Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[C:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:25])[CH2:23][NH2:24]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:24][CH2:23][CH2:22][NH2:25])=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[C:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN
Reactant: Cc1c(N=C=S)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-t-butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzimidazole (1.15 g, 3.8 mmol) in methylene chloride (100 mL) is added dropwise over 15 minutes to 1,2-ethylenediamine (1.26 mL, 18.9 mmol) in solution in methylene chloride (200 mL). The mixture is stirred for 2 hours at room temperature. The mixture is rotary evaporated and the residue is triturated with ether (150 mL) for 1 hour at room temperature. The solid is filtered and dried in vacuo to afford N-(1-t-butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl)-N′-2-aminoethylthiourea as a white solid.
Reaction SMILES: C(OC(=O)CBr)(C)(C)C.[C:10]([O:14][C:15]([CH2:17][N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:21][CH:20]([NH:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([O:47]CC3C=CC=CC=3)=[O:46])[CH:40]=2)=[O:37])[C:19]1=[O:55])=[O:16])([CH3:13])([CH3:12])[CH3:11].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].O=C1NC2C=CC=CC=2N(C2CCCCC2)CC1NC(NC1C=CC=C(C(OCC2C=CC=CC=2)=O)C=1)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[C:10]([O:14][C:15]([CH2:17][N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:21][CH:20]([NH:35][C:36](=[O:37])[NH:38][C:39]2[CH:40]=[C:41]([CH:42]=[CH:43][CH:44]=2)[C:45]([OH:47])=[O:46])[C:19]1=[O:55])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)CN(C2CCCCC2)c2ccccc21
Agent: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(Nc1cccc(C(=O)OCc2ccccc2)c1)NC1CN(C2CCCCC2)c2ccccc2NC1=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 295.3 %

Procedure:
Preparation of 1-(1-tert-butoxycarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea Tert-butyl bromoacetate (503 mg), potassium iodide (23 ml), tetra n-butylammonium bromide (23 mg) and potassium carbonate (713 mg) were added to a solution of 1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea (800 mg) in dimethylsulfoxide (10 ml), the mixture was stirred at room temperature for one hour. Ice-water was added thereto, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby obtain 970 mg of the titled compound (Yield: 90%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.[CH2:24](Cl)[CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([O:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1)[CH2:25][CH2:26][CH3:27]
Reactant: OC1CCCN(c2nc(-c3ccccc3)nc3ccccc23)C1
Reactant: CCCCCl
Solvent: CN(C)C=O
Product: CCCCOC1CCCN(c2nc(-c3ccccc3)nc3ccccc23)C1

Procedure:
Equimolar amounts of 4-(3-hydroxypiperidinyl-2-phenylquinazoline and soda amide are mixed in dimethylformamide and reacted with butyl chloride to prepare the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=1[C:32]([F:35])([F:34])[F:33]>CN(C=O)C>[CH3:20][C:7]1[C:8]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:9]([O:13][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=2[C:32]([F:33])([F:35])[F:34])[C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3C(F)(F)F)c(-c3ccccc3)c(C)cc2c1
Temperature: 0 °C
Yield: 61.1 %

