Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[C:19]([N:26]1[CH2:33][C:32](=[O:34])[CH2:31][C@@H:27]1[C:28]([OH:30])=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])=[CH:38][CH:37]=1.COC(C)(C)C>C1(C)C=CC=CC=1>[O:34]=[C:32]1[CH2:33][N:26]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:27]([C:28](=[O:30])[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][CH:37]=2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1C(=O)O
Reactant: Nc1ccc(-n2ccccc2=O)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.2 742 mg (3.00 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 459 mg (2.00 mmol) of Boc-4-keto-D-proline and 372 mg (2.00 mmol) of 1-(4-aminophenyl)-1H-pyridin-2-one in 25 ml of toluene, and the mixture is stirred at room temperature for 18 hours. 200 ml of tert-butyl methyl ether are added, and the precipitate formed is filtered off. 200 ml of petroleum ether are added to the filtrate, and the resultant precipitate is filtered off, giving tert-butyl (R)-4-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a brownish solid; ESI 398.
Reaction SMILES: [C:1]([C:5]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][CH:7]([C:13]([O:15]C)=[O:14])[CH2:6]2)([O:3]C)=[O:2].O.[OH-].[Li+]>O1CCCC1.C(O)(C)C.O>[C:1]([C:5]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][CH:7]([C:13]([OH:15])=[O:14])[CH2:6]2)([OH:3])=[O:2]
Reactant: COC(=O)C1CC2CCC(C(=O)OC)(C2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C1CC2CCC(C(=O)O)(C2)C1
Yield: 86.4 %

Procedure:
A stirred solution of 1,3-dicarbomethoxybicyclo[3.2.1]octane (8.26 g, 36.5 mmol) in tetrahydrofuran (50 mL) and isopropanol (16 mL) was treated with a solution of lithium hydroxide hydrate (4.20 g, 100 mmol) in water (50 mL), and the mixture was heated to 60°-70° C. for 2 h with stirring. The organic solvents were removed in vacuo, and the alkaline aqueous solution was cooled on an ice bath and acidified with concentrated hydrochloric acid (10 mL). The solid was filtered, rinsed with cold water, and partially air dried overnight, then further dried under vacuum, triturated from acetonitrile, and redried in vacuo to afford 6.25 g (86%) of subject material as a white solid. No MS could be obtained. 1H NMR (CDCl3+drop d6-DMSO) δ 2.15-2.25 (m, 1H), 1.95-2.05 (m, 2H), 1.40-1.70 (m, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=O)[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C(=O)(O)[O-].[Na+].O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[S:33])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Temperature: 40 °C
Reaction time: 16 h
Yield: 140.4 %

Procedure:
To a solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate (300 mg, 0.92 mmol) in toluene (9.2 mL) was added Lawesson's Reagent (190 mg, 0.47 mmol). The mixture was stirred at 40° C. After 16 h, the mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. Water was added, and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 90% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (226 mg). MS 365.3 (M+Na).
Reaction SMILES: CC[O:3][CH2:4][CH3:5].[CH3:6]/[C:7](/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8]\[CH2:9]CC#N.CC(C[AlH]CC(C)C)C>CCCCCC>[CH3:6]/[C:7](/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8]\[CH2:9][CH2:5][CH:4]=[O:3]
Reactant: CCOCC
Reactant: CCCCCCCCC/C(C)=C/CCC#N
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Product: CCCCCCCCC/C(C)=C/CCC=O
Temperature: -60 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a cooled and stirred ether (700 ml) solution of the (E)-5-methyl-4-tetradecenenitrile (4) (30.0 g, 136 mmols), an n-hexane solution of DIBAL-H (1.7 M, 123 ml, 209 mmols) was added dropwise at −60° C. under an argon gas. The mixture was stirred for 1 hour at −60° C. and for 3 hours at room temperature. The excess reagent was quenched with the addition of HCO2Et (5 ml). After 30 minutes of stirring, the mixture was poured into a saturated aqueous solution of NH4Cl (1.5 L). The resulting mixture was stirred for 20 minutes, acidified with a 20% aqueous solution (1 L) of H2SO4, and extracted with ether. The ether solution was washed with water, dried (MgSO4), and concentrated in a vacuum. The oily residue was subjected to chromatography on Florisil (450 g), and eluted with n-hexane-ether (50:1) to obtain 29.0 g (95.4%) of (E)-5-methyl-4-tetradecenal (5).