Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH2:9][C:10]1[C:11]([O:23][CH3:24])=[N:12][S:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O1CCCC1.[Li+].[OH-]>O>[F:25][C:6]1[CH:5]=[C:4]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[O:8][CH2:9][C:10]1[C:11]([O:23][CH3:24])=[N:12][S:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(OC)nsc2-c2ccc(OC)cc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2snc(OC)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(3,5-difluoro-4-[[3-methoxy-5-(4-methoxyphenyl)-1,2-thiazol-4-yl]methoxy]phenyl)propanoate (50 mg, 0.11 mmol, 1.00 equiv), tetrahydrofuran (3 mL), water (1 mL), LiOH (50 mg, 2.09 mmol, 19.30 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5 with hydrogen chloride (2 mol/L). The solids were collected by filtration, washed with n-hexane, dried. This resulted in 8.2 mg (17%) of 3-(3,5-difluoro-4-[[3-methoxy-5-(4-methoxyphenyl)-1,2-thiazol-4-yl]methoxy]phenyl) propanoic acid as a white solid. 1H NMR (300 MHz, CD3OD) δ7.53 (d, J=11.6 Hz, 2H), 7.05 (d, J=11.6 Hz, 2H), 6.81 (d, J=11.6 Hz, 2H), 5.16 (s, 2H), 4.06 (s, 3H), 3.92 (s, 3H), 2.88 (m, 2H), 2.71 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H19F2NO5S, 436.1 (M+H). found 436.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH:17]1(O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CC(OC)(C)C>[CH:17]1([O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)C(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)C(C)(C)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethylmalonic acid mono-t-butyl ester [CAS No. 143688-40-8] (800 mg), DMAP (104 mg), and dichloromethane (8 mL), cyclohexanol (0.494 mL) and WSC (976 mg) were sequentially added at 0° C. The resulting mixture was stirred overnight at room temperature, and TBME (50 mL) was added thereto. The resulting mixture was sequentially washed with water (30 mL) and saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (817 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCC1CCCCO1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydro-2H-pyran (0.61 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.71 g, 46%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:9](Cl)=[CH:8][C:6]([NH2:7])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.Cl.[F:17][C:18]([F:26])([F:25])[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:1][C:2]([F:15])([F:14])[C:3]1[C:9]([N:22]2[CH2:23][CH2:24][CH:19]([C:18]([F:26])([F:25])[F:17])[CH2:20][CH2:21]2)=[CH:8][C:6]([NH2:7])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCC(C(F)(F)F)CC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from 4-trifluoromethyl-5-chloro-2-nitro-aniline (100 mg, 0.42 mmol), 4-trifluoromethyl-piperidine hydrochloride (394 mg, 2.1 mmol) and K2CO3 (600 mg, 4.4 mmol) in NMP (2 mL) in analogy to example 3, step (a).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:36][CH2:37][CH2:38][OH:39]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:36]([CH2:37][CH2:38][OH:39])[CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[O:28])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: OCCNCc1ccccn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)N(CCO)Cc2ccccn2)c2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH2:28]O)=[C:21]3[C:25]([OH:27])=[O:26])=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2].[NH2:39][N:40]1[C:44]([N:45]2[C:49]([CH3:50])=[CH:48][C:47]([CH3:51])=[N:46]2)=[N:43][N:42]=[C:41]1[SH:52].C(=O)([O-])[O-].[Na+].[Na+].Cl>CC(C)=O.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[C:21]([C:25]([OH:27])=[O:26])=[C:20]([CH2:28][S:52][C:41]4[N:40]([NH2:39])[C:44]([N:45]5[C:49]([CH3:50])=[CH:48][C:47]([CH3:51])=[N:46]5)=[N:43][N:42]=4)[CH2:19][S:18][C@H:17]23)=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CO)CSC23)c2ccc(O)cc2)C(=O)C1=O
Reactant: Cc1cc(C)n(-c2nnc(S)n2N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(-n5nc(C)cc5C)n4N)CS[C@H]23)c2ccc(O)cc2)C(=O)C1=O
Reaction time: 2 h

Procedure:
