Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1(C)[C:17](C)(C)OB(C(C)=C)O1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]=[C:13]([C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[CH3:17]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ncnn2c(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)c1ccc2c(N)ncnn12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (426 mg, 2 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (420 mg, 2.5 mmol) were dissolved in a mixture of 1,2-dimethoxyethane (10 mL) and aqueous sodium carbonate solution (2 M, 4 mL). The reaction mixture was degassed, and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (73 mg, 0.1 mmol) was added. After stirring at 90° C. overnight, the reaction mixture was diluted with ethyl acetate (40 mL), water (10 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×40 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (puriFlash, Interchim, cyclohexane/ethyl acetate 1:1 to 100% ethyl acetate gradient) to yield the title product as a slightly yellow solid. Yield: 304 mg (81% of th.).
Reaction SMILES: [F:1][CH:2]1[C:7]([F:9])([F:8])[C:6]2([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:11][C:3]1([O:15]C(CCCCC)=O)[CH2:4][CH2:5]2.[OH-].[K+].O.Cl>C(OCC)(=O)C.C(O)C>[F:1][CH:2]1[C:7]([F:8])([F:9])[C:6]2([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:11][C:3]1([OH:15])[CH2:4][CH2:5]2
Reactant: CCCCCC(=O)OC12CCC(CCC)(CC1)C(F)(F)C2F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC12CCC(O)(CC1)C(F)C2(F)F
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2,3,3-trifluoro-1-pentylcarbonyloxy-4-n-propylbicyclo[2.2.2]octane (3) (0.12 g), potassium hydroxide (0.11 g), water (0.5 mL) and ethanol (2.0 mL) was stirred at 70° C. for 20 minutes. The mixture was neutralized with hydrochloric acid, added with ethyl acetate (30 mL), and the organic layer was washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was vaporized off under reduced pressure, to thereby obtain a crude product. The crude produce was purified by silica gel column chromatography (hexane/ethyl acetate=3:1), to thereby obtain 2,3,3-trifluoro-1-hydroxy-4-n-propylbicyclo[2.2.2]octane (4) (yield=82 mg, yield ratio=98%) as a colorless clear solid.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2>N1C=CC=CC=1>[C:1]1([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cccc2cnccc12
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: c1ccc(-c2cccc3cnccc23)cc1
Temperature: 90 °C
Yield: 53.6 %

Procedure:
Cupric oxide (0.2 g) was added in one portion to a mixture of phenol (2 g, 21 mmol), potassium carbonate (2.7 g, 20 mmol), and 5-bromoisoquinoline (2.1 g, 10 mmol) in pyridine (20 ml) heated at 90° C. under nitrogen. The mixture was then heated at 140° C. for 18 h. After this time the pyridine was removed in vacuo, the residue suspended in ether and the mixture filtered through a pad of silica gel. The solvent was evaporated and the residue purified by column chromatography on silica with ethyl acetate/hexane (1:3-1:1) as eluant to give the title compound as a colourless solid (1.1 g, 49%); δH (CDCl3) 7.1-7.5 (7H, m, ArH), 7.75 (1H, d, J 8 Hz, ArH), 8.02 (1H, d, J 8 Hz, ArH), 8.57 (1H, d, J 8 Hz, ArH), and 9.3 (1H, s, 1-H).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH2:14])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.O1CCCC1>C(OCC)(=O)C>[CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][Br:22])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(c1ccccc1)c1ccc2nc(N)n(C(C)C)c2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1c(N)nc2ccc(C(=CBr)c3ccccc3)cc21

Procedure:
Three hundred milligrams (1.08 mmoles) of 1-isopropyl-2-amino-6-(1-phenylethenyl)benzimidazole and 192 mg. (1.08 mmoles) of N-bromosuccinimide were refluxed overnight in 20 ml. of dry tetrahydrofuran. After cooling, ethyl acetate was added and the solution was washed with a saturated solution of sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed over silica gel, first eluting with ethyl acetate to remove impurities, and then with 10% methanol/90% ethyl acetate. The title product was crystallized from ether giving 200 mg. of the cis/trans mixture, M+ =357.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:28]=3)[CH2:23][CH2:22]2)=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4Cl)CCCC3)CC2)c1

