Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=O)[CH3:13].Cl.[Li+].[OH-].C[CH2:19][O:20][C:21]([CH3:23])=[O:22].CCCCCC.[CH3:30][CH2:31][O:32][C:33](C)=O>O.CO>[CH3:19][O:20][C:21]([C:23]1[C:30]([CH2:31][O:32][CH3:33])=[N:1][C:2]2[C:3]([C:12]=1[CH3:13])=[CH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[O:22]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: COCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OC
Temperature: 75 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
A mixture of 4.0 g (19.7 mmol) 1-(2-amino-4-(trifluoromethyl)phenyl)ethanone, 11.5 ml (98.5 mmol) 4-chloro-diacetic acid ethyl ester and 1.7 ml (19.7 mmol) conc. hydrochloric acid was heated to 75° C. for 6 min in a sealed vessel by microwaves (50 W). The mixture was subsequently diluted with EtOAc and water. The organic phase was separated, washed with a 1M aq. NaHCO3 sol., dried over MgSO4 and concentrated in a vacuum. The raw product (7.47 g) obtained after CC (EtOAc/hexane 3:17) of the residue was dissolved in MeOH (76 ml) and 35.3 ml (70.6 mmol) of a 2M aq. LiOH sol. was added. The mixture was subsequently stirred for 16 h at RT and heated to 60° C. for a further 24 h. After cooling to RT, the mixture was diluted with water and EtOAc. The organic phase was separated, dried over MgSO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:3) of the residue, 985 mg (3.1 mmol, 16%) 2-(methoxymethyl)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid methyl ester was obtained.
Reaction SMILES: C(OP([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1)Br)(=O)OCC)C.C([O:21]P(=O)OCC)C.C(C1C=CC(CBr)=CC=1)#N.C(=O)([O-])[O-].[Ba+2]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:9][OH:21])=[CH:12][CH:13]=1)#[N:18]
Reactant: CCOP(=O)(OCC)C(Br)c1ccc(CN)cc1
Reactant: CCO[PH](=O)OCC
Agent: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Product: N#Cc1ccc(CO)cc1

Procedure:
The chemical synthesis of PTP probes I and II involved synthesizing a common intermediate 10 in a 7-step procedure (Scheme 1) and its subsequent coupling with the biotin-NHS ester analogues, followed by the deprotection of the phosphonate diethyl ester (Scheme 2). Thus, 4-cyanobenzyl bromide 3 was hydrolyzed in the presence of barium carbonate to produce 4-cyanobenzyl alcohol 4, which was subsequently reduced with lithium aluminum hydride under strict argon atmosphere to yield 4-hydroxymethyl-benzyl-ammonium chloride 5, upon acidic aqueous extraction (17). The amine functionality of 5 was then first masked by t-butyl carbamate to render (4-hydroxymethyl-benzyl)carbamic acid tert-butyl ester 6 (Far et al., 2002). Corey oxidation (Corey & Suggs, 1975) with pyridinium chlorochromate/sodium acetate gave the reactive aldehyde 7. The condensation of 7 with diethyl phosphite in the presence of triethylamine produced {[4-(tert-butoxycarbonylamino-methyl)-phenyl]-hydroxy-methyl}-phosphonic acid diethyl ester 8 as a racemic mixture. This racemic mixture of 8 was used as such in the following step of the synthesis. Bromination of the secondary alcohol, 8, to yield 9 was achieved using dibromotriphenyl phosphorane in pyridine (Gaida, 1990). Finally, deprotection of t-butyloxycarbonyl with neat trifluoroacetic acid gave [(4-aminomethyl-phenyl)-bromo-methyl]-phosphonic acid diethyl ester (10). The coupling of 10 with (+) biotin N-hydroxysuccinimide ester (for I) and (+) biotinamidohexanoic acid N-hydroxysuccinimide ester (for II) in DMF gave 11 and 12 respectively. The phosphonate diesters (11 & 12) were deprotected with bromotrimethylsilane in DMF to yield I and II (McKenna et al., 1977).
Reaction SMILES: [ClH:1].[NH2:2][OH:3].[CH2:4]([CH:6]([CH2:9][CH3:10])[CH:7]=O)[CH3:5].[OH-].[Na+].ClN1C(=O)CCC1=O>CN(C)C=O.O.C1(C)C=CC=CC=1>[CH2:4]([CH:6]([CH2:9][CH3:10])[C:7]([Cl:1])=[N:2][OH:3])[CH3:5]
Reactant: CCC(C=O)CC
Reactant: Cl
Reactant: NO
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)C(Cl)=NO
Temperature: 8 °C

