Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35]([O:22][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:36]
Reactant: CC(C)CCCC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Br)nc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Br)nc2n1
Yield: 66.7 %

Procedure:
The procedure is as in Example 7, but starting with 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (8.55 g) in methylene chloride (110 cc), triethylamine (11.1 g), 5-methylhexanoyl chloride (7 g) and 4-dimethylaminopyridine (50 mg). After the residue obtained has been crystallized in hexane and then recrystallized in ethanol, 2-(7-bromo-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (7.5 g), m.p. 136° C., is obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[NH:9][C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][N:2]=2)=[N:10]1
Reactant: N=C(N)c1cnccn1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Yield: 41 %

Procedure:
Pyrazine-2-carboximidamide hydrochloride (5 g, 31.5 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde (5 g, 31.5 mmol) and ethyl 3-oxobutanoate (4.1 g, 31.5 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (4.84 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[C:16]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:25][CH3:26])(=[O:11])=[O:10].[Cl:27][C:28]1[CH:41]=[CH:40][C:31]2[S:32][C:33]([S:36](Cl)(=[O:38])=[O:37])=[C:34]([CH3:35])[C:30]=2[CH:29]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:26][O:25][C:13]1[CH:14]=[CH:15][C:16]([S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])=[CH:17][C:12]=1[S:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:36]([C:33]1[S:32][C:31]2[CH:40]=[CH:41][C:28]([Cl:27])=[CH:29][C:30]=2[C:34]=1[CH3:35])(=[O:38])=[O:37])(=[O:10])=[O:11]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1sc2ccc(Cl)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of of N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide (0.5 mmol, prepared as in Example A) in DCM (1 mL) and pyridine (1 mL), 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (0.55 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 202 mg of 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-trifluoromethanesulfonyl-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.32 min, MS: 655.4 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 2.14 (s, 3H), 4.29 (s, 3H), 6.33 (bs, 1H), 6.54 (d, 1H), 6.98 (t, 1H), 7.24 (t, 1H), 7.35 (d, 1H), 7.45 (dd, 1H), 7.49 (dd, 1H), 7.70 (d, 1H), 7.75 (d, 1H), 8.14 (bs, 1H), 8.17 (dd, 1H), 8.31(d, 1H) ppm.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]([N:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=O)([CH3:8])[CH3:7].[CH:15]([NH:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C(OCC)C.ClCCl>[Cl-:3].[CH:6]([N:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[N+:18]([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])([CH3:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)N(C=O)C(C)C
Reactant: CC(C)NC(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)N(C=[N+](C(C)C)C(C)C)C(C)C
Product: [Cl-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of phosphorus oxychloride (10.58 g) and diethyl ether (50 ml) is stirred at 0° C. for 10 min. Diisopropylformamide (8.91 g) in diethyl ether (20 ml) is then added drop-wise over a period of 10 min. The resulting mixture is then stirred at room temperature for 30 min. The formed precipitate is allowed to settle and the supernatant removed. Dichloromethane (60 mL) is then added to the mixture. Diisopropylamine (6.98 g) in dichloromethane (20 ml) is then added drop-wise at 0° C. over 10 min. The mixture is then warmed at room temperature and stirred for a further 1.5 h. Diethyl ether (30 ml) is added and the resulting precipitate is removed by filtration. The mother liquor is concentrated in vacuo. Acetone (30 ml) is added and the mixture filtered. The mother liquor is then concentrated in vacuo and subsequently is crystallised with diethyl ether (30 ml) to give N,N,N′,N′-tetraisopropylformamidinium chloride (18, R6=iPr, R7=iPr). 1H NMR (DMSO-d6), 7.49 (1H), 4.15-3.95 (4H), 1.33 (12H), 1.31 (12H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[C:4]([OH:7])(=O)[CH3:5]>>[CH3:2][CH:1]([OH:3])[CH:4]([OH:7])[CH3:5].[OH:7][CH:4]([CH3:5])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCO
Product: CC(=O)C(C)O
Product: CC(O)C(C)O