Procedure:
Example 38 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.52 (s, 1H), 7.45–7.36 (m, 1H), 7.34–7.29 (m, 1H), 7.23 (t, 1H, J=8.0 Hz), 7.17–7.13 (m, 1H), 6.95–6.90 (m, 2H), 6.00–5.94 (m, 1H), 3.30 (q, 2H, J=6.4 Hz), 2.92–2.84 (m, 2H), 2.57–2.38 (m, 3H), 2.47–2.39 (m, 1H), 2.31 (t, 1H, J=7.2 Hz), 1.95–1.73 (m, 7H), 1.68–1.48 (m, 8H), 1.24 (d, 6H, J=7.2 Hz); ESMS m/e: 528.3 (M+H)+.
Reaction SMILES: [CH2:1]([S:9][C:10]1[C:11](=[O:16])[NH:12][CH:13]=[CH:14][N:15]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:18]1[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])=[C:20]([CH3:30])[CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>O1CCOCC1.[Cu](I)I>[OH:26][C:24]([CH3:27])([CH3:25])[CH2:23][O:22][C:21]1[CH:28]=[CH:29][C:18]([N:12]2[CH:13]=[CH:14][N:15]=[C:10]([S:9][CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:11]2=[O:16])=[CH:19][C:20]=1[CH3:30]
Reactant: O=c1[nH]ccnc1SCCc1ccccc1
Reactant: Cc1cc(Br)ccc1OCC(C)(C)O
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(-n2ccnc(SCCc3ccccc3)c2=O)ccc1OCC(C)(C)O
Temperature: 115 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 3-(phenethylthio)pyrazin-2(1H)-one (25 mg, 0.108 mmol), which was prepared by the procedure described in Method 7 except for substitution of 2-phenethylthiol for 2-(4-chlorophenethanol), 1-(4-bromo-2-methylphenoxy)-2-methylpropan-2-ol (33.5 mg, 0.129 mmol), copper iodide (20.50 mg, 0.108 mmol), K3PO4 (70 mg, 0.323 mmol) and N,N′-dimethylethylenediamine (28.5 mg, 0.323 mmol) in dioxane (1.0 ml) was stirred at 115° C. for 2 hours. The reaction mixture, after cooling to RT, was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 100% ethyl acetate) to elute to yield 1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(phenethylthio)-pyrazin-2(1H)-one (26.74 mg, 0.062 mmol, 57.5% yield) as off-white solid. MS (M+1=411). 1H NMR (500 MHz, methanol-d3) δ ppm 7.38 (1H, d, J=4.40 Hz), 7.25-7.32 (4H, m), 7.16-7.24 (4H, m), 7.00 (1H, d, J=8.25 Hz), 3.83 (1H, s), 3.24-3.39 (2H, m), 2.90-3.05 (2H, 2.29 (3H, s), 1.35 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13]N=C3)=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C=CC2N=[CH:23][S:24]C=2C=1.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1ccc2[nH]ncc2c1
Reactant: Brc1ccc2ncsc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccc2ncsc2c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
6-(2-Chloropyridin-3-yl)benzo[d]thiazole was prepared analogous to 5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of 6-bromobenzo[d]thiazole (2.0 g, 9.3 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (2.7 g, 11.2 mmol), Pd(PPh3)4 (500 mg, 0.43 mmol) and 2M aq.Na2CO3 (14 mL, 28 mmol) in 1,4-dioxane (100 mL). The reaction mixture was concentrated at the completion of the reaction (12 h) and diluted with CH2Cl2 (200 mL/100 mL). Mixed organic layers were stirred with MgSO4 and Celite® for 30 min. The slurry was suction filtered and concentrated by rotary evaporator under vacuum. The crude concentrate was dissolved in CH2Cl2, adsorbed on silica gel and dried. The dry powder thus obtained was purified by silica gel flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g, 30-70% EtOAC/hexanes eluting solvent gradient). 6-(2-chloropyridin-3-yl)benzo[d]thiazole (1.9 g, 82%) was obtained as a white solid upon concentration of the product fractions. 1H NMR (DMSO-d6): δ 9.46 (s, 1H), 8.46 (dd, 1H, J=1.7 and 4.7 Hz), 8.30 (d, 1H, J=1.4 Hz), 8.17 (d, 1H, J=8.2 Hz), 7.96 (dd, 1H, J=1.7 and 7.6 Hz), 7.63 (dd, 1H, J=1.4 and 8.5 Hz), 7.53 (dd, 1H, J=4.7 and 7.6 Hz). LCMS: rt 6.71 min (A), purity 99%, MS (m/e) 247.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][OH:12])[N:5]=1)(=[O:3])[CH3:2].[C:13](Cl)([Cl:15])=[O:14]>ClCCl.C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][C:13]([Cl:15])=[O:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)c1cc(C)n(CCO)n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)c1cc(C)n(CCOC(=O)Cl)n1
Reaction time: 1.5 h