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:15]=[CH:16][N:17]=1)[CH2:6][CH2:5]2.C(N(CC)CC)C.[F:34][C:35]([F:52])([F:51])[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:43]([C:48](Cl)=[O:49])=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:14]2[C:13]([CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:48]([C:43]5[C:42]([C:39]6[CH:40]=[CH:41][C:36]([C:35]([F:34])([F:51])[F:52])=[CH:37][CH:38]=6)=[CH:47][CH:46]=[CH:45][CH:44]=5)=[O:49])[CH:3]=4)[CH2:8]3)=[N:17][CH:16]=[N:15]2)=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(Cn2ncnc2CN2CCc3cc(N)ccc3C2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2ncnc2CN2CCc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3C2)cc1
Reaction time: 4 h
Yield: 97 %

Procedure:
The title product of Example 3 (0.38 g, 1.1 mmol) and triethylamine (0.17 mL, 1.2 mmol) were dissolved in methylene chloride (14 mL) and stirred at room temperature while a solution of 4'-trifluoromethylbiphenyl-2-carbonyl chloride (0.31 g, 1.1 mmol) in methylene chloride (40 mL) was added dropwise. After four hours, 10% aq sodium carbonate solution was added and the mixture was stirred for thirty minutes. The methylene chloride layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford the title product as a hard foam, 0.63 g, 97% yield. 1H NMR (CDCl3) δ 7.79 (s, 1), 7.72 (d, 1), 7.64 (d, 2), 7.58-7.34 (m, 6), 7.12 (d, 2), 7.01 (s, 1), 6.90-6.72 (m, 4), 5.38 (s, 2), 3.73 (s, 3), 3.69 (s, 2), 3.50 (s, 2), 2.79 (t, 2), 2.68 (t, 2). IR (KBr) 1668, 1615, 1599, 1567, 1536, 1514 cm-1. Mass spectrum: m/z: 598 (M+ -1).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=O)[NH:4][CH2:3][C:2]1=S.C(Cl)Cl.CI.[OH-:19].[Na+].[OH2:21]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH:3]1[N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][N:4]([CH2:5][CH2:6][C:7]([OH:21])=[O:19])[CH2:3][C:2]2=[N:1][CH:2]=1
Reactant: [OH-]
Reactant: O=C1NCC(=S)Nc2ccccc21
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Product: O=C(O)CCN1Cc2ccccc2-n2ccnc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a biphasic solution of 7-[[4-cyanophenyl]methoxy]-4-propanoic acid, 3,4-dihydro-1H-1,4-benzodiazepine-2-thione-5-one, ethyl ester (1 gram, 2.36 mmol), methylene chloride (10 mL), water (10 mL), methyl iodide (0.2 mL) and a catalytic amount of tetrabutyl ammonium hydrogen sulphate at room temperature with vigorous stirring was added 1.2 mL of a 2N solution of sodium hydroxide. After 16 hours (overnight) the layers were seperated, the aqueous layer was washed 2×60 mL methylene chloride, and the combined organics were dried over sodium sulfate, decanted, and concentrated in vacuo. The resulting residue, 7-[[4-cyanophenyl]methoxy]-4-propanoic acid, 3,4-dihydro-1,4-benzodiazepine-2-methylmercaptyl-5-one, ethyl ester (1H NMR (CDCl3, δTMS) 7.70 (2H, d, 3JHH =8 Hz, 3,5H:4-NCC6H4), 7.56 (2H, 3JHH =8 Hz, 2,6H:4-NCC6H4), 7.49 (1H, d, 4JHH =3 Hz, C6 ArH), 7.18 (1H, d, 3JHH =9 Hz, C9 ArH), 7.15 (1H, dd, 4JHH =3 Hz, 3JHH =9 Hz, C8 ArH), 5.18 (2H, s, OCH2Ar), 4.16 (2H, q, 3JHH =7 Hz, OCH2), 3.94 (2H, t, 3JHH =7 Hz, NCH2), 3.91 (2H, s, C(S)CH2), 2.78 (2H, t, 3JHH =7 Hz, CH2CO2), 2.52 (3H, s, SMe), 1.24 (3H, t, 3JHH =7 Hz, CH2CH3); MS (FAB) cald. for C23H23N3 O4S 437.1, found MH+ 438.1), was dissolved in dry toluene (15 mL) and allowed to react with 0.23 grams pyridinium hydrogen chloride and 0.64 mL propargyl amine. The reaction was heated to reflux. After 5 hours, the reaction was allowed to cool to room temperature and the reaction concentrated in vacuo. The crude material was purified by column chromatography (SiO2, using ethyl acetate as the eluting solvent, Rf =0.1) to yield 4H-imidazo[1,2-a][1,4]benzodiazepine-5(6H)-propanoic acid, 8-[[4-cyanophenyl]methoxy]-1-methyl-6-oxo, ethyl ester (0.23 grams, 22%). 