A suspension of 294.78 mg. of 7-[2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)acetamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, 3-acetate and 157.7 mg. of 4-amino-5-(3,5-dimethyl-1-pyrazolyl)-4H-1,2,4-triazole-3-thiol in 10 ml. of water is adjusted to pH 6.5 with aqueous sodium carbonate. A 2 ml. portion of acetone is added producing solution. This solution is stirred at 60°-63° C. for 51/2 hours, then stripped free of acetone under reduced pressure and acidified to pH 2.0 with 2 N hydrochloric acid. The resulting solid is filtered, washed repeatedly with ethyl acetate, then with ether and dried, giving 190 mg. of the desired product as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH2:23][C:24](Cl)=[O:25].Cl>C(OCC)C>[Br:22][CH2:23][C:24]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:25]
Reactant: O=C(Cl)CBr
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Agent: Cl
Solvent: CCOCC
Product: O=C(CBr)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 0 °C

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (2 g, 0.0071 mol) was dissolved in bromoacetylchloride (15 g, 8 mL, 0.096 mol) by heating in an oil bath (70°-80° C. bath temperature) for about 15 minutes, until the formation of HCl ceased The mixture was cooled and 30 mL of ethyl ether were added. White crystals formed. The mixture was cooled to 0° C., then the crystals were removed by filtration and dried over P2O5. Yield: 2.15 g (75%), m.p. 179°-183° C. Anal. calc. for C18H15N2O4Br: C, 53.61, H, 3.75; N, 6.95; Br, 19.82. Found: C, 53.60; H, 3.79., N, 6.92; 8r, 19.90. The product had the formula: ##STR72##
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27](B(O)O)[CH:28]=2)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.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>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:2]3[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)[CH:28]=2)[CH:23]=[N:22]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccc4cn[nH]c4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL) was added 1H-indazol-6-ylboronic acid (386.0 mg, 2.38 mmol), K3PO4 (434.0 mg, 2.05 mmol), Pd(PPh3)4 (39.0 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 20 min at 90° C., the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1%-10% ethyl acetate in petroleum ether to afford methyl 2-(1H-indazol-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (200 mg, 78%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3nnsc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (50 mg, 0.13 mmol) in CH2Cl2 (5 mL) was added triethylamine (26 mg, 0.25 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (26 mg, 0.19 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (60 mg, 95% yield). 1H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 7.75-7.72 (d, 2H), 7.35 (m, 1H), 3.35 (m, 1H), 1.70 (m, 2H), 0.87 (m, 2H).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:16])[CH:10]=[CH:9]2)=[O:5].[C:17]1([CH2:25]Cl)[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=1>CN(C)C=O>[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:16][CH2:25][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:16][C:11]3[CH:10]=[CH:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=4)[CH:12]=3)[CH:18]=1)[CH:10]=[CH:9]2)([O:3][CH3:2])=[O:5]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: ClCc1cccc(CCl)c1
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OCc3cccc(COc4ccc5cc(C(=O)OC)ccc5c4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