Procedure:
Compound 7 (215 mg, 0.81 mmol, 1 equiv) was dissolved in DMF (5 mL) and cooled to 0° C. under N2. Sodium hydride, 60% dispersion (36 mg, 0.89 mmol, 1.1 equiv), followed by 4-fluoro-3-(trifluoromethyl)benzaldehyde (311 mg, 1.62 mmol, 2 equiv) were added and the entire reaction mixture was heated to 70° C. for 3 days. The mixture was then partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chromatography (10% EtOAc in hexanes) to provide compound 33 (216 mg, 61%) as a clear oil. 1HNMR (400 MHz, DMSO-d6): δ 9.84 (s, 1H), 8.10 (m, 1H), 7.87 (m, 1H), 7.81 (s, 1H), 7.48-7.13 (m, 8H), 6.64 (m, 1H), 3.88 (s, 3H), 2.22 (s, 3H). MS m/z 437.4 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C@H:13]([CH3:14])[CH2:12][O:11][CH2:10][C@@H:9]1[CH3:15])=O)(C)(C)C.[ClH:16].O1CCOCC1>>[ClH:16].[CH3:15][C@H:9]1[CH2:10][O:11][CH2:12][C@@H:13]([CH3:14])[NH:8]1
Reactant: C[C@@H]1COC[C@H](C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1COC[C@H](C)N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Cis-4-tert-butoxycarbonyl-3,5-dimethylmorpholine g, 8.18 mmol) was dissolved in 4N-hydrochloric acid/1,4-dioxane (50 mL), and the solution was stirred for 3 days at room temperature. The reaction liquor was concentrated under reduced pressure and dried, to obtain the title compound as an oily matter. This compound was used in the subsequent reaction without performing further purification.
Reaction SMILES: F[C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H:5]([C:17]2N(C)N=[CH:19][C:18]=2[N+]([O-])=O)[O:4]C1.N[C:27]1[S:31][C:30]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])=[N:29][C:28]=1[C:40]([NH:42][C:43]1[CH:44]=[N:45][N:46]([CH3:57])[C:47]=1[CH:48]1[CH2:54][CH2:53][C@@H:52]([NH2:55])[C@H:51]([F:56])[CH2:50][O:49]1)=[O:41]>>[NH2:55][C@H:52]1[C@H:51]([F:56])[CH2:50][O:49][C@H:48]([C:47]2[N:46]([CH3:57])[N:45]=[CH:44][C:43]=2[NH:42][C:40]([C:28]2[N:29]=[C:30]([C:32]3[C:33]([F:39])=[CH:34][C:35]([CH:18]4[CH2:17][CH2:5][O:4][CH2:19]4)=[CH:36][C:37]=3[F:38])[S:31][CH:27]=2)=[O:41])[CH2:54][CH2:53]1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@@H](N)[C@H](F)CO1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cc(C4CCOC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2,6-difluoro-4-(tetrahydrofuran-3-yl)phenyl)thiazole-4-carboxylic acid (Intermediate 145) gave 216. The product was isolated as a mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.61 (s, 1H), 7.80 (s, 1H), 7.27 (d, J=10.0 Hz, 2H), 4.81 (dd, J=10.8, 3.7 Hz, 1H), 4.46-4.22 (m, 1H), 4.24-4.09 (m, 1H), 4.08-3.89 (m, 3H), 3.86-3.75 (m, 4H), 3.63 (dd, J=8.4, 6.9 Hz, 1H), 3.58-3.45 (m, 1H), 3.34-3.16 (m, 3H), 2.42-2.29 (m, 1H), 2.11-1.91 (m, 2H), 1.87-1.79 (m, 1H), 1.72-1.62 (m, 4H). LCMS (ES+) m/z 522 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].[CH:37]1(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)CC1>>[CH:1]1([NH:3][C:4](=[O:36])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH:30]4[CH3:35])[C:15]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:18][C:16]=4[N:17]=3)=[CH:8][CH:7]=2)[CH2:37][CH2:2]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Product: CC1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
Method as described for intermediate 5 using 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea.
Reaction SMILES: [CH2:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Li]CCCC.[CH2:14]1[O:16][CH2:15]1>C1COCC1>[CH2:1]([C:4]1[O:5][C:6]([CH2:14][CH2:15][OH:16])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: C1CO1
Reactant: CCCc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(CCO)o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91 %

Procedure:
To a solution of 2-propylfuran (3.00 g, 31.2 mmol) in THF (31 mL) at −78° C. was added n-BuLi (15.0 mL, 2.5 M, 37.4 mmol) dropwise over 10 min. The reaction was warmed to rt and stirred for 3.5 h. After cooling to 0° C., ethylene oxide (2.33 mL, 46.8 mmol) was added, the reaction was warmed to rt and stirring was continued for 19 h. The reaction was then cooled to 0° C. and quenched with sat. NH4Cl (20 mL), followed by extraction with Et2O (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 4.38 g (91%) of compound 501A as a bright orange oil. This material was used without further purification. HPLC: 94% at 2.91 min (retention time) (YMC Combiscreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 137.13 [M−H2O+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:9]O)(=[O:5])=[O:4].S(Cl)([Cl:19])=O>C(Cl)Cl>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:9][Cl:19])(=[O:5])=[O:4]
Reactant: COc1ccc(CO)cc1S(=O)(=O)N(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCl)cc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of OBS02053 (2.33 g, 8.89 mmol) in anhydrous DCM (50 mL) was added thionyl chloride (0.97 mL, 13.34 mmol). The mixture was stirred at room temperature for 2 h and the volatiles removed in vacuo. The residue was re-dissolved and co-evaporated three times with DCM (3×20 mL) to give OBS02058 as a light-sensitive brown oil (2.07 g, 83%); 1H-NMR (270 MHz, CDCl3)=2.98 (6H, s), 3.899 (3H, s), 4.54 (2H, s), 6.94 (1H, d, J=8.4), 7.25 (1H, dd, J=2.2, 8.4), 7.40 (1H, d, J=2.2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2>CN(C)C=O.C(N(CC)CC)C.[Pd]>[NH2:15][C:3]1[C:2]([NH2:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([OH:14])[C:7]([OH:13])=[N:8]2
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Yield: 72.3 %