Procedure:
3-Acetyl-1-(2-hydroxyethyl)-5-methylpyrazole (505 mg, prepared as described in Example 12, Preparation 1 in dry dichloromethane (5 ml) under an atmosphere of arson was treated with a solution of phosgene in toluene (12.5% w/w, 5.22 ml) and the mixture stirred for 1.5 h. The solvents were then removed, dichloromethane was added and removed using a rotary evaporator to give 3-acetyl-1-[2-(chlorocarbonyloxy)ethyl]-5methylpyrazole; νmax (CH2Cl2) 1777 and 1684 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:24])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[CH:18]=1)[CH3:11].Cl[CH2:26][P:27](=[O:30])([CH3:29])[CH3:28]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:24])=[N:15][CH:16]=[C:17]([C:19]2[CH:23]=[N:22][N:21]([CH2:26][P:27]([CH3:29])([CH3:28])=[O:30])[CH:20]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cn[nH]c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CP(C)(=O)CCl
Product: CC(Oc1cc(-c2cnn(CP(C)(C)=O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrazol-4-yl)-pyridin-2-ylamine and chloromethyl-dimethyl-phosphine oxide following the same procedure as Example 2. ESMS: m/z 457 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:4]=1[NH2:5].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1>C1COCC1>[Br:10][C:7]1[CH:6]=[C:4]2[C:3]([CH2:2][NH:1][C:16](=[O:17])[NH:5]2)=[CH:9][CH:8]=1
Reactant: NCc1ccc(Br)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1NCc2ccc(Br)cc2N1
Temperature: 80 °C
Reaction time: 6 h
Yield: 71.4 %

Procedure:
To a solution of compound 12 (0.90 g, 4.5 mmol) in THF (10 mL) at room temperature was added CDI (0.80 g, 4.95 mmol), and the reaction was stirred at 80° C. for 6 hr. The mixture was cooled to room temperature, and the solid formed was filtered, washed with diethyl ether to afford 0.73 g (72%) of compound 13 as off-white solid. IR (KBr) νmax. cm−1: 3308, 3158 (NH), 3022 (Ar—H), 1682 (C═O), 1514, 1411 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=5.25 (s, 2H, CH2); 6.82 (d, 1H, J=8.2 Hz, H-5); 7.42 (m, 2H, H-4, H-6); 10.29 (br. s, 1H, NH); 13C NMR (125.7 MHz, DMSO-d6)=66.85 (CH2), 113.70 (C-10), 115.70 (C-8), 121.03 (C-7), 127.52 (C-6), 131.41 (C-5), 135.88 (C-9), 151.42 (C═O). Calculated (%) for C8H7BrN2O (225.97); C: 42.32, H: 3.11, N: 12.34. found (%); C: 42.27, H: 3.16, N: 12.28.
Reaction SMILES: Cl.[NH:2]1[C@H:6]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH2:5][C@@H:4]2[CH2:17][CH2:18][CH2:19][C@H:3]12.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH:4]2[CH2:17][CH2:18][CH2:19][CH:3]12
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C1CC2CCCC2N1
Reaction time: 16 h

