Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14](C(OC(C)(C)C)=O)[N:15]=[C:16]([CH3:17])[C:11]3=[C:10]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[C:9]=2[C:44]#[N:45])=[C:4]([F:46])[CH:3]=1.[CH3:47][O-].[Na+].C=O.[BH4-].[Na+]>CO.O>[C:44]([C:9]1[C:10]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[C:11]2[C:16]([CH3:17])=[N:15][NH:14][C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH3:47])=[CH:3][C:4]=1[F:46])#[N:45]
Reactant: C[O-]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2nc(-c3ccc(N)cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1ccc(-c2nc3[nH]nc(C)c3c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2C#N)c(F)c1
Yield: 20.8 %

Procedure:
To a solution of 0.20 g (0.32 mmol) of tert-butyl 6-(4-amino-2-fluorophenyl)-4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-5-cyano-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate in 40 ml of MeOH are added 0.16 mg (2.9 mmol) of sodium methoxide and 0.10 g (3.2 mmol) of paraformaldehyde. The reaction mixture is refluxed for 2 h. The mixture is then cooled, 0.24 g (6.34 mmol) of sodium borohydride is added, and the mixture is refluxed for 1 h. The mixture is then cooled, diluted with iced water, then extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The solid obtained is then purified by chromatography on silica (methanol gradient in dichloromethane: 1 to 2%) to give 0.036 g (18%) of tert-butyl 4-(4-(5-cyano-6-(2-fluoro-4-(methylamino)phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate in the form of yellow crystals. Deprotection of the piperazine following general procedure E2 gives 0.02 g (68%) of 6-(2-fluoro-4-(methylamino)phenyl)-3-methyl-4-(4-(piperazine-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile hydrochloride in the form of orange crystals.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]([CH:17]([CH3:19])[CH3:18])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:8]#[N:9])C.O.O.C(O)(=O)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]([CH:17]([CH3:19])[CH3:18])([CH2:6][CH2:5][CH:4]=[O:3])[C:8]#[N:9]
Reactant: CCOC(CCC(C#N)(c1ccccc1C)C(C)C)OCC
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccccc1C(C#N)(CCC=O)C(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of 5,5-diethoxy-2-isopropyl-2-(2-methylphenyl)-valeronitrile (267 g) in acetone (2000 ml) is added under stirring a solution of oxalic acid dihydrate (121.7 g) in water (730 ml) and the mixture is warmed under continuous stirring for 4 hours at 40° C. Thereafter it is cooled and under external cooling to 520 C. adjusted by the addition of a 50% aqueous potassium carbonate solution to pH within the range of 6 to 6.5. The formed potassium oxalate precipitate is filtered off and washed with acetone (500 ml). From the filtrate the solvent is evaporated under reduced pressure (bath temperature above 30° C.). The residue is mixed with water (600 ml) and ether (500 ml), the separated aqueous phase is extracted with ether (2×300 ml), the combined organic solutions are washed with aqueous sodium hydrogencarbonate, water and staturated brine until neutral reaction, dried over anhydrous magnesium sulfate and the solvent is evaporated (bath temperature about 30° C.) under reduced pressure, finally at about 1.3 kPa, to yield 203 g of the oily crude product (claimed compound content of 93.2% as determined by gas-liquid chromatography). The obtained material is used without separate purification for the subsequent reductive alkylation.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Br:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>ClCCCl>[Br:15][C:16]1[N:21]=[C:20]([CH2:22][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Brc1cccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
