Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:31])=O.CN(C=O)C>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:31])=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Cl)CC1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoic acid (4.0 g, 10.6 mmol) in dichloromethane (20 mL) at 0° C., was added oxalyl chloride (13 mmol), followed by a small amount of DMF. After 30 min, the solvents were removed in vacuo and the residue was dissolved in dichloromethane to make a solution of the title compound, approximately 0.1 g/mL.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1)#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-:26].[NH4+].[Cl-].[Li+]>CN(C)C=O>[ClH:26].[ClH:26].[NH:22]1[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:8]=2)=[N:2][N:24]=[N:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: [Cl-]
Reactant: N#CCCCCc1cn(-c2cccnc2)c2ccccc12
Agent: [Li+]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: c1cncc(-n2cc(CCCCc3nnn[nH]3)c3ccccc32)c1

Procedure:
A mixture of 5.16 g of 3-(4-cyanobutyl)-N-(3-pyridyl)indole, 1.88 g of sodium azide, 1.57 g of ammonium chloride and 10 mole % of lithium chloride is heated in 14 ml of dry N,N-dimethylformamide at 125° C. for 17 hours. The reaction mixture is cooled, filtered and evaporated to a residual oil which is partitioned between 50 ml of water and 50 ml of ethyl acetate. The aqueous phase is adjusted to pH=2, extracted with 20 ml of ethyl acetate, adjusted to pH=5 and the resulting solid collected by filtration. Treatment with 6.2 ml of 3N ethereal hydrogen chloride yields 3-[4-(5-tetrazolyl)butyl]-N-(3-pyridyl)indole hydrochloride.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15]1[CH:24]=[C:23]3[C:18]([C:19](=[O:31])[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]3[CH:25]3[CH2:27][CH2:26]3)=[CH:17][C:16]=1[F:32])[CH2:9]2)(=O)C.[ClH:33].O>C(O)C>[ClH:33].[NH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15]1[CH:24]=[C:23]3[C:18]([C:19](=[O:31])[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]3[CH:25]3[CH2:27][CH2:26]3)=[CH:17][C:16]=1[F:32])[CH2:9]2
Reactant: CC(=O)NCc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: NCc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
304 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro--4-oxoquinoline-3-carboxylic acid was added to a mixed solution of 12 ml of concentrated HCl, 2.5 ml of water, and 5 ml of ethanol, and the mixture was heated under reflux for 15 hours. After cooling under atmosphere, the crystals deposited were collected by filtration and washed with ethanol to obtain 264 mg of 7-(5-aminomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([S:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:4]1.C(N(CC)C(C)C)(C)C.[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39].CCOC(C)=O>CN(C=O)C>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[S:12][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]=1[S:7]([N:5]1[CH2:6][CH:3]([CH2:2][NH:1][CH2:39][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40])[CH2:4]1)(=[O:8])=[O:9]
Reactant: NCC1CN(S(=O)(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Reactant: C=CC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNCC1CN(S(=O)(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Reaction time: 18 h
Yield: 37 %

Procedure:
To a stirring mixture of Example 2 (160 mg, 0.31 mmol) and N,N-diisopropyl-ethylamine (57 μL, 31 mmol) in DMF (5 mL) was added ethyl acrylate (51 μL, 0.31 mmol) and the mixture allowed to stir for 18 hours. After this time EtOAc (25 mL) was added to the reaction mixture which was then washed with brine (3×25 mL), dried (sodium sulfate) and then reduced in vacuo. The resulting oil was purified by column chromatography (SiO2, 50% DCM in EtOAc) to afford the title compound as a colourless oil (71 mg, 38%). δH (CDCl3) 8.97 (1H, s), 8.30 (1H, dd, J 1.6, 4.7 Hz), 8.12 (1H, dd, J 1.6, 8.2 Hz), 7.51 (2H, m), 7.33 (1H, dd, J 8.7, 8.7 Hz), 7.23 (1H, dd, J 4.7, 8.2 Hz), 4.04 (2H, q, J 7.2 Hz), 3.88 (2H, dd, J 8.0, 8.0 Hz), 3.55 (2H, dd, J 5.6, 8.0 Hz), 2.71 (2H, t, J 6.3 Hz), 2.64 (2H, d, J 7.3 Hz), 2.53 (1H, m), 2.33 (2H, t, J 6.3 Hz), 1.17 (3H, t, J 7.2 Hz). Exchangeable protons were not observed. LCMS (pH 10) RT 3.19 minutes, (ES+) 619 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1.Cl>CN(C=O)C.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[N:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ccc(F)cc2)nc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 13.3 %

