Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][C:7]#[N:8])[CH3:2].Cl.[NH2:13][OH:14].C(=O)(O)[O-].[Na+]>CO>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7](=[NH:8])[NH:13][OH:14])[CH3:11]
Reactant: NO
Reactant: CCOC(CCC#N)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(CCC(=N)NO)OCC
Temperature: 25 °C

Procedure:
A mixture of 4,4-diethoxybutanenitrile (5.0 g, 32 mmol), hydroxylamine hydrochloride (2.4 g, 35 mmol) and sodium bicarbonate (2.9 g, 35 mmol) in methanol (50 mL) was refluxed for 5 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue was diluted with EtOAc and water. The water layer was extracted with EtOAc (2×). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to give the product, which was used next step without purification. 1HNMR (300 MHz, CD3Cl): δ 4.73 (br, 1H), 4.51 (t, J=5.5 Hz, 1H), 3.66 (m, 2H), 3.50 (m, 2H), 2.21 (t, J=8.2 Hz, 2H), 1.86 9 m, 2H), 1.19 (t, J=8.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:23])([CH3:22])[CH2:12][C:13]([C:18]([F:21])([F:20])[F:19])([OH:17])[CH2:14][C:15]#[CH:16])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[C:27](I)[CH:26]=1>CN(C=O)C.C(N(CC)CC)C.[Cl-].[NH4+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:35]1([S:32]([N:31]2[C:28]3[C:29](=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=3)[CH:16]=[C:15]2[CH2:14][C:13]([OH:17])([CH2:12][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)([CH3:23])[CH3:22])[C:18]([F:21])([F:19])[F:20])(=[O:34])=[O:33])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C#CCC(O)(CC(C)(C)c1cc(Cl)cc2c1OCC2)C(F)(F)F
Reactant: O=S(=O)(Nc1ccc(Br)cc1I)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(CC(O)(Cc1cc2cc(Br)ccc2n1S(=O)(=O)c1ccccc1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 39.1 %

Procedure:
A mixture of 6-(5-chloro-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (170 mg, 0.49 mmol), N-(4-bromo-2-iodophenyl)benzenesulfonamide (220 mg, 0.50 mmol), dichlorobis(triphenylphosphine)palladium (II) (20 mg, 0.03 mmol), and copper (I) iodide (10 mg, 0.05 mmol) in 1 nL of DMF and 0.7 mL of triethylamine was warmed at 70° C. After 45 minutes, the mixture was cooled and diluted with 7 mL of saturated aqueous ammonium chloride solution and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with two 7 mL portions of saturated aqueous ammonium chloride solution, four 7 mL portions of brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified on silica gel eluting with ethyl acetate-hexanes (0-30% gradient) to afford 126 mg (39% yield) of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][C:17]#N)=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CI>>[CH:1]1([CH2:6][C@H:7]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH3:17])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SC#N)s2)cc1
Solvent: CI
Product: CSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
The title compound was prepared from (R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamide and methyl iodide as described in Example 10. 1H-NMR (CDCl3): δ 11.8 (broad s, 1H), 7.86 (d, 2H), 7.52 (d, 2H), 7.44 (s, 1H), 3.79 (t, 1H), 3.04 (s, 3H), 2.46 (s, 3H), 2.27 (m, 1H), 1.89 (m, 1H), 1.81-1.44 (m, 7H), 1.12 (m, 2H); HPLC-MS: m/z: 425 (M+1).
Reaction SMILES: [C:1](=[O:19])([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[O:14][C:15]([F:18])([F:17])[F:16])[O:2][CH3:3]>C(OCC)(=O)C.[Pd]>[C:1](=[O:19])([O:2][CH3:3])[O:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[O:14][C:15]([F:18])([F:17])[F:16]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])ccc1OC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(N)ccc1OC(F)(F)F
Yield: 83.3 %

Procedure:
A solution of methyl 5-nitro-2-(trifluoromethoxy)phenyl carbonate (120 mg, 0.43 mmol) in ethyl acetate (10 mL) was stirred in presence of 10% Pd/C (45 mg) under H2 atmosphere for 4 h. The reaction was filtered through a pad of Celite and concentrated in vacuo to provide 5-amino-2-(trifluoromethoxy)phenyl methyl carbonate (90 mg, 84% yield). 1H NMR (400.0 MHz, CDCl3) δ 7.09 (dd, J=1.1, 8.7 Hz, 1H), 6.54 (d, J=2.7 Hz, 1H), 6.51 (dd, J=2.8, 8.7 Hz, 1H), 3.91 (s, 3H), 3.80 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:3]([C:11]([F:12])([F:13])[F:14])=[CH:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1c([N+](=O)[O-])cccc1C(F)(F)F
Yield: 83 %

Procedure:
A solution of 17 mmol 2-methyl-3-nitrobenzotrifluoride and 43 mmol N,N-dimethylformamide-dimethylacetal in 30 ml N,N-dimethylformamide was hold at 120° C. overnight. The reaction mixture is concentrated in vacuo to give the crude title compound. Yield 83%. MS (m/e): 261.1 ([M+H]+, 90%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].[O-]Cl.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](C=O)C1
Temperature: 5 °C
Yield: 87 %