NaBH(OAc)3 (68.5 g, 0.323 mol) was added to a solution of 6-bromopicolinaldehyde 62 (40 g, 0.22 mol) and morpholine 63 (20.9 g, 0.24 mol) in 1,2-dichloroethane (500 mL). The mixture was stirred at room temperature for 16 h. Saturated NaHCO3 (500 mL) was added and the mixture was extracted with EtOAc, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether:ethyl acetate (10:1) to give 64 (38 g, 68% yield).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>CN(C=O)C>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil, 0.650 g, 16.4 mmol) in DMF (40 mL) was added tert-butyl ethyl propanedioate (2.8 g, 15.1 mmol) at room temperature. The mixture was stirred for 30 min. A solution of 5-chloro-2-nitropyridine (2.00 g, 12.6 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. and stirred for 4 hours. The solvent was removed under reduce pressure. Water was added and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography with silca gel to give tert-butyl ethyl (6-nitropyridin-3-yl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.20˜8.27 (m, 2H), 4.69 (s, 1H), 4.21˜4.26 (m, 2H), 1.45 (s, 9H), 1.28 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:21])([CH:19]=[CH2:20])[CH3:18])[CH3:13])[CH3:8])[CH3:3].C([O:26]O)(C)(C)C.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>[O-2].[O-2].[O-2].[O-2].[O-2].[V+5].[V+5]>[O:26]1[CH:19]([C:17]([CH3:18])([OH:21])[CH2:16][CH2:15][CH2:14][CH:12]([CH3:13])[CH2:11][CH2:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:20]1
Reactant: CC(C)(C)OO
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: [V+5]
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)(O)C1CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
A three-necked flask of 2-liter capacity, fitted with a stirrer, reflux-condenser and thermometer, was charged with 463.6 g (1.57 moles) of isophytol, 221.8 g (1.72 moles) of a 70% (by weight) aqueous solution of t-butyl hydroperoxide and 710 mg of vanadium pentoxide and the reaction was conducted at 90° C. for 6 hours. Then, 350.4 g of a 14% (by weight) aqueous solution of sodium sulfite was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was transferred to a separatory funnel. The upper layer was mixed with the same volume of 1N aqueous sodium hydroxide solution and stirred at room temperature and, then, extracted with n-hexane. The extract was washed with the same volume of water 3 times and the n-hexane was distilled off to give 467.0 g of 1,2-epoxy-3,7,11,15-tetramethylhexadecan-3-ol. Yield 96%.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:22]([O:24][C:25](=[O:28])[NH:26][NH2:27])[CH3:23]>C(O)(=O)C.C(O)C>[CH2:22]([O:24][C:25]([NH:26][N:27]=[CH:14][C:13]1[C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:12]=1)=[O:28])[CH3:23]
Reactant: O=Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: CCOC(=O)NN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)NN=Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 97 %

Procedure:
Heat 0.6 g of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehyde together with 0.27 g of ethylcarbazate and 2 drops of glacial acetic acid in 8 ml of ethanol for 1.5 hours at boiling point. Cool the resulting product for a 97% yield of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehyde-ethoxycarbonylhydrazone [m.p. 215° to 216° C (with decomposition) from toluene].
Reaction SMILES: [S:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](C(OC)=O)[S:3][C:2]1=[S:14].O.[Br-].[Li+].O>CN(C)P(=O)(N(C)C)N(C)C>[S:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[S:1][C:2]1=[S:14]
Reactant: COC(=O)c1sc(=S)sc1C(=O)OC
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1csc(=S)s1
Temperature: 25 °C
Yield: 70 %

Procedure:
30 Grams (0.12 mol) of dimethyl 1,3-dithiol-2-thion-4,5-dicarboxylate synthesized according to the method of G. C. Papavassiliou, et al [Synthetic Metals, Vol. 27 (1988) B-373-B378] was dissolved in 30 ml of hexamethylphosphorictriamide (HMPA), and 12.6 g (0.12 mol) of lithium bromide monohydrate was added. The resultant mixture was heated at 60° C. for 1 hour, the reaction mixture was allowed to cool to room temperature, 200 ml of water was added, and a yellow solid formed was separated by filtering and washed with water. The solid obtained was dried and recrystallized from carbon tetrachloride to give 16.2 g of yellow acicular crystals of methyl 1,3-dithiol-2-thione-4-carboxylate (yield 70%).