Procedure:
A solution of 3 g (11,9 mmol) 6-amino-7-chloro-5-nitro-2,3-dihydroxyquinoxaline in a mixture of 80 ml dimethylformamide and 7,5 ml triethylamine was hydrogenated at atm. pressure using 5% Pd-C (0,5 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with 100 ml water, added 4N hydrochloric acid to pH 5-6, and the precipitate was filtered off to give 2,1 g of a crude product. Recrystallization (dimethylformamide-methanol) gave 1,95 g (74%) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline, m.p. >300° C. NMR (DMSO-d6): 11.6 (1H, broad s), 11.0 (1H, broad m), 6.47 (1H,s), 5.1 (2H, broad s), 4.6 (2H, broad s).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]1.Cl.[NH2:19][OH:20].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[Br:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[N:19][OH:20])[NH2:12])[CH2:7][CH2:6]1
Reactant: N#CN1CCC(Oc2cc(F)ccc2Br)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)N1CCC(Oc2cc(F)ccc2Br)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-(2-bromo-5-fluorophenoxy)piperidine-1-carbonitrile (1.6 g, 5.3 mmol), hydroxylamine hydrochloride (1.1 g, 16.1 mmol) and Na2CO3 (2.3 g, 92 mmol) in EtOH/water 4:1 (26 ml) was heated at 80° C. for 1 h. The solvent was evaporated. The residue was acidified with 6N HCl and washed with Et2O (2×10 mL). The aqueous layer was made basic with solid Na2CO3 and extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated under reduced pressure to give the title compound as a foam which was used in the next step without further purification. MS: m/z 332, 334 (MH+).
Reaction SMILES: N[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].N([O-])=O.[Na+].[ClH:21]>O.Cl[Cu]>[Cl:21][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a stirring solution of methyl 3-amino-5-phenylthiophene-2-carboxylate 82 (1.166 g, 5 mmol) in water (14 mL) and concentrated hydrochloric acid (7 mL) cooled to 0° C. was added a solution of sodium nitrite (0.431 g, 6.25 mmol) in water (2 mL). The reaction mixture was stirred for 30 min then the resulting solution was poured into a solution of CuCl (1.732 g, 17.50 mmol) in concentrated hydrochloric acid (20 mL) still at 0° C. The reaction was allowed to slowly warm to room temperature over 4 h then poured into ice cold water and extracted with ether (3×). The combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 3-chloro-5-phenylthiophene-2-carboxylate 83 as a white solid (0.850 mg, 67% yield) after purification by ISCO (40 g column, 5 to 40% ethyl acetate in hexane). LRMS (ESI): (calc) 252.72 (found) 253.06 (MH)+
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH:8]([C:10](OC)=O)[C:7](=O)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].Cl.C([O-])(=O)C.[Na+].[C:22]1([NH:28]N)C=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(O)C>[CH2:1]([N:5]1[CH2:9][C:8]2[C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:7]=2[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: NNc1ccccc1
Reactant: CCCCN1CC(C(=O)OC)C(=O)C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCN1Cc2c([nH]c3ccccc23)C1=O

Procedure:
1-n-Butyl-4-carbomethoxy-2,3-dioxopyrrolidine, 107 g., [Southwick and Owellen, J. Org. Chem. 25(1960)1133] is heated to boiling in a mixture of 600 ml. of a twenty percent aqueous hydrochloric acid solution and about 100 ml. of ninety-five percent ethanol. Solids dissolved in about ten minutes to give a yellow solution. After one hour of heating, the flask is cooled to about room temperature. Sodium acetate is then added to neutralize the reaction mixture to a pH of 4-5. In addition about 500 ml. of water is added during the neutralization to insure that most materials will remain in solution. Phenylhydrazine, 54 g., is then washed into the stirred mixture with methanol, 20 ml. The phenyl hydrazone starts to separate immediately, and is collected after ten minutes of cooling and stirring. The material is dissolved in 200 ml. of acetic acid at 65° and treated with 100 ml. of concentrated hydrochloric acid. A strong exotherm takes the temperature up to about 110° which causes vigorous refluxing. Filtration of the cooled slurry yields 78 g. of the title compound, m.p. 215°-218° sinters at 210°. Dilution of the filtrate with water gives additional product, 7 g., m.p. after recrystallization from methanol: 216°-218°.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([CH2:13][NH:14][CH3:15])=[CH:5][CH:4]=[C:3]3[CH2:2]1.[NH2:16][C:17]1[N:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.[ClH:58]>CN(C=O)C.O>[ClH:58].[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([CH2:13][N:14]([CH3:15])[C:25](=[O:27])/[CH:24]=[CH:23]/[C:20]2[CH:21]=[N:22][C:17]([NH2:16])=[CH:18][CH:19]=2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CNCc1ccc2c3c(cccc13)CC2
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(Cc1ccc2c3c(cccc13)CC2)C(=O)/C=C/c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of acenaphthen-5-ylmethyl-methylamine (216 mg, 1.1 mmol), (E)-3-(6-amino-pyridin-3-yl)acrylic acid (164 mg, 1 mmol), HOBt (148 mg, 1.1 mmol) and diisopropylethylamine (0.8 mL, 4.4 mmol) in DMF (20 mL) was added EDC hydrochloride (210 mg, 1.1 mmol). The mixture was stirred overnight at room temperature. Water (100 mL) was added and the solution stirred for 1 hour. The precipitate was collected by filtration. The yellow solid was preabsorded onto silica gel and purified by column chromatography (95:5 CH2Cl2/MeOH). The residue was dissolved into methylene chloride followed by addition of 1M HCl/ether. The precipitate was collected by filtration to afford (E)-N-acenaphthen-5-ylmethyl-3-(6-amino-pyridin-3-yl)-N-methyl-acrylamide hydrochloride (120 mg, 32%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 8.44-8.28 (m, 3H), 7.84-7.72 (m, 1H), 7.59-7.12 (m, 6H), 7.07-6.92 (m, 1H), 5.15-5.02 (2×s, 2H), 3.35-3.15 (bs, 2H), 3.18 (s, 4H), 3.07-2.90 (2×s, 3H); ESI MS m/z 344 [C22H21N3O+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+].CCCCCC>C(#N)C.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccccn1
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: [K+]
Solvent: CCCCCC
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1-c1ccccn1
Temperature: 80 °C
Yield: 95.6 %