Procedure:
Sodium hydride (0.653 g, 60% in mineral oil, 16.338 mmol) was suspended in DMF (10 mL) under argon, and 4-fluorophenol (0.915 g, 8.169 mmol) added in two portions. The mixture was stirred for 20 minutes then ethyl 6-chloro-3-pyridinecarboxylate (1.515 g, 8.169 mmol) was added together with additional DMF (4 mL) added to aid solubility. The mixture was heated to 80° C. for 2.5 h. The reaction mixture was allowed to cool to room temperature and water (30 mL) was added. The solution was acidified to pH 3 with 2M HCl and extracted with ethyl acetate (×3). The combined ethyl acetate layers were dried and concentrated to produce a brown oil. The crude product was purified by chromatography. Elution with a 0-25% Et2O/petroleum ether gradient gave the title compound as a colourless oil (0.284 g). δH (CDCl3, 400 MHz) 8.81 (1H, dd), 8.28 (1H, dd), 7.11 (4H, m), 6.95 (1H, d), 4.37 (2H, q), 1.38 (3H, t). MS (ES): MH+ 262.2.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:4].[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>C(OCC)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]([NH:5][C:6]3[CH:7]=[C:8]4[C:12](=[CH:13][CH:14]=3)[NH:11][N:10]=[CH:9]4)=[O:4])[CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: O=C(CCl)Nc1ccc2[nH]ncc2c1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2[nH]ncc2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-indazol-5-yl)-acetamide (Example 147a) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 149-152° C. (diethylether)
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7](/[CH:9]=[N:10]/O)=O)=[CH:3][CH:2]=1.Cl.[NH2:13][CH:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]#[N:16]>Cl[Ti](Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:16][C:15]1[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:13][C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:9][N:10]=1
Reactant: O=C(/C=N/O)c1ccccc1
Reactant: N#CC(N)Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
A round bottomed flask was charged with 5 g (33.5 mmol) of 2-isonitrosoacetophenone, 6.7 g (36.8 mmol) of 2-amino-3-phenylpropanenitrile hydrochloride and 100 mL of dry pyridine. The mixture was cooled to −20° C. and 4.6 mL (40.0 mmol) of TiCl4 was added dropwise. The reaction was kept at −20° C. for 30 min and heated to 80° C. for 2.5 hrs. The solvent was evaporated, and the residue taken up in 1 L of DCM. This solution was washed with saturated NaHCO3 and brine. All volatiles were evaporated, and the residue redissolved in ethanol (400 mL). Raney Ni (2.0 g, aqueous suspension) was added, and the reaction allowed to stir for 5 days under 1 atm of hydrogen. The mixture was passed through celite, and volatiles removed. The residue was chromatographed on silica gel (heptanes/DCM) to give 2.5 g (29%) of 2-amino-3-benzyl-5-phenylpyrazine.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC=C(F)C=1)=[O:10].Cl>O1CCCC1.O.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1cccc(F)c1)c1cc(Br)ccc1OCc1cccc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1cccc(F)c1
Temperature: 71 °C
Reaction time: 16 h

Procedure:
Solid LiOH (0.50 g, 20.95 mmol) was added in one charge to a stirred solution of (3-fluorophenyl)methyl 5-bromo-2-{[(3-fluorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 82; 1.65 g, 3.81 mmol) in tetrahydrofuran (15 ml) and water (5 ml) in air at 20° C. The reaction mixture was stirred at 71° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 ml). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over Na2SO4, and concentrated to yield the title compound as a white solid. 1.5 g.
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1.[NH3:14].[H][H]>[Cr].[Cu]>[CH3:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[CH:8]=1)[O:4][CH2:3][CH:2]([NH2:14])[CH3:1]
Reactant: N
Reactant: Cc1cc(C)cc(OCC(C)O)c1
Reactant: [H][H]
Agent: [Cr]
Agent: [Cu]
Product: Cc1cc(C)cc(OCC(C)N)c1
Temperature: 240 °C
Reaction time: 7 h
Yield: 51 %