Reaction SMILES: S(=O)(=O)(O)O.[C:6](O)(=O)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:13][CH:12]=1.C=O>O>[Br:10][C:11]1[CH:12]=[C:13]2[C:14]([CH2:17][CH2:18][N:19]([C:20](=[O:25])[C:21]([F:23])([F:24])[F:22])[CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=C(NCCc1ccc(Br)cc1)C(F)(F)F
Reactant: CC(=O)O
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (35 mL) was added to glacial acetic acid (45mL) with stirring and ice-cooling. After stirring for 30 minutes the mixture was treated with N-2-(4-bromophenyl)ethyl trifluoroacetamide (10.4 g, Reference Example 8) and then with paraformaldehyde (1.75 g). This mixture was allowed to warm to room temperature and after stirring for a further 24 hours the pale brown solution was treated with a further aliquat of paraformaldehyde (0.8 g). After stirring for a further 24 hours the reaction mixture was treated with iced-water (500 mL) and then extracted three times with ethyl acetate (200 mL). The combined extracts were washed twice with water (200 mL), then four times with aqueous sodium bicarbonate solution (200 mL), then twice with water (200 mL), then dried over magnesium sulfate and then evaporated. The residual yellow oil was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (3:97, v/v) to give the title compound as a white crystalline solid. LC-MS: RT=4.76 minutes; no molecular ion observed.
Reaction SMILES: C(O[CH2:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([NH2:17])[C:11]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])C1C=CC=CC=1.[BrH:26]>C(O)(=O)C>[NH2:16][C:14]1[N:13]=[C:12]([NH2:17])[C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[C:10]([CH2:9][Br:26])[N:15]=1
Reactant: Br
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(COCc2ccccc2)n1
Solvent: CC(=O)O
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2,4-Diamino-6-benzyloxymethyl-5-(2,4-dichlorophenyl)pyrimidine (Example 26) (6.5 g) was dissolved in a 47% solution of hydrobromic acid in acetic acid (75 ml) and the mixture stirred and heated at 100° C. for 6 hours. After standing at room temperature overnight the dihydrobromide salt was filtered off, washed with ether and dried in vacuo, 6 g. To a stirred solution of the dihydrobromide salt (0.43 g) in dimethylsulphoxide (4 ml) was added dropwise a solution of sodium bicarbonate (0.84 g) in water (10 ml). After 30 minutes the precipitate was filtered off washed with water then ether and dried in vacuo, 0.26 g, mp.>270° C. (decomposes).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[Cl:16])[C:5]([CH3:7])=O.[C:18]1(=[O:37])[N:22]([CH2:23][CH2:24][O:25][C:26](=[O:31])/[CH:27]=[C:28](\[NH2:30])/[CH3:29])[C:21](=[O:32])[C:20]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:19]12>>[CH3:7][C:5]1[NH:30][C:28]([CH3:29])=[C:27]([C:26]([O:25][CH2:24][CH2:23][N:22]2[C:21](=[O:32])[C:20]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:19]3[C:18]2=[O:37])=[O:31])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[C:4]=1[C:3]([O:2][CH3:1])=[O:17]
Reactant: C/C(N)=C/C(=O)OCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc(Cl)c1Cl

Procedure:
Prepared by a method analogous to that of Example 1(a) from 13.0 g (48 mmol) of 2-(2,3-dichlorobenzylidene)-acetoacetic acid methyl ester and 13.1 g (48 mmol) of 3-amino-crotonic acid-(2-phthalimido ethyl)ester. 14.2 g (57%) of pale yellow crystals melting at 195°-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][C:57]([NH:59][CH3:60])=[O:58]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][CH2:56][C:57](=[O:58])[NH:59][CH3:60])=[CH:13][CH:12]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CNC(=O)CCc1ccccc1O