Procedure:
Combined hydrolysis and fermentation of hemicelluloses for the direct production of fuels and chemicals: Xylanase enzyme preparations from 1 can be used in conjunction with fermentative organisms to simultaneously hydrolyze hemicellulose to sugars and ferment the sugars released to a variety of fuels and chemicals. An example of this is the use of Klebisella pneumoniae (Klebsiella oxytoca ATCC 8724) with the enzyme preparation to produce 2,3-butanediol, ethanol, acetoin, and acetic acid from xylan and steamexploded aspenwood hemicellulose (Table 7).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:34]C)=[C:15]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=2)[CH:16]=1.[CH:36]1[C:44]2[C:43]3[CH:45]=[CH:46][CH:47]=[CH:48][C:42]=3[O:41][C:40]=2[C:39]([C:49]([OH:51])=O)=[CH:38][CH:37]=1.C(Cl)Cl>CC(C)=O>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:15]2[CH:16]=[C:11]([NH:10][C:49]([C:39]3[C:40]4[O:41][C:42]5[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=5[C:44]=4[CH:36]=[CH:37][CH:38]=3)=[O:51])[CH:12]=[CH:13][C:14]=2[CH3:34])=[O:33])[CH2:27][CH2:28]1
Reactant: O=C(O)c1cccc2c1oc1ccccc12
Reactant: CCc1ccc(N)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
Diisopropylethylamine (0.4 ml) was added to a stirred mixture of N-(5-amino-2-ethylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide (0.2 g), dibenzofuran-4-carboxylic acid (0.133 g), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.22 g) and methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was dissolved in acetone and reprecipitated by the addition of isohexane. There was thus obtained the title compound (0.164 g); NMR Spectrum: (DMSOd6) 1.15 (t, 3H), 2.25 (s, 3H), 2.35-2.5 (m, 8H), 2.6 (m, 2H), 3.55 (s, 2H), 7.3 (d, 1H), 7.4-7.6 (m, 5H), 7.65 (m, 1H), 7.8-7.9 (m, 5H), 8.2 (d, 1H), 8.35 (d, 1H), 9.95 (s, 1H), 10.43 (s, 1H); Mass Spectrum: M+H+ 547.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]4[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=4[N:18]=3)=O)=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].[OH2:37].[CH2:38]1[CH2:42][O:41][CH2:40][CH2:39]1>>[CH3:1][C:2]1([CH3:34])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]4[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=4[N:18]=3)=[CH:39][C:40]([O:41][CH2:42][CH3:38])=[O:37])=[CH:11][CH:10]=2)[O:3]1
Reactant: O
Reactant: C1CCOC1
Reactant: CC1(C)OB(c2ccc(C(=O)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl](1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)methanone (1.0 g) was added to a solution of triethyl phosphonoacetate (0.498 mL) and NaH (60% in oil, 0.109 g) in THF (10 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The mixture was poured into water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (1.0 g).
Reaction SMILES: [CH3:1][Si:2]([NH:5][Si](C)(C)C)([CH3:4])[CH3:3].[NH:10]1[CH:14]=[CH:13]N=[CH:11]1>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:4])([CH3:3])[N:5]1[CH:13]=[CH:14][N:10]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C[Si](C)(C)n1ccnc1

Procedure:
HMDS (11.46 mL, 0.055 mol, 1.5 eq) was added dropwise over 20 min to a solution of imidazole (5.0 g, 0.074 mol, 2 eq) in 150 ml of toluene under argon, then the reaction mixture heated to reflux for 3 h. The reaction mixture was then concentrated to dryness under reduced pressure. Distillation of the residue gave AA2-2 as a colorless oil in 85%. For best results, this product should be stored at 0° C. under argon.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:20])[CH2:12][O:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=C[C:26](C#N)=[C:25](N)[CH:24]=1)=[O:4].[N:32]1[CH:37]=[N:36][CH:35]=[N:34][CH:33]=1.CC(O)=O>CCO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:20])[CH2:12][O:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=[C:33]2[C:26]([C:37]([NH2:32])=[N:36][CH:35]=[N:34]2)=[CH:25][CH:24]=1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Reactant: c1ncncn1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Yield: 40.8 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol), 1,3,5-triazine (207 mg, 2.55 mmol), and glacial HOAc (157 mg, 2.55 mmol) in absolute EtOH (5 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated to dryness and then purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 50 mg (32%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.34-3.89 (m, 2H), 3.60 (s, 3H), 4.14-4.54 (m, 3H), 4.64 (br d, J=14.4 Hz, 1H), 4.78-5.11 (m, 3H), 6.19 (d, J=4.1 Hz, 1H), 6.73 (d, J=4.1 Hz, 1H), 7.64 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.79 (s, 1H), 9.71 (br s, 2H) ppm; MS (ion spray): m/z 490 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][CH2:5][O:4]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].[CH2:17]([OH:19])[CH3:18]>N1C=CC=CC=1>[C:10]([O:1][CH2:2][C@@H:3]1[C@@H:7]([CH2:8][O:9][C:17](=[O:19])[CH3:18])[O:6][CH2:5][O:4]1)(=[O:12])[CH3:11]
Reactant: CCO
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1OCO[C@@H]1CO
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OCO[C@@H]1COC(C)=O
Temperature: 25 °C