Procedure:
1150 g of hydroxylamine hydrochloride, 1000 g of water and 3500 g of toluene were mixed, to which 1580 g of 2-ethyl-butyraldehyde was added with stirring. At 8-12° C., a solution of sodium hydroxide (ca. 30%, 4630 g) was added within 1 hour. After completion of the addition, the reaction mixture was further stirred for 60 minutes. Then, the reaction mixture was stratified by standing, and the upper toluene layer containing compound 14 was taken out and directly used in the following step. 4212 g of N-Chlorosuccinimide (NCS) was suspended in 5000 ml of dimethylformamide, and cooled down to 8° C. The suspension of NCS in dimethylformamide was added dropwise to the above toluene solution containing compound 14 within 2.5 hours, whilst keeping the reaction temperature not exceeding 23° C. After completion of the addition, the reaction mixture was further stirred for 1 hour. Then, 10000 ml of water was added, followed by stirring for 30 minutes. The aqueous layer was discarded, and the organic layer was washed with 10000 ml×3 of water. The toluene layer containing compound 15 (chloro-oxime) was separated, and directly used in the following step.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[CH:6]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[O:18][CH3:19])([CH3:8])[CH3:7]>C(Cl)Cl.[Zn]>[Br:2][C:1]([Br:5])=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[C:11]([O:18][CH3:19])[CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(C=O)ccc1OC(C)C
Agent: [Zn]
Solvent: ClCCl
Product: COc1cc(C=C(Br)Br)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 100.5 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (0.1 g, 154.5 mmol) and PP3 (40.5 g, 159.4 mmol) in CH2Cl2 (350 ml) maintained at 0° C. on an ice-salt bath. This suspension was allowed to warm to room temperature and then stirred at for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and vanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. and allowed to stir at room temperature for 1 h. After dilution with hexane (200 ml) the resulting mixture was filtered through a sintered glass funnel and the filtrate concentrated on to silica gel (30 g). The resulting solid was added to the top of a flash chromatography column (silica gel: 20 cm long×10 cm wide) which was subjected to gradient elution (2:1, 1:1 and then 1:2 hexane/CH2Cl2). Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) then afforded the title compound (27.2 g, 99.8%) as white crystalline masses, m.p. 36-38° C. IR(KBr disc, cm−1) 2976, 2973, 1599, 1510.1464, 1418, 1383, 1373, 1267, 1235, 1141, 1110, 1036. 1H NMR (300 MHz, CDCl3) δ7.41 (s, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.07 (dd, J=2.1, 8.4 Hz, 1H), 6.87 (d, J=8.4 Hz), 4.58 (septet J=6.0 Hz, 1H), 3.87 (s, 3H), 1.39 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ149.7 (C), 147.7 (C), 136.5 (CH), 127.9 (C), 121.9 (CH), 114.4 (CH), 111.8 (CH), 87.1 (CH), 71.1 (CH), 56.0 (CH3), 22.1 (CH3). MS (70 eV) m/z(%): 352 (28), 350 (49), 448 (31) (M+•), 310 (51), 308 (100), 306 (54) M+•−CH2CHCH3), 295 (34), 293 (38), 291 (36) (M+•−CH2CHCH3—CH). Anal. Calcd for C12H14O2Br2, 41.17; H. 4.03; Br, 45.65. Found: C, 41.21; H, 3.92; Br, 45.47.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[CH2:16]([OH:29])[CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>CN(C=O)C>[OH:29][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: OCCCCC#CC#CCCCCO
Reactant: CCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOCCCCC#CC#CCCCCO
Reaction time: 0.08 h
Yield: 33.4 %

