Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[C:8]2=[O:25])[S:4][C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]2=[O:25])[S:4][C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1sc(N2CCN(CCOS(=O)(=O)c3ccc(C)cc3)C2=O)cc1C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCN(CCOc3ccccc3)C2=O)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 3-methyl-5-(2-oxo-3-(2-(tosyloxy)ethyl)imidazolidin-1-yl)thiophene-2-carboxylate (0.16 g, 0.35 mmol), phenol (0.03 g, 0.36 mmol) and potassium carbonate (0.05 g, 0.35 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 16 h, cooled to ambient temperature, and partitioned between ethyl acetate (75 mL) and water (35 mL). The organic layer was washed with brine (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-40% ethyl acetate in hexanes to afford the title compound as a colorless solid 72% yield (0.10 g): 1H NMR (300 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.00-6.94 (m, 1H), 6.89 (d, J=7.6 Hz, 2H), 6.14 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.17 (t, J=4.9 Hz, 2H), 3.81 (br s, 4H), 3.72 (t, J=4.9 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 375.2 (M+1).
Reaction SMILES: [CH3:1][N+:2]([O-])([CH3:4])[CH3:3].[C@@H:6]12[C@@H:11]([C:12]3[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[C:14]([I:20])[CH:13]=3)[C@@H:10]1[CH2:9][CH:8]=[CH:7]2.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.O>[I:20][C:14]1[CH:13]=[C:12]([C@H:11]2[C@@H:10]3[CH2:9][CH:8]4[C@H:7]([C@H:6]23)[CH2:3][N:2]([CH3:4])[CH2:1]4)[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=1
Reactant: C[N+](C)(C)[O-]
Reactant: CC(C)n1nc(I)cc1[C@@H]1[C@H]2C=CC[C@H]21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1nc(I)cc1[C@H]1[C@@H]2CC3CN(C)C[C@H]3[C@@H]21
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To an ice-cooled solution of trimethylamine oxide (717 mg, 9.55 mmol) and 5-((1S,5R,6S)-bicyclo[3.1.0]hex-2-en-6-yl)-3-iodo-1-isopropyl-1H-pyrazole (2.0 g, 6.4 mmol) in tetrahydrofuran (10 mL) under nitrogen was added lithium diisopropylamide (28 mmol). After 1 h at 0° C., the reaction mixture was diluted with water (50 mL), and the resulting solution was extracted with ethyl acetate (2×20 mL). The collected organic was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (17% ethyl acetate in petroleum ether) afforded a brown oil (110 mg, 4.7%). LCMS (ESI): [MH]+=372.2.
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)C.[CH3:10][C:11]([CH3:28])([O:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=CC=C[CH:20]=1)=[O:15])[CH3:12].N[C@H](C(OC)=O)CC(C)C.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:10][C:11]([CH3:28])([O:13][C:14]([NH:16][C@H:17]([C:25]([O:27][CH3:1])=[O:26])[CH2:18][CH:19]([CH3:24])[CH3:20])=[O:15])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COC(=O)[C@@H](N)CC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of diisopropylethylamine (8.7 ml., 50 mmole) in tetrahydrofuran (50 ml.) is added dropwise to a mixture of N-[(1,1-dimethylethoxy) carbonyl]-L-phenylalanine (13.265 g., 50 mmole), L-leucine, methyl ester (9.085 g., 50 mmole) and 1-hydroxybenzotriazole hydrate (7.65 g., 50 mmole) in tetrahydrofuran (100 ml.) at 0°. This is followed by the addition of dicylcohexylcarbodiimide (10.315 g., 50 mmole). The reaction is stirred at 0°for 2 hours and left stirring overnight at room temperature. The nexy day, the precipitated dicyclohexyl urea is filtered off, the solvents are stirred down and the residue is diluted with ethyl acetate (200 ml.). The organic solution is washed sequentially with saturated aqueous sodium bicarbonate solution (2×100 ml.) and saturated aqueous sodium chloride (2×100 ml.), dried over sodium sulfate, filtered, and concentrated to give crude product. Crystallization from ethyl ether gives 7.05 g. of pure product. Concentration of the mother liquor solutions gives 4.57 g. of crystalline product. An additional 1.35 g. of product is obtained by chromatographic purification of the crude product obtained from the left-over mother liquors (40 g. silica gel, eluting with 4:1 hexane:ethyl acetate). Thus, a total of 12.96 g. of N-[N-[(1,1 -dimethylethoxy)carbonyl]-L-leucine, methyl ester is obtained;
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[CH:6][C:5](I)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>O1CCOCC1>[CH3:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:9]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([C:32]4[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=4)[CH:6]=[C:7]3[N:8]=2)[N:13]=[C:14]([NH2:19])[CH:15]=1
Reactant: Cc1cc(N)nc(CCC(=O)Nc2cc(I)cnc2N)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccc(C(F)(F)F)cc4)cnc3[nH]2)c1