Procedure:
To a solution of N-(5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pivalamide (23.4 g, 72.97 mmol) in acetonitrile (280 mL) was added 2-bromopyridine (16.14 g, 102.12 mmol) and aqueous solution of K2CO3 (50.40 g, 364.90 mmol). The reaction mixture was degassed by purging N2 for 15 min followed by addition of tetrakis(triphenylphosphine)palladium(0) (8.40 g, 7.30 mmol). The mixture was again degassed for 10-15 min then heated up to 80° C. for 8 h. After completion of reaction (by TLC), the mixture was poured into 100 mL of ice-cold water and extracted with EtOAc (3×250 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 2.0% EtOAc:hexane to obtain the desired product as a colourless liquid (19.0 g, 96% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CO>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
To a stirred solution of 4-bromo-2-nitrophenol (5.00 g, 22.9 mmol) in MeOH (120 mL) was added tin(II) chloride dihydrate (15.53 g, 68.8 mmol). The reaction mixture was heated at reflux and monitored by LC/MS. When significant reduction was complete, the reaction mixture was cooled to rt, poured over ice, and made basic (pH 9) with 50% saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×150 mL) and the combined extracts washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-amino-4-bromophenol as a dark gray solid. 1H NMR (CDCl3, 300 MHz) δ 9.29 (br s, 1H), 6.71 (d, 1H), 6.56 (d, 1H), 6.49 (dd, 1H), 4.83 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.[CH2:31]([O:33][C:34](Cl)=[O:35])[CH3:32]>N1C(C)=CC(C)=CC=1C>[CH2:31]([O:33][C:34](=[O:35])[O:17][CH2:16][C@:12]12[O:15][C@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=4)[CH:4]=3)([O:14][CH2:13]1)[C@H:9]([OH:20])[C@@H:10]([OH:19])[C@@H:11]2[OH:18])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a vigorously stirred solution of (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol (1A, 288 mg, 0.659 mmol) in collidine (6.6 mL) cooled to −35 degrees Celsius was added drop-wise over 10 minutes ethylchloroformate (0.112 mL, 1.19 mmol). The reaction mixture was allowed to stir overnight at room temperature. The reaction was quenched with an aqueous solution of saturated citric acid and extracted with ethyl acetate (2 times). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel using the biotage automated chromatography unit (50 g silica gel column) and eluting with a gradient of 0 to 20% methanol in dichloromethane. 134 mg (40% yield) of desired product as a white solid.
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[CH:18][C:13]3=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[N:5]1)([CH3:3])[CH3:2].[N+:24]([O-])([OH:26])=[O:25].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[C:13]3=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2ccsc2nc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc2c([N+](=O)[O-])csc2nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 3 °C
Reaction time: 3 h

Procedure:
Methyl 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)thieno[2,3-b]pyridine-5-carboxylate (3.94 g, 0.0119 mol) is dissolved in 200 mL concentrated H2SO4 at room temperature. While cooling to 3° C. in an ice bath, 1.5 mL (0.024 mol) concentrated HNO3 is added, then the mixture is allowed to warm to room temperature. After three hours, the reaction mixture is poured onto ice, neutralized with solid NaHCO3 to pH 6 and is extracted with methylene chloride. The extract is filtered, then dried over sodium sulfate, refiltered and concentrated to a yellow solid weighing 4.33 g (97%), which upon crystallization from methanol water has mp 201°-202.5° C.