Procedure:
The crude (4R,5R)-4,5-bis(hydroxymethyl)-1,3dioxolane obtained in Example 3 was dissolved in 300 ml of pyridine. After the addition of 150 g of excessive amount of acetic anhydride under ice cooling, the mixture was reacted for about 16 hours while stirring at room temperature. 20 ml of ethanol was added in portions while cooling over a water bath in order to decompose the excessive amount of acetic anhydride. After concentration by evaporator, the concentrate was extracted with 500 ml of ethyl acetate and washed with water, followed by removal of the solvent by evaporator. Although this product may be used for the next reaction as it was, the purification by silica gel column chromatography afforded 79.29 g of light yellow oil of (4R,5R)-4,5-bis(acetoxymethyl)-1,3-dioxolane.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.O.[CH3:17][CH2:18][CH:19]([OH:22])[CH2:20][CH3:21]>CN(C=O)C>[CH2:18]([CH:19]([O:22][C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)[CH2:20][CH3:21])[CH3:17].[CH3:19][O:22][C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn2c(N)nnc2c(C)c1C
Product: COc1nn2c(N)nnc2c(C)c1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Pentanol (1.5 ml) was initially charged at RT with stirring and cooled almost to 0° C. with an ice bath. Subsequently, the mixture was admixed with portions of sodium hydride (117 mg). The suspension formed was heated to 55° C. for 1.5 h and then admixed with portions of 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 100 mg), suspended in 3-pentanol (1 ml) and DMF (1.5 ml). After stirring at 55° C. for 2 h, the mixture was left to stand at RT overnight, admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 79 mg of 6-(1-ethylpropoxy)-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine and 10 mg of 6-methoxy-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine were obtained, which formed in the reaction mixture as a result of contamination with methanol.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:21]([O:28][C:29](=[O:32])[CH2:30]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.CCOC(C)=O>[CH2:21]([O:28][C:29](=[O:32])[CH2:30][N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CBr)OCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a stirring solution of 4-benzylpiperidine (6) (2.00 g, 11.41 mmol) in dichloromethane (20 mL) at 0° C. was added triethylamine (1.59 mL, 11.41 mmol), followed by benzyl-2-bromoacetate (1.81 mL, 11.41 mmol). After 10 minutes a white precipitate was observed. The reaction mixture was allowed to warm to room temperature. After 45 minutes the reaction mixture was condensed to dryness in vacuo, redissolved in EtOAc (50 mL), the organic phase washed with saturated aqueous sodium hydrogen carbonate (50 mL), and saturated brine (50 mL). The organic phase was dried (MgSO4) and condensed to dryness to give (4-benzylpiperidin-1-yl)acetic acid benzyl ester (3.69 g, 100%) as a pale yellow oil:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=4)[N:16]=3)[C:12]([Cl:31])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O.Br[CH2:43][CH2:44][CH2:45][CH2:46]Br>C(Cl)Cl>[Cl:31][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([N:1]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: BrCCCCBr
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cc(F)cc(F)c4)n3)c(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Fc1cc(F)cc(CNc2cccc(-c3cc(N[C@H]4CC[C@H](N5CCCC5)CC4)ncc3Cl)n2)c1
Temperature: 60 °C