Procedure:
A 150 cc autoclave was charged with 30.0 g (166 mmol) of 1-methyl-2-(3,5-dimethylphenoxy)ethanol, 3.0 g of a copper-chromium catalyst (N203SD, supplied by Nikki Chemical Co., Ltd.: CuO 44%, Cr2O3 44%, MnO2 5G %) and 30.0 g of a solvent (toluene). Further, 9.6 g (564 mmol) of ammonia was added, a hydrogen pressure of 40 kg/cm2G was applied, and then the temperature of the mixture was increased up to 240° C. The mixture was stirred at a reaction pressure of 104 to 97 kg/cm2G for 7 hours. The reaction mixture was allowed to cool, and the pressure of an excess of ammonia and hydrogen was released. Then, the catalyst was removed by filtration. The resultant filtrate was extracted with 100 ml of a 20% hydrochloric acid aqueous solution. The extracted aqueous layer was neutralized with a 20% sodium hydroxide aqueous solution, and 200 ml of ethyl ether was added to the aqueous layer for extraction. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give 15.2 g of the intended compound, 1-(3,5-dimethylphenoxy)-2-aminopropane (yield 51%). The selectivity to the intended compound, calculated on the basis of the total amount of the starting compound, was 81%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36](B(O)O)=[CH:35][CH:34]=[N:33]2)=[CH:28][CH:27]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[CH3:11][NH:10][C:8]([C:6]1[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]([CH3:23])=[C:2]([C:36]2[N:32]([C:29]3[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)[N:33]=[CH:34][CH:35]=2)[N:7]=1)=[O:9]
Reactant: CNC(=O)c1nc(Br)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: N#Cc1ccc(-n2nccc2B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CNC(=O)c1nc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 19.6 %

Procedure:
6-Bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (SM2, 0.05 g, 0.128 mmol), 1-(4-cyanophenyl)-1H-pyrazol-5-boronic acid (SM4, 0.062 g, 0.256 mmol), Cs2CO3 (0.125 g, 0.384 mmol) and DME (3 ml) were added to a glass tube for microwave synthesis. The mixture was degassed with nitrogen and Pd(PBut3)2 (0.010 g) was added. The tube was sealed and heated with stirring at 110° C. (150 W) in a microwave heater for 10 minutes. The mixture was diluted with EtOAc (5 ml), and filtered. The solution was concentrated in vacuo and was purified by chromatography on silica to give a reasonably pure material that was further purified by preparative HPLC to give 0.012 g (20%) of the title compound as a white solid.
Reaction SMILES: [N:1]#[C:2][Br:3].[NH2:4][C:5]1[C:6]([Cl:25])=[N:7][C:8]2[C:13]([C:14]=1[NH:15][CH2:16][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])([CH3:19])[CH3:18])=[CH:12][CH:11]=[CH:10][CH:9]=2.O>C(O)C>[BrH:3].[NH2:1][C:2]1[N:15]([CH2:16][C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])([CH3:19])[CH3:18])[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([Cl:25])[C:5]=2[N:4]=1
Reactant: N#CBr
Reactant: CC(C)(CNc1c(N)c(Cl)nc2ccccc12)NS(C)(=O)=O
Solvent: CCO
Solvent: O
Product: Br
Product: CC(C)(Cn1c(N)nc2c(Cl)nc3ccccc3c21)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
Cyanogen bromide (0.945 g, 8.93 mmol) was added to a solution of N-{2-[(3-amino-2-chloroquinolin-4-yl)amino]-1,1-dimethylethyl}methanesulfonamide (2.55 g, 7.44 mmol) in ethanol (25 mL), and the solution was stirred at ambient temperature for two hours. An analysis by HPLC indicated that no reaction had taken place, and the reaction was then heated overnight at 90° C. and allowed to cool to ambient temperature. Water was added; a precipitate was present and was isolated by filtration and washed with diethyl ether to provide 510 mg of N-[2-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide hydrobromide as a brown solid. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol. Diethyl ether was added, and a gummy precipitate formed, which was dissolved again in methanol and concentrated under reduced pressure to provide an additional 1.1 g of the product as a dark brown solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:31])[C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])=[CH:18][CH:17]=1.O>CN(C)C(=O)C>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[C:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:17][CH:18]=1)=[O:31]
Reactant: Nc1ccc(C(=O)c2cc(F)ccc2F)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2cc(F)ccc2F)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.95 g, 6.0 mmol) in N,N-dimethylacetamide (15 mL) was added thionyl chloride (0.72 g, 6.0 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4'-Amino-2,5-difluoro benzophenone (1.00 g, 4.3 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered to yield a brown solid. Recrystallization from methylene chloride/hexane yielded the title propanamide as a white solid (1.03 g, 69%); mp 145°-147° C. 1H-NMR (250 MHz, d6-DMSO): 1.59 (s, 3H, CH3) 7.44-7.47 (m, 3H, aromatic) 7.57 (s, 1H, OH) 7.77 (d, 2H, J=8.0 Hz, aromatic) 7.97 (d, 2H, J= 8.0 Hz, aromatic) 10.40 (s, 1H, NH). MS (CI, CH4): 374 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[F:33][C:34]([F:45])([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](Cl)=[O:36].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH:25][C:35](=[O:36])[C:34]([F:33])([F:45])[O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Reactant: O=C(Cl)C(F)(F)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=NOCc2cccc(NC(=O)C(F)(F)Oc3ccccc3)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 88 %