Procedure:
To a solution of commercially available (2S,3aS,6aS)-benzyl octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride (4.70 g, 16.68 mmol) in methylene chloride (42 mL) was added Di-tert-butyl dicarbonate (7.28 g, 33.36 mmol), N,N-diisopropylethylamine (5.82 mL, 33.36 mmol) and 4-(Dimethylamino)pyridine (0.20 g, 1.67 mmol). The solution was stirred under air for 16 hours. Upon completion, the reaction was concentrated in vacuo, diluted in ethyl acetate, and washed with 1N HCl. The aqueous layers were backextracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (5-40% ethyl acetate in hexanes) to afford (2S,3aS,6aS)-1-tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid which was used without further purification. MS (ESI) m/z 368.47 [M+Na]+.
Reaction SMILES: [H-].[Na+].C([Cl:6])(=O)C.[C:7]([N:10]([C:14]1[C:23]2[C:18](=[N:19][C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH:22]=2)[N:17]([CH3:39])[C:16](=[O:40])[C:15]=1C)C(=O)C)(=[O:9])[CH3:8].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CO.CCOC(C)=O.CN(C=O)C>[Cl:6][C:15]1[C:16](=[O:40])[N:17]([CH3:39])[C:18]2[C:23]([C:14]=1[NH:10][C:7](=[O:9])[CH3:8])=[CH:22][C:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[C:20]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38])[N:19]=2
Reactant: CC(=O)N(C(C)=O)c1c(C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1c(Cl)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
To the product to Step A (100 mg) in THF (1.5 mL) and DMF (0.3 mL) was added NaH (13 mg, 60% dispersion in mineral oil) at 0° C. After about 10 minutes acetyl chloride (61.4 μL) was added. An additional portion of acetyl chloride (30 μL) was added. Analysis of the reaction solution indicated a distribution between the 4-amino, 4-N-acetamide and 4-di-N-acetamide. The imide was cleaved by adding a solution of Cs2CO3 (about 200 mg) in methanol (about 5 mL). The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and then brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the title compound. HPLC/MS: 506.0 (M+1), 508.0 (M+3); Rt=4.50 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:35]2[CH2:34][CH2:33][N:32]([C:25]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:37][CH2:36]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c(N2CCNCC2)c1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(OC)c(N2CCN(CC(O)COc3ccc(OCc4ccccc4)cc3)CC2)c1
Yield: 33.9 %

Procedure:
2.56 g of 1-(4-benzyloxyphenoxy)-2,3-epoxypropane was dissolved in 100 ml of dioxane, and to this were added 2.95 g of 1-(2,5-dimethoxyphenyl)piperazine dihydrochloride and 3.5 ml of triethylamine and reaction and workup were carried out as in Example 1-A. The residue obtained was purified by column chromatography (silica gel, elution with ethyl acetate:hexane=1:1) to give 1.62 g of brown oil.
Reaction SMILES: C(OC([NH:8][N:9]1[CH2:14][C:13]([C:15]2[CH2:19][C:18]([CH3:21])([CH3:20])[O:17][N:16]=2)=[N:12][N:11](C(OC(C)(C)C)=O)[C:10]1=[O:29])=O)(C)(C)C.C(Cl)(=O)C.C[O-].[Na+]>CCO.CO>[NH2:8][N:9]1[CH2:14][C:13]([C:15]2[CH2:19][C:18]([CH3:20])([CH3:21])[O:17][N:16]=2)=[N:12][NH:11][C:10]1=[O:29]
Reactant: CC(C)(C)OC(=O)NN1CC(C2=NOC(C)(C)C2)=NN(C(=O)OC(C)(C)C)C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Solvent: CCO
Product: CC1(C)CC(C2=NNC(=O)N(N)C2)=NO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-6-(5,5-dimethyl-4H-isoxazol-3-yl)-3-oxo-5H-1,2,4-triazine-2-carboxylate (2.50 g, 5.51 mmol) in EtOH (30 mL) at 0° C. was slowly added acetyl chloride (2.16 mL, 27.6 mmol). After completion of the addition, the reaction mixture was allowed to warm to room temperature and stirring was continued for an additional 20 h. The reaction mixture was cooled to 0° C. and carefully treated with NaOMe in MeOH until pH 7 was reached. The volatiles were removed in vacuo and the residual was repeatedly diluted with acetonitrile and evaporated. The remaining solids were stirred for 10 min with hot acetonitrile and filtered. Concentration of the filtrate furnished the desired product as an off-white solid. LCMS (Method K) RT 0.47 min. [M+H]+ 212.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:22])[C@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:2]=1.C(=O)([O-])O.[Na+].[CH2:28](Br)[CH3:29].O>CN(C)C=O>[CH2:28]([O:12][C:11](=[O:13])[CH2:10][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:22])[CH3:29]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)O)C(=O)Nc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 57.8 %