1H NMR (CDCl3, δTMS) 7.71 (2H, d, 3JHH =8 Hz, 3,5H:4-NCC6H4), 7.56 (2H, 3JHH =8 Hz, 2,6H:4-NCC6H4), 7.53 (1H, d, 4JHH =3 Hz, C6 ArH), 7.24 (1H, d, 3JHH =9 Hz, C9 ArH), 7.18 (1H, dd, 4JHH =3 Hz, 3JHH =9 Hz, C8 ArH), 5.21 (2H, dd, OCH2Ar), 4.52 (1H, d, 2JHH =16 Hz, C5H), 4.30 (1H, d, 2JHH =16 Hz, C5H), 4.16 (2H, q, 3JHH =7 Hz, OCH2), 3.89 (2H, m, NCH2), 2.66 (2H, m, CH2CO2), 2.29 (3H, s, C1-Me), 1.22 (3H, t, 3JHH =7 Hz, CH2CH3).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:15][CH2:16][CH3:17])=[C:4]([NH:9][C:10](=O)[CH2:11][C:12]#[N:13])[C:5]([Cl:8])=[N:6][CH:7]=1.BrC1C2N(CC)C(CC#N)=NC=2C(Cl)=NC=1.[N+:34]([O-])([O-])=[O:35].[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:3]2[N:15]([CH2:16][CH3:17])[C:10]([C:11](=[N:34][OH:35])[C:12]#[N:13])=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCNc1c(Br)cnc(Cl)c1NC(=O)CC#N
Reactant: O=[N+]([O-])[O-]
Agent: CCn1c(CC#N)nc2c(Cl)ncc(Br)c21
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1c(C(C#N)=NO)nc2c(Cl)ncc(Br)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 114.4 %

Procedure:
A solution of N-[5-bromo-2-chloro-4-(ethylamino)-3-pyridinyl]-2-cyanoacetamide III, (458 g, 1.45 mol) in glacial acetic acid (4.6 L) was heated to 100° C. After 3 h, LC/MS analysis indicated that the conversion to (7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)acetonitrile (IV) was completed. After allowing to cool to ambient temperature, the reaction was charged with sodium nitrate (230 g, 3.34 mol) in portions. Vigorous gas evolution and foaming was observed together with a ˜10° C. exotherm. After stirring at ambient temperature for 16 h, the solid was collected by filtration and dried to a constant weight to give 545 g of the desired product (V) as a light yellow solid. This was used in the next step without further purification. MS (ES+) m/z 328 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:30](O)(=[O:32])[CH3:31]>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
(R)-2-(3-(Aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 8; 0.034 g, 0.085 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.085 mmol) were placed in a THF-DCM solution (1:1, 3 ml) at 0° C. The resulting suspension was shaken vigorously at 0° C. for 45 min. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.018 g, 48%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.36 (m, 2H), 7.12 (d, J=9.6 Hz, 1H), 7.04-6.99 (m, 2H), 6.09 (br s, 1H), 5.19-5.02 (m, 1H), 4.36-4.17 (m, 2H), 3.83-3.71 (m, 2H), 1.99 (s, 3H), 1.88-1.83 (m, 1H), 0.98-0.87 (m, 2H), 0.72-0.66 (m, 2H). MS: Calcd.: 442. Found: [M+H]+ 443.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:25]([C:26]([NH2:28])=[O:27])=[C:17]3[NH:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH4-].[Na+].O>C1COCC1.C(Cl)Cl>[CH2:29]([N:21]1[CH2:22][CH2:23][C:24]2[N:16]3[N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:25]([C:26]([NH2:28])=[O:27])=[C:17]3[NH:18][C:19]=2[CH2:20]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c1cnccc12
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CN(Cc1ccccc1)CC3
Temperature: 65 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a suspension of 2-(4-phenoxyphenyl)-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carbox-amide (2.46 g, 0.0067 mol) in 150 mL of THF was added benzyl bromide (1.14 g, 0.0067 mol) dropwise, then the mixture was stirred at 65° C. overnight. After cooling down to RT, the mixture was concentrated, the residue was suspended in 150 mL of MeOH, NaBH4 (10 g, 0.26 mol) was added portionwise. The mixture was stirred at RT overnight. To the reaction was added 200 mL of water followed by 200 mL of DCM. The aqueous phase was further extracted with 100 mL of DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to get the crude product which was chromatographed on 10 g of silica gel using DCM/MeOH (200/1 to 80/1) as eluant to afford 0.786 g (26%) of 6-benzyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide as a tan foam. MS (ESI) m/e [M+1]+ 463.9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=O)[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH:28][C:29](=[O:34])[CH2:30][C:31]([CH3:33])=O)[CH2:22][CH2:21]1.C([O-])(=O)C.[NH4+:39].[ClH:40]>CO>[ClH:40].[ClH:40].[CH3:33][C:31]1[C:30]([C:29](=[O:34])[NH:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:39]=1