Temperature: 110 °C
Yield: 54.1 %

Procedure:
96 mg N-(2-amino-5-iodo-pyridin-3-yl)-3-(6-amino-4-methyl-pyridin-2-yl)-propionamide (compound A10) is dissolved in 3.0 ml anoxic dioxane under a nitrogen atmosphere. Subsequently, 0.7 ml of an aqueous sodium bicarbonate solution (2.0 M), 52 mg 4-(trifluoromethyl)phenyl-boronic acid, and 14 mg trans-dichloro-bis(tricyclohexylphosphane)palladium-(II) are added. The reaction mixture is refluxed at 110° C. for 20 h. Thereafter, the volatile components are removed in vacuo and the remaining residue is re-dissolved in a mixture of water/dichloromethane (1:1). The aqueous phase is extracted several times with dichloromethane. The organic layer is separated, dried using sodium sulfate, and evaporated to dryness to yield 161 mg of a colourless, crude solid. Subsequently, the residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethanol 8:1) to afford 52 mg of the title compound. M.p. 170° C. ESI-MS: 398.3 (MH+). TLC: Rf=0.25 (dichloromethane/methanol 8:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:7]=1[Cl:22])[CH3:2].CCO>CCCCCC.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:7]=1[Cl:22])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(Nc2ncccc2N)cc1Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The title compound is prepared as described in Step 7.3 but using [2-chloro-4-(3-nitropyridin-2-ylamino)-phenyl]-acetic acid ethyl ester and EtOH as the solvent. The reaction mixture is stirred for 22 h at rt. Title compound: ES-MS: 306.1 [M+H]+; single peak at tR=3.06 min (System 1); Rf=0.16 (Hexane/EtOAc, 1:1).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH3:35][S:32]([C:29]1[CH:28]=[CH:27][C:26](/[C:19](/[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20]/[CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)=[CH:31][CH:30]=1)(=[O:33])=[O:34]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C/C2CCCO2)c2cc3cccnc3[nH]2)cc1
Yield: 75.1 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.24 g, 0.47 mmol) in ethanol (2 mL), tetrahydrofuran (2 mL) and an aqueous sodium hydroxide solution (10%, 1 mL) was heated at 50° C. for 2 h. The mixture diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded (Z)-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (130 mg, 75%): LC/MS m/e calcd for C20H20N2O3S [M+H]+ 369.46, observed 369.3; and (E)-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (5 mg, 2%): LC/MS m/e calcd for C20H20N2O3S [M+H]+ 369.46, observed 369.3; 1H NMR (400 MHz, CD3OD) δ ppm 8.28 (d, J=5.1 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.07-8.11 (m, J=8.3 Hz, 2H), 7.61-7.66 (m, J=8.1 Hz, 2H), 7.29-7.34 (m, 1H), 6.59 (d, J=9.1 Hz, 1H), 6.15 (s, 1H), 4.24 (q, J=7.4 Hz, 1H), 3.98 (q, J=7.0 Hz, 1H), 3.75-3.81 (m, 1H), 3.23 (s, 3H), 2.05-2.15 (m, 2H), 1.80-1.99 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CN(C=O)C>[O:20]([C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=Cc1cc(C(F)(F)F)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred solution of 2-chloro-5-(trifluoromethyl)benzaldehyde (500 mg, 2.40 mmol) in DMF (5 ml) was added phenol (226 mg, 2.40 mmol), K2CO3 (663 mg, 4.79 mmol). The reaction suspension was stirred at room temperature for 1 hr, then at 80° C. for 1.5 hr. The reaction mixture was neutralizing for acetic acid (0.5 ml), the solvent was removed. To the solid residue was added water and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with sat. NaHCO3 aq., dried with MgSO4, and concentrated to give crude Compound 6 as a yellow oil. This was purified with chromatography to give pure Compound 6 as a yellow oil (466 mg, 72.9%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][NH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH2:47][CH3:48])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH2:47]([O:46][C:40]1[CH:39]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[N:11]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH3:45])[CH3:48]
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OC
Reactant: NNc1ncccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)ccc1OC
Temperature: 85 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
After adding 28 mg of (3-nitropyridin-2-yl)hydrazine and 32 μl of triethylamine to a solution of 105 mg of {2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (17e)) in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 4 ml of a methanol:THF=1:1 mixed solvent. After adding 46 μl of acetic acid and 71 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 6 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 59 mg of 5-{(3-ethoxy-4-methoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl]-2-(3-nitropyridin-2-yl)-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:23])[C@@H:6]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:7]C(OC(C)(C)C)=O)[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:23])[C@@H:6]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:7])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)[C@H](N)CCc1ccccc1