Procedure:
To a suspension of N-(3-pyridyl)-3(R)-(tert-butoxycarbonylamino)succinamic acid (1 g) and sodium hydrogen carbonate (0.54 g) in N,N-dimethylformamide (5 ml) was added to a solution of ethyl bromide (1.76 g) in N,N-dimethylformamide (5 ml). After stirring at room temperature for 4 days, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1) to give N-(3-pyridyl)-3(R)-(tert-butoxycarbonylamino)succinamic acid ethyl ester (0.63 g) as an oil.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=[O:8].[Na+].[C:11]([O:14][C@@H:15]1[C@@H:56]([O:57][C:58](=[O:60])[CH3:59])[C@H:55]([O:61][C:62](=[O:64])[CH3:63])[C@@H:54]([C:65]([O:67][CH3:68])=[O:66])[O:53][C@H:16]1[O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([O:38][C:39](=[O:41])[CH3:40])[C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:26](=[O:42])[N:25]2[C:43]2[CH:48]=[CH:47][C:46]([C:49]#[C:50][CH:51]=[O:52])=[CH:45][CH:44]=2)=[CH:20][CH:19]=1)(=[O:13])[CH3:12]>C(O)(C)(C)C.O1CCOCC1.CC(=C)C>[C:11]([O:14][C@@H:15]1[C@@H:56]([O:57][C:58](=[O:60])[CH3:59])[C@H:55]([O:61][C:62](=[O:64])[CH3:63])[C@@H:54]([C:65]([O:67][CH3:68])=[O:66])[O:53][C@H:16]1[O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([O:38][C:39](=[O:41])[CH3:40])[C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:26](=[O:42])[N:25]2[C:43]2[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]([OH:8])=[O:52])=[CH:45][CH:44]=2)=[CH:20][CH:19]=1)(=[O:13])[CH3:12]
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](OC(C)=O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CC=O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](OC(C)=O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CC(=O)O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1.5 h

Procedure:
An aqueous solution (0.1 mL) of sodium dihydrogenphosphate (9.00 mg, 0.065 mmol) and sodium chlorite (5.00 mg, 0.055 mmol) was added to a solution of 10c (37.0 mg, 0.046 mmol) in tert-butyl alcohol (0.4 mL), dioxane (0.2 mL) and isobutylene (˜0.1 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated in vacuo and the crude residue triturated repeatedly with ethyl acetate. The organic washings were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound 10d.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:30]3[O:29][C:28]([C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=4)=[C:27]([CH3:40])[C:26](=[O:41])[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:11][CH2:10]1>C(O)C.C(O)(=O)C.[Ni]>[NH2:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[O:29][C:30]3[C:21]([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15][N:12]4[CH2:13][CH2:14][N:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[CH2:10][CH2:11]4)=[CH:22][CH:23]=[CH:24][C:25]=3[C:26](=[O:41])[C:27]=2[CH3:40])=[CH:36][CH:35]=1
Reactant: COc1ccccc1N1CCN(CCCNC(=O)c2cccc3c(=O)c(C)c(-c4ccc([N+](=O)[O-])cc4)oc23)CC1
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(CCCNC(=O)c2cccc3c(=O)c(C)c(-c4ccc(N)cc4)oc23)CC1
Reaction time: 6 h

Procedure:
2.22 g of compound of Example 113 and 0.56 g of Raney-Nickel in 96 ml of ethanol and 4.8 ml of acetic acid was hydrogenated in a Parr apparatus (pH2 =1 atm) at room temperature. After 6 hours shaking, the catalyst was filtered off and the filtrate was alkalinized with 3N aqueous sodium hydroxide solution and diluted with water. After standing for 2 days at 0° C., the precipitated title compound was collected by suction, washed with water, desiccated and recrystallized firstly from ethyl acetate then from ethanol yielding 1.5 g of the title compound (m.p. 192°-194° C.).
Reaction SMILES: [CH2:1]([OH:10])[C@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].C(O)[C@@H]([C@@H](CO)O)O.C(O)[C@H]([C@@H](CO)O)O.OCC(O)CCC(O)CO>>[CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3]
Reactant: OC[C@@H](O)C(O)[C@H](O)CO
Agent: OCC(O)CCC(O)CO
Agent: OC[C@@H](O)[C@@H](O)CO
Agent: OC[C@@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
lyxitol; erythritol; threitol; 1,2,5,6-tetrahydroxyhexane;