To sodium salt of 2-hydroxynaphthalene-6-carboxylic acid methyl ester (44.8 g) N,N-dimethylformamide (200 ml) was added with stirring at room temperature. Then a solution of m-xylylenedichloride (17.5 g, 0.1 mol) in N,N-dimethylformamide was added in drops thereto in 10 minutes. The reaction mixture was stirred at 105° C. for 4 hours and then cooled to give a precipitate. The precipitate was rinsed with N,N-dimethylformamide, treated with hot water at 80° C. for 30 minutes with stirring, and then with methanol at 60° C. for 30 minutes with stirring; cooled, filtered and dried to give a white crystals of 1,3-bis(6-carbomethoxy-2-naphthoxymethyl)benzene (39.7 g, yield 77.8%): m.p. 177.3°-178.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:23][C:24]1[CH:33]=[CH:32][C:27]([CH:28]=[CH:29][CH2:30]Br)=[CH:26][CH:25]=1>CN(C)C=O.C(Cl)Cl>[Br:23][C:24]1[CH:33]=[CH:32][C:27]([CH:28]=[CH:29][CH2:30][NH:22][CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Reactant: BrCC=Cc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNCC=Cc2ccc(Br)cc2)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethylamine (261 mg in a mixture of 3 mL N,N-dimethylformamide and 8 mL methylene chloride) at 0° C. was added a solution of 81 mg of 4-bromocinnamyl bromide in 2 mL methylene chloride and the mixture allowed to warm to room temperature. After 27 hours the reaction was quenched by the addition of water followed by extraction with ethyl acetate. The organic portion was dried over over sodium sulfate and purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (93 mg). m/e=491 (M)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][C:7]#[N:8])[CH3:2].Cl.[NH2:13][OH:14].C(=O)(O)[O-].[Na+]>CO>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7](=[NH:8])[NH:13][OH:14])[CH3:11]
Reactant: NO
Reactant: CCOC(CCC#N)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(CCC(=N)NO)OCC
Temperature: 25 °C

Procedure:
A mixture of 4,4-diethoxybutanenitrile (5.0 g, 32 mmol), hydroxylamine hydrochloride (2.4 g, 35 mmol) and sodium bicarbonate (2.9 g, 35 mmol) in methanol (50 mL) was refluxed for 5 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue was diluted with EtOAc and water. The water layer was extracted with EtOAc (2×). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to give the product, which was used next step without purification. 1HNMR (300 MHz, CD3Cl): δ 4.73 (br, 1H), 4.51 (t, J=5.5 Hz, 1H), 3.66 (m, 2H), 3.50 (m, 2H), 2.21 (t, J=8.2 Hz, 2H), 1.86 9m, 2H), 1.19 (t, J=8.2 Hz, 6H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[C:15]([F:32])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:33]([CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]3)=[C:15]([F:32])[CH:14]=2)[CH2:8]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
A solution of the 16.8 g (35.5 mmol) of the mesylate 3 in 400 mL of dimethylformamide was treated with 11.5 g (177.5 mmol) of sodium azide followed by warming at 60° C. for 16 h. The solution was diluted with ethyl acetate and extracted with water. The organic layer was dried (Na2SO4) and concentrated in vacuo to afford 14.9 g (100%) of the azide 4 as a light yellow solid, mp 101°-104° C., sufficiently pure for further use.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OCC)(=O)C.[ClH:38]>C(O)C>[ClH:38].[ClH:38].[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CCc2ccccc2NCc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1[nH]cccc1CN1CCC(CCc2ccccc2NCc2ccccc2)CC1

Procedure:
In ethanol (8 ml) was dissolved 294 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(benzylamino)phenyl]ethyl]piperidine. To the mixture was added 3 ml of a 4N-hydrogen chloride-ethyl acetate solution, followed by heating under reflux for 3 hours. After cooling as it was, the resulting precipitates were collected by filtration and recrystallized from ethanol, to give 273 mg of the title compound as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:19]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A solution of 4-hydroxy-3-nitro-benzaldehyde (6.9 g) and ethyl bromoacetate (5.0 mL) in dimethylformamide (250 mL) was treated with anhydrous potassium carbonate (10 g) and the mixture was heated at 60° C. for 18 hours and evaporated to dryness. The residue was partitioned between water and diethyl ether, and the diethyl ether layer was washed with 0.5M sodium hydroxide. It was then dried over anhydrous sodium sulfate and evaporated to give an oil that was chromatographed on silica gel (ethyl acetate/dichloromethane) to afford an oil (1.9 g).