Temperature: 25 °C

Procedure:
The allyl ester from Step A of this Example (1.96 g; 6.136 mmol) was dissolved in dry methylene chloride (10 ml) and anisole (5 ml) was added. The mixture was stirred at room temperature and trifluoroacetic acid was added drop by drop to the ester over 5 minutes. The reaction mixture was stirred at room temperature for a further 2 h then the volatiles removed on a rotary evaporator under reduced pressure to give a thick oil. The oil was dissolved in methylene chloride (50 ml) and shaken with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was discarded and the methylene chloride layer dried over anhydrous magnesium sulfate powder, filtered and the volatiles removed under reduced pressure. The oil that remained after evaporation was chromatographed on silica gel using a solvent gradient beginning with ethyl acetate and hexanes (1:1) to neat ethyl acetate and then with a eluant of ethanol and ethyl acetate in the ratio 1:4 v/v. The product (1.1 g; 81.7%) was isolated after the chromatography. FAB-MS:- calculated for C13H17NO2 219.1; found 219.8 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]3)[N:7]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:6]=2[CH:21]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:32](=[O:33])[CH2:31][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:35][C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:37]=4)[CH2:11]3)[N:7]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:6]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(Cl)cc21

Procedure:
(R)-6-Chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (32D) (0.135 mmol, 0.055 g) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.197 mmol, 0.053 g) and N-methylmorpholine (0.706 mmol, 0.079 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.197 mmol, 0.075 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-Butyl (R)-4-((R)-3-(6-chloro-1-(3-methoxypropyl)-1H-benz o[d]imidazol-2-yl)piperidine-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (32E) as a clear oil that was used directly onto the next step. ESI-MS: m/z 619.5 (M+H)+,
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:12][CH2:13][CH:14](C)[C:15]([NH2:17])=[O:16])[CH2:10][CH3:11])=[C:5]([F:19])[C:4]=1[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21].[OH-].[Na+].C([NH2:34])(=O)C=C.Cl>C(O)C.O.C(Cl)Cl>[NH2:34][C:25]1[N:24]=[CH:23][C:22]([C:20]([C:4]2[C:5]([F:19])=[C:6]([C@H:9]([NH:12][CH2:13][CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH3:11])[CH:7]=[CH:8][C:3]=2[Cl:2])=[O:21])=[CH:27][CH:26]=1
Reactant: CC[C@@H](NCC(C)C(N)=O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reactant: C=CC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC[C@@H](NCCC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
Example 1 (200 mg, 0.58 mmol) was partitioned between DCM (5 mL) and water (3 mL) basified to pH 12 with 5M NaOH. The organic phase was isolated by phase separator and blown down into a microwave vial. Acrylamide (41 mg, 0.58 mmol, 1 eq.) and MnCl2.4H2O (57 mg, 0.29 mmol, 0.5 eq.) was heated in ethanol (0.9 mL) and water (0.1 mL) in the microwave at 100 degC for 30 min. Only partial reaction, so further acrylamide and MnCl2 (same amounts) were added and the reaction heated for 30 min at 100° C. Still not complete so reaction heated as is for another 30 min at 100° C. The mixture then partitioned between EtOAc (15 mL) and water (10 mL) (plus drop of 5M NaOH) and then the aqueous extracted with further EtOAc (15 mL). Combined organics were washed with water (10 mL) and brine (10 mL) and then dried (MgSO+), filtered and concentrated. Purified by chiral HPLC normal phase, eluting EtOH and heptane. Concentrated and then dissolved in DCM (2 mL) and 1.1 eq. 2M HCl in Et2O added. Concentrated and dried in a vacuum oven to give 3-{[(1R)-1-{3-[(6-aminopyridin-3-yl)carbonyl]-4-chloro-2-fluorophenyl}propyl]amino}-propanamide (56 mg, 0.15 mmol, 25%) as an HCl salt and white solid.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:17])[CH2:15][CH3:16]>>[CH2:14]([O:17][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH2:15][CH3:16]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCO
Agent: [Na]