Reactant: CC(=O)CC(=O)NCCN1CCOCC1
Reactant: O=C(C=Cc1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Product: Cc1nc(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)c1C(=O)NCCN1CCOCC1

Procedure:
2-Methyl-3-(2-morpholinoethylcarbamoyl)-6- 3-nitrophenyl)-4-phenylpyridine, which was obtained according to a similar manner to that of Example 1 from 1-(3-nitrophenyl)-3-phenyl-2-propen-1-one (3.8 g), N-(2-morpholinoethyl)acetoacetamide (5.8 g) and ammonium acetate (2.0 g), was treated with a solution of hydrogen chloride in methanol to give 2-methyl-3-(2-morpholinoethylcarbamoyl)-6-(3-nitrophenyl)-4-phenylpyridine dihydrochloride (1.92 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:32][CH:33]=[C:34]([CH:36]=[O:37])[N:35]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl([O-])=[O:39].[Na+].P([O-])(O)(O)=O.[Na+]>CC(=CC)C.C(#N)C.C(O)(C)(C)C.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:15][C:16]3[CH:17]=[C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:32][CH:33]=[C:34]([C:36]([OH:39])=[O:37])[N:35]=5)[CH:26]=4)[CH:19]=[CH:20][C:21]=3[CH2:22][CH2:23]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5nc(C=O)c[nH]5)c4)cc3C2)c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5nc(C(=O)O)c[nH]5)c4)cc3C2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of N-(3-tert-butylphenyl)-7-{[2-(4-formyl-1H-imidazol-2-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (570 mg, 1.2 mmol) in 2-methyl-2-butene (3 mL), acetonitrile (6 mL) and tert-butyl alcohol (6 mL) was cooled to 0° C. To this cold reaction mixture was added a solution of sodium chlorite (646 mg, 5.71 mmol) and sodium dihydrogenphosphate (680 mg, 5.6 mmol) in water (3 mL). The yellow solution was allowed to stir at 0° C. overnight. The reaction was quenched by the addition of brine (3 mL) and extracted with EtOAc (15 mL×3). The combined organic solutions were washed with brine and dried over Na2SO4, filtered and concentrated to give 2-{4-[(7-{[(3-tert-butylphenyl)amino]carbonyl}-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]pyridin-2-yl}-1H-imidazole-4carboxylic acid (I-155), which was used without further purification. LCMS: (FA) ES+ 511.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=S)[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.CCN(CC)CC.Cl.[NH2:23][OH:24]>CCO.O>[OH:24][NH:23][C:9](=[N:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=1)[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=S)Nc1ccc(I)cn1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=Nc1ccc(I)cn1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
N-(5-Iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionamide (example 39, step 2) (5.1 g, 15.9 mmol) was dissolved in 50 ml of EtOH and Et3N (2.9 ml, 20.7 mmol, 1.3 equiv.) and hydroxylamine hydrochloride (1.3 g, 19.1 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred for 2 hours at room temperature. The suspension was diluted with 100 ml of water and filtered. The crystals were washed with water and dried for 2 hours at 50° C. and <10 mbar. The desired N-hydroxy-N′-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamidine (4.35 g, 86% yield) was obtained as a white solid, MS: m/e=319.9 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]=2[N:8]=1.Cl.[NH2:25][NH:26][C:27](=[O:30])[O:28][CH3:29]>C(O)(=O)C.CO.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11]/[C:10](=[N:25]\[NH:26][C:27](=[O:30])[O:28][CH3:29])/[C:9]=2[N:8]=1
Reactant: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCC2
Reactant: COC(=O)NN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)N/N=C1\CCCc2ccc(-c3sc(-c4cccnc4)nc3C)nc21