Product: CNC(=O)CCc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method G, 0.30 g tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.16 g of 3-(2-hydroxyphenyl)-N-methylpropionamide are reacted. The title compound is obtained as a colourless oil. Rf=0.20 (3:1 EtOAc-heptane); Rt=5.61.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([O-])=[O:11])[C:5]=1[CH3:13].[BH4-].[Na+]>C(O)C>[F:14][CH:2]([F:1])[O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([CH2:10][OH:11])[C:5]=1[CH3:13]
Reactant: Cc1c(OC(F)F)ncnc1C(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(CO)ncnc1OC(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6-(difluoromethoxy)-5-methylpyrimidine-4-carboxylate 48b (14 g, 60.30 mmol) in ethanol (200 mL), NaBH4 (4.58 g, 120.59 mmol) was added at 0° C. and the mixture was stirred for 16 h at RT. Then the solvent was evaporated under the reduced pressure and the reaction mixture was poured in to water and extracted with ethyl acetate. The organic layer was washed with water brine and concentrated under reduced pressure to afford (6-(difluoromethoxy)-5-methylpyrimidin-4-yl)methanol 39 as a yellow solid. Yield: 8.4 g (73.3%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10]C(F)(F)F)[C:5]([F:15])=[C:4]([F:16])[N:3]=1.FC1C(F)=C(OC(CF)CF)C(F)=C(F)N=1>>[CH3:10][O:9][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[C:4]([F:16])[C:5]=1[F:15]
Reactant: Fc1nc(F)c(F)c(OCC(F)(F)F)c1F
Agent: FCC(CF)Oc1c(F)c(F)nc(F)c1F
Product: COc1c(F)c(F)nc(F)c1F

Procedure:
In a similar manner, the following compounds were made: 2,3,5,6-tetrafluoro-4-(2,2,2-trifluoroethoxy)pyridine; and 2,3,5,6-tetrafluoro-4-(1,3-difluoroprop-2-oxy)pyridine.
Reaction SMILES: C([O:5][C:6](=[O:51])[CH2:7][N:8]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[O:37][C:36]=3[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:44]([C:36]1[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:35]=1[C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][C:23]([S:20]([N:8]([CH2:7][C:6]([OH:51])=[O:5])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)(=[O:22])=[O:21])=[CH:24][CH:25]=2)=[CH:30][CH:31]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-Butyl-{[4′-(2-benzylbenzofuran-3-yl)biphenyl-4-sulfonyl]-(3-trifluoromethyl-benzyl)amino}acetate (90 mg) was dissolved in methylene chloride (4 mL). TFA (1 mL) was added and the reaction mixture was stirred at room temperature for 16 h, and then concentrated in vacuo. Purification by flash column chromatography (5% methanol in methylene chloride) afforded the title compound as an off white solid (45 mg).
Reaction SMILES: O[CH:2]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].CCN(S(F)(F)[F:23])CC.C(O)C>O1CCOCC1>[F:23][CH:2]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OCC(O)Cn1ccnc1[N+](=O)[O-]
Reactant: CCN(CC)S(F)(F)F
Solvent: CCO
Solvent: C1COCCO1
Product: CC(=O)OCC(F)Cn1ccnc1[N+](=O)[O-]
Yield: 29.1 %

Procedure:
To a solution of 3.93 g (17.1 mmol) of 1-(2'-hydroxy-3'-acetoxypropyl)-2-nitroimidazole in 30 ml of dry dioxane, 4.00 g of DAST was dropwise added with stirring and cooling by ice. After addition, the mixture was reacted for 5 hours at room temperature with stirring. Thereafter, to the solution, 10 ml of ethanol was added to decompose excess DAST. The solution was then concentrated and partitioned between chloroform and an aqueous solution of sodium hydrogen carbonate. The chloroform phase was dried on magnesium sulfate and filtered. The filtrate was concentrated and subjected to isolation and purification by silica gel column chromatography to give 1.15 g of 1-(2'-fluoro-3'-acetoxypropyl)-2-nitroimidazole.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:19])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.Cl.C(=O)(O)[O-].[Na+].