Product: CCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of sodium (440 mg, 17 mmol) in 1-propanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (650 mg, 3.3 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to yield 700 mg (96%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8]O)=[C:6]([CH2:10][CH3:11])[O:5][N:4]=1)[CH3:2].[Br:12]P(Br)Br>C(Cl)Cl>[Br:12][CH2:8][C:7]1[C:3]([CH2:1][CH3:2])=[N:4][O:5][C:6]=1[CH2:10][CH3:11]
Reactant: CCc1noc(CC)c1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCc1noc(CC)c1CBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3,5-diethyl-1,2-oxazol-4-yl)methanol (710 mg, 4.6 mmol) in anhydrous DCM (30 mL) was added tribromophosphane (465 μL, 4.9 mmol). The mixture was stirred at room temperature for 5 hours, and then DCM was evaporated. The residue was dried in vacuo, affording 4-(bromomethyl)-3,5-diethyl-1,2-oxazole, which was used without further purification.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C:27](O)=O.[NH2:37][NH2:38]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:38][N:37]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: O=C(O)C(CCCCCl)c1ccc(Cl)nc1
Reactant: NN
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(Cl)nc3)n2)ccc1-n1cnc(Cl)c1
Yield: 23 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (500 mg, 1.69 mmol, from preparation A) and 6-chloro-2-(6-chloropyridin-3-yl)hexanoic acid (442 mg, 1.69 mmol, from preparation AJ) were coupled and then reacted with hydrazine (0.211 mL, 6.74 mmol) using a procedure analogous to Step A of Example 13. The crude products were purified using silica gel chromatography (40-100% ethyl acetate/chloroform) to afford 5-(5-chloro-1-(6-chloropyridin-3-yl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (190 mg, 0.375 mmol, 23% yield) as a pink foam. LC-MS (M+H)+ 508.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][C:3]=1[CH:12]([CH2:15][OH:16])[C:13]#[N:14].C(#N)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].OS(O)(=O)=O>O>[C:20]([O:16][CH2:15][CH:12]([C:3]1[CH:4]=[C:5]([O:8][CH:9]([F:11])[F:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:13]#[N:14])(=[O:22])[CH3:21]
Reactant: N#CC(CO)c1cc(OC(F)F)ccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CC(=O)OCC(C#N)c1cc(OC(F)F)ccc1Cl
Yield: 80.4 %

Procedure:
A 5 mL screw-capped test tube was charged with 250 mg (1.00 mmol) of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile, 0.4 mL of acetonitrile and 122 μL (1.3 mmol) of acetic anhydride. This mixture was stirred briefly with a melting point capillary having the tip wetted with conc. H2SO4 to give an immediate exotherm. After 15 minutes the mixture was diluted with water and extracted with butyl chloride. The extract was washed with water 3 times, dried (Na2SO4), and stripped of solvent under high vacuum to give 233 mg (96%) of the desired ester product, i.e., 3-acetoxy-2-(2-chloro-5-(difluoromethoxy)phenyl)propanenitrile, as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:6]=2[O:7][C:8]=1[CH3:9])(=O)[CH3:2].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+].O>C(O)C>[OH:19][N:18]=[C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:6]=2[O:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CC(=O)c1c(C)oc2c([N+](=O)[O-])cccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1c(C)oc2c([N+](=O)[O-])cccc12
Yield: 72.5 %

Procedure:
A mixture of 3-acetyl-2-methyl-7-nitrobenzo[b]furan (413 mg), hydroxylamine hydrochloride (393 mg) and sodium bicarbonate (792 mg) in ethanol (10 ml) was refluxed for 30 minutes. The reaction mixture was cooled and water was added to the solution. The separated solid was collected, washed with water and dried to give 3-(1-hydroxyiminoethyl)-2-methyl-7-nitrobenzo[b]furan (320 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>C(OCC)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]([CH2:13][CH:12]=[CH2:11])[OH:5]
Reactant: O=Cc1ccc(F)cc1F
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCC(O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under anhydrous condition at 0° C., a mixture of 18.0 g of freshly distilled 2,4-difluorobenzaldehyde and 120 ml of diethyl ether is treated, dropwise, with 139 ml of 1M allyl magnesium bromide. The reaction is stirred at 0° C. for 1 hour then slowly allowed to warm to room temperature. After 5 hours, thin layer chromatography indicates complete reaction. The mixture is cooled to 0° C. and quenched by the dropwise addition of 100 ml of ice cold saturated ammonium chloride. Two hundred ml of diethyl ether is added and the layers are separated. The aqueous layer is extracted with diethyl ether. The organic layers are combined, washed twice with saturated sodium chloride, dried , filtered and concentrated in vacuo. The residue is purified by Kugelrohr distillation (100° C.) to give 19.9 g of the desired product as a mixture of isomers.