Temperature: 75 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A solution of 2-[4-methyl-2-(3-pyridyl)thiazol-5-yl]-6,7-dihydro-5H-quinolin-8-one (0.030 g, 0.093 mmol), methyl N-aminocarbamate hydrochloride (0.018 g, 014 mmol)) and acetic acid (1drop) were dissolved in methanol (0.9 mL) at ambient temperature and the resulting orange solution was stirred at 75° C. for 1 hour: LC-MS after this time showed reaction completion. The mixture was diluted with ethyl acetate, and then washed successively with saturated aqueous NaHCO3 and then water. The organic phase was, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with 0%-10% Methanol: Dichlormethane gradient gave the title product (29 mg, 79%) as yellow-orange solid. mp: 194-200° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]([Si:12]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1)([CH3:11])[CH3:10].N1C=CC=CC=1.CCCCCC>C1COCC1>[Br:8][C:15]1[CH:16]=[CH:17][N:13]([Si:12]([CH:9]([CH3:11])[CH3:10])([CH:18]([CH3:20])[CH3:19])[CH:21]([CH3:23])[CH3:22])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
NBS (N-bromosuccinimide; 0.8 g, 4.5 mmol) was added to a stirred solution of N-(triisopropylsilyl)pyrrole (1.0 g, 4.5 mmol) in anhydrous THF (10 mL) at −78° C. The reaction mixture was kept at −78° C. for 1-2 h and then left to reach room temperature (ca. 1 h). Pyridine (0.1 mL) and hexane (10 mL) were added, the resulting suspension was filtered through a plug of neutral alumina, and the filtrate was evaporated in vacuum. Purification by column chromatography on silica gel (hexane/ethyl acetate=10:1) gave oil (1.22 g, 90.1% yield). 1H NMR (CDCl3) δ 6 1.08 (d, 18 H, Hz, Me), 1.42 (sept, 3 H, CH), 6.26 (dd, 1H, H-4), 6.66 (t, 1 H, H-5), 6.72 (dd, 1H, H-2). MS (M+H) m/z 302.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH2:10][Cl:11].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1CCCCC1>[CH2:20]([N:19]([CH2:8][CH2:9][CH2:10][Cl:11])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Product: ClCCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 20 h
Yield: 52.8 %

Procedure:
To a stirred suspension of K2CO3 (200 g, 1.5 mole) in cyclohexane 200 mL and 1-bromo-3-chloropropane (540 gms, 3.4 mole) is added dropwise over a period of 1 h at 20° C. dibenzyl amine (442 g, 2.24 mole). After complete addition the reaction is allowed to stir for an additional 20 h. The crude reaction mixture is filtered and then washed with saturated NaCl (3×100 mL). The organic phase is extracted with 3N HCl (3×100 mL). The resulting aqueous phase, containing the desired product as the hydrochloric salt, is washed with hexanes (3×100 mL) to remove any residual BCP. The aqueous phase is subsequently basified with 50wt % NaOH and extracted with cyclohexane (3×100 mL). After solvent removal 324 g (53% yield) of the title compound was isolated as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]2[CH2:8][C@H:4]([CH:5]=[CH:6]2)[N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH2:16].C[N+]1([O-])CC[O:21]CC1.S(=O)(O)[O-].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[OH:16][C@H:6]1[C@@H:5]([OH:21])[C@H:4]2[CH2:8][C@@H:7]1[C:2](=[O:1])[N:3]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C=C[C@H]1C2
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)[C@H]2C[C@@H]1[C@H](O)[C@@H]2O
Yield: 72 %

Procedure:
To a solution of tert-butyl (1R,4S)-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (500. mg, 2.39 mmol) in acetone (20.0 mL) was added a 4% aqueous solution of osmium tetroxide in H2O (0.015 mL, 0.00239 mmol). To the resulting mixture was added a 10.2 M aqueous solution of N-methylmorpholine N-oxide (0.262 mL, 2.67 mmol) dropwise over 1 h. At this point, a 0.240 M solution of aqueous sodium bisulfite (1.00 mL, 0.240 mmol) was added, the mixture was filtered through celite and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 20 to 70% EtOAc in DCM to afford the title compound (420. mg, 72%). LC/MS: Rt=0.94 min, ES+ 244 (FA standard).