Procedure:
To a stirred solution of 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine (90 mg, 0.26 mmol) in dry 1,4-dioxane (10 mL) were added pyridine (31 μL, 0.38 mmol) and 2,2-difluoro-2-phenoxyacetyl chloride (105 mg, 0.51 mmol). The reaction mixture was stirred at room temperature for 25 h, then poured into aq. NaHCO3 (10 g/L, 30 mL). After extraction with ethyl acetate (50 mL), the organic layer was dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded N-(6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-yl)-2,2-difluoro-2-phenoxyacetamide as an oil [123 mg, yield 88%; HPLC/MS:m/z=523 (M+H); log P(HCOOH)=4.14].
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([S:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:38])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]([S:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:17])[CH3:16].Br[CH2:60][CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65]>CC#N>[C:64]([CH2:63][CH2:62][CH2:61][CH2:60][CH2:1][N:10]([CH2:9][C:8]([CH3:7])([S:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH3:38])[CH2:11][CH2:12][NH:13][CH2:14][C:15]([S:18][C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH3:16])[CH3:17])([O:66][CH2:67][CH3:68])=[O:65]
Reactant: CC(C)(CNCCNCC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCCCBr
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCCN(CCNCC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 64.6 %

Procedure:
K2CO3 (1.92 g, 13.9 mmol, 100 mol %) was added to N,N'-bis(2-methyl-2-triphenylmethylthiopropyl)ethylenediamine (10.03 g, 13.9 mmol) in CH3CN (60 mL), followed by ethyl 5-bromovalerate (3.30 mL, 20.8 mmol, 150 mol %). The reaction was heated at reflux under argon overnight. The solution was then concentrated to a paste and partitioned between 0.25M KOH (100 mL)and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (1×50 mL) and the combined ethyl acetate layers were washed with 50 mL water and NaCl solution (2×50 mL), dried with Na2SO4 and concentrated to an orange oil. Purification by flash chromatography (300 g flash silica, 100% CHCl3 to 5% MeOH/CHCl3) gave pure title compound (7.75 g, 66% yield). FABMS analysis yielded an (MH+) of 849 (compared with a calculated molecular weight of 849.24 for the compound C55H64N2O2 S2).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1([CH2:17][CH:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[N:25][CH:26]=1)[CH2:17][C:14]1([C:13]([F:12])([F:31])[F:32])[CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=485.1, tR (minutes, Method G)=2.63. [α]D20=+27.63 (c=1.52 mg/mL,CHCl3)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=O.Cl.O[NH2:13]>C(O)=O.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:13]
Reactant: O=Cc1c(Br)cncc1Br
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: N#Cc1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-dibromoisonicotinaldehyde (2.0 g, 0.0075 mol) in formic acid was added hydroxyl amine hydrochloride (14 mL) and concentrated sulfuric acid (5 drops) under argon atmosphere. The reaction mixture was heated to reflux for 8 h. After 8 h, the mixture was cooled to room temperature and concentrated. The residue was dissolved in diethyl ether, washed diethyl ether with saturated solution of sodium bicarbonate, water, saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated to afford the title compound. 1H NMR (400 MHz, CdCl3) δ 8.81 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:17]([OH:22])[OH:18])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Under nitrogen stream, 1-(benzyloxy)-4-bromo-2-fluorobenzene (12.0 g, 43 mmol) was dissolved in tetrahydrofuran, followed by addition of triisopropyl borate (11.8 mL, 51 mmol), and then the mixture was cooled to −78° C. Butyl lithium (1.55M hexane solution) (30 mL, 47 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour at −78° C. A 1N aqueous hydrochloric acid solution (100 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off under reduced pressure. The aqueous phase was extracted with ethyl acetate, the extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was suspended in hexane, and was then collected by filtration to give the title compound (9.27 g, 88%).