Reaction SMILES: [S-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]>C(COC)OC>[CH2:2]([S:1][C:6]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH3:3]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: COCCOC
Product: CCSc1cc(NC(C)=O)ccc1[N+](=O)[O-]

Procedure:
To a suspension of 25.2 g (0.3 mol) of sodium thioethoxide in 220 ml of dimethoxyethane at room temperature are added, portionwise over 30 minutes with stirring, 46.2 g (0.216 mol) of 2-chloro-4-acetylaminonitrobenzene.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Al+3].[Cl-].[Cl-].[Cl-].[C:16](Cl)(=[O:18])[CH3:17]>[N+](C1C=CC=CC=1)([O-])=O>[OH:11][C:3]1[C:2]([CH3:1])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][C:4]=1[C:16](=[O:18])[CH3:17]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc([N+](=O)[O-])c(C)c1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a solution of 2-methyl-3-nitrophenol (2.0 g, 13 mmol) in nitrobenzene (16 mL) at RT under Ar gas is added AlCl3 (3.9 g, 29 mmol). The reddish mixture is heated to 50° C. To the reddish mixture is added dropwise via addition funnel a solution of acetyl chloride (1.2 mL, 17 mmol) in nitrobenzene (10 mL). The reaction is heated to 120° C. After 2 h at 120° C., the reaction mixture is cooled to RT and quenched slowly into a 1N HCl/ice mixture. The resulting mixture is stirred for 30 min and extracted with EtOAc (3×). The organic layers are combined and concentrated. Water is used to azeotrope off the nitrobenzene. The resulting residue is purified by flash column chromatography using 20% EtOAc/hexane. Obtained is the title compound as reddish oil (1.2 g). The title compound is 60% pure by LC-MS. Compound is used as is in the next step. LC-MS (m/e): 194 (M−1).
Reaction SMILES: [NH2:1][C:2](=[O:35])[CH:3]([OH:34])[CH:4]([NH:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26]C2C=CC=CC=2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O[C:39](=O)[CH3:40])C>>[NH2:1][C:2](=[O:35])[C:3](=[O:34])[CH:4]([NH:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:8][CH2:7][CH:6]([C:39]3[CH:40]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11]2)=[N:21]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(C)=O
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CNc2ccccc2)n1
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCC(c3ccccc3)C2)n1

Procedure:
Oxidation of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(3-((phenylamino)methyl)-1H-pyrazol-1-yl)nicotinamide (120 mg, 0.255 mmol) as described in example 1.4, subsequent crystallization of the crude product from 2-propanole and then from ethylacetate afforded the title compound as white amorphous solid; 80 mg, ESI-MS [M+H]+: 523.3. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.93 (m, 1H), 8.50 (m, 1H), 8.32 (m, 1H), 8.06 (m, 1H), 7.82 (m, 1H), 7.71 (m, 1H), 7.42-7.25 (m, 10H), 6.42 (m, 1H), 5.38 (m, 1H), 3.49 (m, 2H), 3.25 (m, 1H), 3.17 (dd, 1H), 2.88 (m, 2H), 2.63 (m, 2H), 2.39 (m, 1H), 2.21 (m, 1H), 1.72 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:13]=[O:14].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][OH:14])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2c[nH]cn2)cc1
Reactant: C=O
Solvent: O
Solvent: CCO
Product: OCn1cnc(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a stirred solution of 4-(4-fluorophenyl)-1H-imidazole (10 g, 62 mmol) in 95% ethanol (25 mL) was added aqueous formaldehyde solution (37%, 9 mL) slowly. The reaction mixture was stirred at RT for 1 hr before water (25 mL) was added. The reaction mixture was stirred at RT for an additional 3 hr. The solid that separated from solution out was filtered, washed with aqueous ethanol solution, and dried to give (4-(4-fluorophenyl)-1H-imidazol-1-yl)methanol (11.4 g, 59 mmol, 96% yield) as a solid. MS found: (M+H—CH2O)+=163.1.