Procedure:
In a glass reaction vessel, a suspension of 120 milligrams of sodium hydride was prepared in 10 mL dry DMF and 972 milligrams of 5,7-dodecadiyn-1,12-diol (HO(CH2)4C≡C—C≡C(CH2)4OH), was added. After stirring for 5 minutes, 1.31 grams of CH3(CH2)11Br was added and the resulting mixture was stirred for 15 hours. The mixture was then quenched by addition of saturated NH4Cl solution and diluted with 100 milliliters of diethyl ether. The organic layer was separated and washed 3 times with brine, dried over MgSO4, filtered and the solvent was removed to yield a yellow oil. The oil was purified over silica gel (25%-35% by volume of ethyl acetate in hexane gradient) to yield 606 milligrams of HO(CH2)4C≡C—C≡C(CH2)4O(CH2)11CH3 as a white solid.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1.[O:42]=[CH:43][CH:44](CO)O.C([BH3-])#N.[Na+]>CO>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:37][CH2:38][N:39]([CH2:44][CH2:43][OH:42])[CH2:40][CH2:41]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1
Reactant: O=CC(O)CO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide trihydrochloride (0.2 mmol; see Example 88) in methanol (2 mL) was added glyceraldehyde (2 mmol), and the resulting mixture was stirred at RT for 60 min. The reaction mixture was then charged with solid sodium cyanoborohydride (1 mmol), and the stirring was continued at RT for 10 h. The reaction mixture was then concentrated in vacuo, and the residue was suspended in water (10 mL) with vigorous stirring. After 30 min, the solid was filtered, washed with water, and dried under vacuum to afford 6-[4-(2-hydroxyethyl)-piperazin-1-yl]-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)amide as a white solid. MS: m/z 565 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([C:5]2[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:24][CH2:25]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncc(Br)cc2[N+](=O)[O-])CC1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A suspension of 1.00 g (4.21 mmol) 5-bromo-2-chloro-3-nitro-pyridine, 0.993 g (4.63 mmol) of piperidin-4-ylmethyl-carbamic acid tert-butyl ester, and 1.16 g (8.42 mmol) of potassium carbonate in N,N-dimethylformamide (10 mL) is stirred for 2 hours under argon. The mixture is diluted with water which causes a solid to precipitate from solution. The formed solid is collected by filtration, washed with water, and dried for 1 hour under vacuum at 50° C. to give 1.57 g (90.0%) of (5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[O:8][C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)=[CH:6][CH:5]=1)#[N:2].Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[NH2:2][CH2:1][CH2:3][C:4]1[O:8][C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(-c2csc(N=C(N)N)n2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NCCc1ccc(-c2csc(N=C(N)N)n2)o1
Temperature: 25 °C
Yield: 29 %

Procedure:
To this mixture was dropwise added a mixture of 4-(5-cyanomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (16.0 g) in tetrahydrofuran (30 ml) for 30 minutes under ice-cooling and the mixture was stirred for an hour at ambient temperature. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 1 with 6N-hydrochloric acid. The separated aqueous layer was adjusted to pH 10 with 10% aqueous sodium hydroxide and the mixture was extraced with a mixture of tetrahydrofuran and ethyl acetate. The extract layer was washed with brine and dired over magnesium sulfate. The solvent was concentrated to give 4-[5-(2-aminoethyl)furan-2-yl]-2-(diaminomethyleneamino)thiazole (4.71 g).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:36])=[C:14]([C:16]2[CH:17]=[C:18]3[C:24]([C:25]([O:27]C)=[O:26])=[C:23]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[O:22][C:19]3=[N:20][CH:21]=2)[CH:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.C1COCC1.CCOC(C)=O>[C:3]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:36])=[C:14]([C:16]2[CH:17]=[C:18]3[C:24]([C:25]([OH:27])=[O:26])=[C:23]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[O:22][C:19]3=[N:20][CH:21]=2)[CH:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)OC(C)(C)C)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1-c1cnc2oc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Reaction time: 4 h
Yield: 100 %

Procedure:
NaOH (1.4 mL, 1.37 mmol) was added to a stirring solution of methyl 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylate (211 mg, 0.457 mmol) in MeOH (2.3 mL) and THF (2.3 mL) at 60° C. It was allowed to stir for 4 hours. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid (205 mg, 0.457 mmol, quant.) consistent by LCMS crude which was used directly in the next step. LC-MS retention time: 1.88 min; m/z (MH+): 448. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:14]([CH2:15][NH:16][C:17]3[C:22]([NH2:23])=[CH:21][C:20]([I:24])=[CH:19][N:18]=3)=[CH:13][C:12]=2[O:27][CH3:28])=[CH:5][CH:4]=1.F[CH:31](F)C1N=CC(COC2C=CC(CN)=CC=2OC)=CC=1.C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[F:29][CH:2]([F:1])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:14]([CH2:15][N:16]3[C:17]4=[N:18][CH:19]=[C:20]([I:24])[CH:21]=[C:22]4[N:23]=[CH:31]3)=[CH:13][C:12]=2[O:27][CH3:28])=[CH:5][CH:4]=1
Reactant: COc1cc(CNc2ncc(I)cc2N)ccc1OCc1ccc(C(F)F)nc1
Reactant: COc1cc(CN)ccc1OCc1ccc(C(F)F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: O
Solvent: CCO
Product: COc1cc(Cn2cnc3cc(I)cnc32)ccc1OCc1ccc(C(F)F)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
To a stirred solution of N2-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-5-iodopyridine-2,3-diamine [prepared from (4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine using the procedures described in Example 3-45-4 and Example 3-45-5] (3.10 g, 6.05 mmol) in ethanol (50 mL) was added triethyl orthoformate (3.0 mL, 18.02 mmol). The mixture was treated with p-toluenesulfonic acid monohydrate (50 mg, 262.86 μmol) and was heated to reflux. After 45 min, the mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. The mixture was concentrated, and the residue dissolved in chloroform (150 mL). The solution was washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered, and concentrated to provide 3.15 g (99%) of 3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridine as a brown solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][C@H:7]([NH2:10])[CH2:8][F:9].C(N(CC)CC)C.C1C=CC=CC=1.[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:27]=1[CH:28]=O>C(OCC)(=O)C>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:27]=1[CH:28]=[N:10][C@H:7]([CH2:8][F:9])[CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:11]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CC[C@H](N)CF
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](CF)N=Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.36 g of 4 and 0.27 ml of triethylamine were mixed with 20 ml of benzene containing 0.5 g of 3A molecular sieve. 0.33 g of 2,6-dichlorobenzaldehyde was added and the mixture was stirred at room temperature overnight. 20 ml of ethyl acetate was added to the mixture, then it was filtered and the solvent was evaporated from the filtrate. The residue was dissolved in ethyl acetate, the solution was washed with saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and the solvent was evaporated from the filtrate. The residue was thin layer chromatographed, using a 4:16:80 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane as eluent. Workup gave 20, as a yellow oil.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>CCOC(C)=O.O>[O:13]1[C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reaction time: 1 h
Yield: 80.3 %