[C:26](OCC)(=O)[CH3:27]>C(O)C>[OH:1][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:19][CH2:26][CH3:27])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: ON=Cc1ccc(C(O)C#Cc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(C#Cc1ccccc1)c1ccc(CNO)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To 5 g of 1-(4-hydroxyiminomethylphenyl)-3-phenyl-prop-2-yn-1-ol syn/anti-mixture prepared according to Example 1 and dissolved in 120 ml of ethanol were added 8 ml of borane-pyridine complex at 0° C. and then 12 ml of an ethanolic 20% by weight solution of hydrochloric acid. After stirring at 0° C. for one hour and at 20° C. for 2 hours, the reaction mixture was added to 1.2 liters of a saturated aqueous solution of sodium bicarbonate and shaken with ethyl acetate. The organic layer was dried over magnesium sulfate. After filtration and evaporation of the solvent at 40° C. and 2.7×103Pa, the resulting residue (8.1 g) was chromatographed with methylene chloride/methanol 4.7:0.3 to yield 2.3 g of 1-(4-hydroxyaminomethylphenyl)-3-phenyl-1-ethoxy-prop-2-yne in the form of a colorless oil. Following the procedure of Example 1, the resulting oil was converted into N-acetoxy-N-[4-[ 1-ethoxy-3-phenyl-prop-2-yn-1-yl]-benzyl]acetamide and then into the yellow oil of N-hydroxy-N-[4-[1-ethoxy-3-phenyl-prop-2-yn-1-yl]benzyl]acetamide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[ClH:27]>CO>[ClH:27].[NH:17]1[CH2:16][CH2:15][CH:14]([O:13][C:8]2[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncccc2N2CCOCC2)CC1
Agent: Cl
Solvent: CO
Product: c1cnc(OC2CCNCC2)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To tert-butyl 4-((3-morpholinopyridin-2-yl)oxy)piperidine-1-carboxylate (3.2 g, 8.8 mmol) was added 4 M HCl in MeOH (100 mL). The solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the title compound (2.2 g, 8.36 mmol, yield 95%). ESI-MS (M+1): 264 calc. for C14H21N3O2 263
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:12]1[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13]1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2cccc(F)c2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(ccn2Cc2cccc(F)c2)c1O

Procedure:
Prepared in analogy to that of Example 1(e) from 1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 344 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:13][CH3:14])(=[O:12])[C:8]([O:10]C)=O.[C:15]([C:18]1[C:23](=[O:24])[C:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][N:20]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:19]=1)(=[O:17])[CH3:16]>C1COCC1>[CH2:32]([N:20]1[CH:21]=[C:22]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23](=[O:24])[C:18]([C:15](=[O:17])[CH:16]=[C:8]([OH:10])[C:7]([O:13][CH3:14])=[O:12])=[CH:19]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)c1cn(Cc2ccccc2)cc(Cc2ccccc2)c1=O
Reactant: COC(=O)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)cc(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of sodium t-butoxide (0.52 g, 5.23 mmol) in anhydrous THF (13 mL) at room temperature was added dropwise dimethyl oxalate (0.42 g, 3.48 mmol) in THF (6 mL) followed by 3-acetyl-1,5-dibenzyl-1H-pyridin-4-one 14 (0.55 g, 1.74 mmol) in THF (8 mL). The resulting mixture was stirred at room temperature for 4 h and then acidified (pH=6). The crude product was extracted with ethyl acetate (100 mL), washed with water (2×100 mL) and brine (2×100 mL), and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by ion exchange chromatography (diethylamino sephadex anion exchange resin (CH3CN:H2O, 1:1) and then by flash chromatography on silica gel (chloroform, 100%). Yield 0.44 g (63%), mp 148-150° C. 1H NMR (CDCl3, 500 MHz): δ 8.34 (d, J=2.5, 1H), 8.12 (s, 1H), 7.40-7.12 (m, 10H), 6.91 (d, J=2.3, 1H), 4.94 (s, 2H), 3.88 (s, 3H), 3.82 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 187.2, 175.2, 170.3, 162.7, 143.9, 138.4, 136.9, 136.1, 133.8, 129.4, 129.5, 129.3, 129.1, 129.1, 128.7, 128.6, 127.5, 127.4, 126.5, 120.2, 102.4, 61.2, 53.0, 33.5. HRMS (M+H)+ calcd for C24H22NO5 404.1498, found 404.1497.