3,6,7,8-hexahydroazocine-7-carboxylate (81 mg, 0.44 mmol, 74.6%) as a colourless oil.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:29]=[O:30]>C1COCC1>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH2:29][OH:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: O=S(=O)(C=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(C(CO)=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 1.25 g (3.90 mmol) of 2,2-diphenyl-1-(phenylsulfonyl) ethene in 20 mL of dry THF at -78° C., was added dropwise under a nitrogen atmosphere 2.8 mL of 1.4M n-BuLi (3.90 mmol). The dark black solution was stirred at -78° C. for 30 minutes. Gaseous fomaldehyde, generated by heating paraformaldehyde at 170° C., was passed through a 5-mm tube into the reaction mixture with the aid of a slow stream of nitrogen at -78° C. for 30 minutes. The mixture was allowed to come to room temperature over a period of 30 minutes while continuing to pass formaldehyde through the reaction mixture until a pale yellow color was observed. The mixture was stirred overnight at room temperature. The mixture was quenched with 50 mL of 5% HCl, and extracted with three 25-mL portions of CH2Cl2. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. The resulting crude oil was flash chromatographed on silica gel (230-400 mesh, 5×16-cm column) with 30% ether/Skelly B as eluant to give 0.47 g (34%) of the colorless alcohol. In a melting point capillary the compound does not melt but decomposes above 290° C. with blackening; IR (KBr) cm-1 3480, 3040, 1590, 1480, 1440, 1370, 1280, 1130, 1020, 960, 790, 730, 700, 680, 610; 1H NMR (CDCl3) δ 3.47 (t, 1H, OH), 4.61 (d, 2H, CH2O), 6.75-7.58 (m, 15H, phenyl).
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[C:22](OCC)=[O:23]>O1CCCC1>[C:1]1([N:7]2[C:22](=[O:23])[C:13]3[CH:14]=[N:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: ONc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c2cnc3ccccc3c2on1-c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
A solution of 9 g of N-phenylhydroxylamine [described in Organique Synthese, Vol. 1, p. 445]was added dropwise at 0° C. with stirring under an inert atmosphere to a suspension of 3.85 g of 50% sodium hydride in 100 ml of tetrahydrofuran, and after stirring at 5° C. for 30 minutes, a solution of 18.8 g of ethyl 4-chloro-3-quinoline carboxylate in 100 ml of tetrahydrofuran was added at 0° C. The mixture was stirred for 16 hours at ambient temperature and after concentration to dryness under reduced pressure, the residue was taken up in ice. The mixture was extracted with methylene chloride and the organic phase was washed, dried, and concentrated to dryness. The residue was purified by chromatography on silica (eluent: ethyl acetate) to obtain 1.2 g of 2-phenylisoxazolo(4,5-c)quinolin-3-(2H)-one (corresponding to the 3rd eluted fraction) melting at 163° C. after crystallization from isopropyl ether.