Procedure:
55% sodium hydride (6.02 g) was added under ice-cooling to a DMSO (250 mL) suspension of trimethylsulfoxonium iodide (33.1 g), and stirring was performed at room temperature for 1 hour. A DMSO (125 ml) solution of tert-butyl 4-oxopiperidine-1-carboxylate (25.0 g) was added, and heated and stirred at 60° C. for 1 hour. Purified water was added to the mixture, and extraction was performed with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (21.5 g),
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].O[Li].O.C(Cl)[Cl:19]>CO.O>[ClH:19].[CH2:7]([N:5]([CH2:4][C:3]([OH:14])=[O:2])[CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCl
Reactant: COC(=O)CN(C)Cc1ccccc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CN(CC(=O)O)Cc1ccccc1
Product: Cl

Procedure:
(Benzyl-methyl-amino)-acetic acid methyl ester (12 g, 62.1 mmol, 1.0 equiv) was dissolved in 50 mL of MeOH to which was added a solution of LiOH hydrate (8.23 g, 196 mmol, 3.0 equiv) in 50 mL of water. The mixture was stirred at room temperature for 1.3 h at which time TLC (5% MeOH in CH2Cl2) indicated consumption of the starting material. The reaction solution was washed 1×50 mL of Et2O and then the aqueous layer was acidified to pH 1 with concentrated HCl. The mixture was then evaporated to dryness under high vacuum. The resulting solid was triturated with EtOH (200 mL) and the mixture was filtered. The filtrate was then concentrated to dryness to yield a white cystalline solid that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[C:16](Cl)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:16]2[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=[C:12]([Br:11])[CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(Br)ncc2[N+](=O)[O-])cc1
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A solution of 4-methoxybenzylamine (0.756 g, 5.51 mmol) in acetonitrile (2 mL) was added to a mixture of 2-bromo-4-chloro-5-nitropyridine (1.19 g, 5.01 mmol) and triethylamine (0.768 mL, 5.51 mmol) in acetonitrile (8 mL). After stirring for 1.5 hours, the solution was diluted with ethyl acetate (100 mL) which was then washed successively with water and brine before being concentrated in vacuo to a light brown oil which solidified on standing to give the title compound (1.31 g, 3.87 mmol, 77%). 1H NMR (d6-DMSO, 400 MHz) δ 9.00 (br t, 1H, J=6.3 Hz), 8.80 (s, 1H), 7.35 (d, 2H, J=8.7 Hz), 7.10 (s, 1H), 6.95 (d, 2H, J=8.8 Hz), 4.60 (d, 2H, J=6.0 Hz), 3.70 (s, 3H). LCMS (1) Rt=2.13 min; m/z (ESI−) 336, 338 (M−H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14]2)=[O:10])=[C:7]([O:29][CH2:30][CH3:31])[CH:6]=1)(=[O:3])[CH3:2].[Cl:32]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([NH:4][C:5]1[C:28]([Cl:32])=[CH:27][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14]2)=[O:10])=[C:7]([O:29][CH2:30][CH3:31])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Solvent: CN(C)C=O
Product: CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 70 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a stirred solution of 4-acetylamino-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (4.0 g) in dimethylformamide (20 ml) is N-chlorosuccinimide (1.3 g), and the resulting mixture is stirred at 70° C. for 2 hours. The reaction mixture is poured into ice-water and extracted with diethyl ether. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue is recrystallized from acetone to give the title compound (3.1 g), mp 161°-163° C.