Procedure:
To a scintillation vial containing N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3,5-difluorobenzyl)-2,4′-bipyridine-2′,6-diamine (12.3 mg, 0.028 mmol) (obtained following example 2) and K2CO3 (15.32 mg, 0.111 mmol) was added DMSO (0.5 ml) and 1,4-dibromobutane (5.98 mg, 0.028 mmol). The reaction mixture was capped and heated at 60° C. for 7 hr. The reaction mixture was diluted with DCM and washed with H2O, sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude solid was purified by reverse phase preparative HPLC to yield 5′-chloro-N6-(3,5-difluorobenzyl)-N2′-(trans-4-(pyrrolidin-1-yl)cyclohexyl)-2,4′-bipyridine-2′,6-diamine (7.8 mg, 46.0%), LCMS (m/z): 498.3 (MH+), retention time=0.65 min as a TFA salt after lypholyzing. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.26-1.40 (m, 2H) 1.48-1.62 (m, 2H) 1.85-1.98 (m, 2H)1.99-2.24 (m, 7H) 2.99-3.14 (m, 4H) 3.51-3.68 (m, 3H) 4.54 (s, 2H) 6.69-6.80 (m, 3H) 6.81-6.90 (m, 3H) 7.60-7.69 (m, 1H) 7.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](C(N=[N+]=[N-])=O)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.[N-:23]=[C:24]=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[S:6][C:5]([NH:23][C:24]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:25])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: [N-]=[N+]=NC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: [N-]=C=O
Reactant: CN1CCC(N)CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCC(NC(=O)Nc2cc([N+](=O)[O-])c(Cl)s2)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 51 %

Procedure:
5-chloro-4-nitrothiophene-2-carbonyl azide (400 mg, 1.23 mmol) from above was dissolved in toluene (10 mL) and the resulting solution was refluxed for 2 hours. After this time, the reaction mixture was cooled to ambient temperature. 1-methylpiperidin-4-amine (155 mg, 1.36 mmol) was added drop-wise to the above solution. The resulting mixture was stirred at ambient temperature for 9 hours. After this time, TLC analysis showed no intermediate isocyanate remaining so the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (Na2SO4), filtered and the solvent was removed to give the crude residue. The crude material was purified by silica gel chromatography using a 95:5 mixture of dichloromethane and methanol as eluent to afford the title product as a brown solid (200 mg, 51% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.03 (1H, br), 6.97 (1H, m), 6.86 (1H, s), 3.51 (1H, m), 2.88 (2H, m), 2.77 (1H, m) 2.32 (4H, m), 1.55 (2H, m), 1.23 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([CH:19]=[O:20])[C:3]=1[Cl:21].CC(=CC)C.O.O.[OH:29]P([O-])([O-])=O.[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:29])=[O:20])[C:3]=1[Cl:21]
Reactant: O=P([O-])([O-])O
Reactant: COc1c(Cl)ccc(-c2nc(C=O)c(Cl)c(N)c2F)c1F
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1c(Cl)ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 25 mL round bottom flask equipped with a magnetic stir bar and reflux condenser was charged with 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-pyridine-2-carbaldehyde (400 mg, 1.201 mmol) and t-butanol (6 mL). Rapid stiffing and warming with a heat gun failed to dissolved all of the aldehyde. Additional t-butanol (2 mL) was added, but still failed to form a homogeneous solution. The mixture was treated with H2O (2 mL), 2-methyl-2-butene (1 mL), sodium phosphate dibasic dihydrate (Na2HPO4; 341 mg, 2.402 mmol, 2 equiv) and finally sodium chlorite (326 mg, 3.60 mmol, 3 equiv) was added in one portion. The mixture was stirred at room temperature for 5 min and then placed in an oil bath and heated to 85° C. After stiffing at 85° C. for 60 min, the reaction mixture finally became a light yellow, homogenous solution. After stirring at 83° C. overnight (12 h), an aliquot of the reaction mixture was partitioned between EtOAc and 1 molar (M) hydrochloric acid (HCl) and analyzed by HPLC and LC-MS. HPLC analysis showed that all of the starting material had been consumed and one major, slightly more polar product formed along with multiple minor products. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). HPLC analysis of the combined aqueous washes showed only trace amounts of the desired product. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give 414 mg of a cream-colored solid. The crude material was stirred with Et2O (5 mL). After stiffing for 3 h, the solid was removed by vacuum filtration washing with Et2O. The solid was air-dried for several hours and then dried under vacuum. The title compound (348 mg, 83%) was isolated as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 13.66 (s, 1H), 7.47 (dd, J=8.5, 1.4 Hz, 1H), 7.31 (dd, J=8.4, 7.1 Hz, 1H), 7.04 (s, 2H), 3.93 (s, 4H); 19F NMR (376 MHz, DMSO-d6) δ −129.10 (d, J=28.3 Hz), −138.56 (d, J=28.4 Hz); ESIMS m/z 349 ([M+H]+), 347 ([M−H]−).