Procedure:
To a solution of (R)-Boc-3-pyrrolidinemethanol (5.0 g, 24.8 mmol) in DCM was added TEMPO (80 mg, 0.5 mmol) and potassium bromide (150 mg, 1.3 mmol). This mixture was cooled to 5° C. and vigorously stirred as a pre-chilled (at 0° C.) 1:1 mixture of NaOCl in water (53 mL) and a saturated, aqueous NaHCO3 solution (53 mL) was added dropwise. The resultant mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with water (50 mL) and saturated aqueous NaCl (50 mL). The organic layer was dried over anhydrous Na2SO4 to yield 4.3 g of the title compound, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.C(Cl)[Cl:17].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([Cl:17])=[O:15]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1F
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-(2-fluoro-4-(trifluoromethyl)phenyl)acetic acid (5 g, 22.509 mmol, CASRN 209991-64-0) in DCM (112 mL, 22.509 mmol) was added oxalyl chloride (2.94 mL, 33.8 mmol) and 3 drops of DMF. The solution was stirred at RT overnight and concentrated to dryness to afford 5.2 g (88.2%) of 2-(2-fluoro-4-(trifluoromethyl)phenyl)acetyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:21]1([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Cc1cc(C2CCCC2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C2CCCC2)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.3 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.6 g), palladium (II) acetate (225 mg), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (933 mg), tripotassium phosphate (6.4 g) and cyclopentylboronic acid (2 g) were added toluene (30 mL) and water (1.5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(5-cyclopentyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g). 4-(5-Cyclopentyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g) was dissolved in chloroform (5 mL), 4N hydrogen chloride/ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (1 g).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]=2[OH:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].S(OC)(O[CH3:26])(=O)=O>O1CCCC1.CN(C)C=O>[CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]=2[O:14][CH3:26])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1oc2ccc(F)cc2c1O)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 0.25 h
Yield: 63 %

Procedure:
Cyclohexyl(5-fluoro-3-hydroxy-1-benzofuran-2-yl)methanone (3.0 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (15 mL) and N,N-dimethylformamide (15 mL). The reaction mixture was ice-cooled, sodium hydride (0.69 mg) was added to the solution, and the mixture was stirred for 15 min. Dimethyl sulfate (1.6 mL) was added to the mixture, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the precipitate was recrystallized from diisopropyl ether-hexane to give the title object compound (2.0 g, 63%) as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:43])[CH2:4][C:5]1[CH:42]=[CH:41][CH:40]=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:43])[CH2:4][C:5]1[CH:42]=[CH:41][CH:40]=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[N:10]=1
Reactant: CNC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-(methylamino)-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I56) (0.087 g, 0.15 mmol) was dissolved in DCM (5 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.222 mL, 2.906 mmol) was added to the solution and the reaction was stirred at room temperature for 6 hours. Volatiles were removed in vacuo, EtOAc (70 mL) and 2 M aq. NaOH (70 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (2×70 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (14) (0.068 g, 94% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.93-7.85 (m, 1H), 7.60-7.53 (m, 2H), 7.23-7.12 (m, 4H), 6.91-6.86 (m, 2H), 3.50 (s, 2H), 3.14-3.06 (m, 2H), 3.02-2.93 (m, 6H), 2.87-2.80 (m, 4H), 2.56 (d, J=4.6 Hz, 3H). LCMS Method A: rt 4.37 min; m/z 499.6 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20](CC3C=CC(C(C)(C)C)=CC=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH3:35])([CH3:6])[CH3:5]>CC(O)=O>[CH3:1][O:2][C:3](=[O:36])[C:4]([CH3:5])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][NH:20][C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH3:35])[CH3:6]
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1C
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)Oc1ccc(CCCC2CNC(=O)N2C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionic acid methyl ester (0.620 g, 1.25 mmole) was dissolved in 20% HOAc in EtOAC (50 mL). After purged the solution with N2 for 15 min, 10% Pd/C (0.600 g). The reaction was stirred under a hydrogen balloon at room temperature for overnight. The catalyst was removed through filtration, and solvent was removed on rota-vapor to provide a colorless oil (0.337 g, 77%). Mass [EI+] 349 (M+H)+.
Reaction SMILES: COP([CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(OC)=O.[Br-].[Mg+2].[Br-].CCN(CC)CC.[CH2:24]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]2[C:44]([Cl:45])=[CH:43][C:40]([CH:41]=O)=[CH:39][N:38]=2)[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.C(OCC)(C)=O.O>[CH2:24]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]2[N:38]=[CH:39][C:40](/[CH:41]=[C:7](\[F:13])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:43][C:44]=2[Cl:45])[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(F)P(=O)(OC)OC
Reactant: O=Cc1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(Cl)c1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(Cl)c1
Temperature: 7.5 °C
Yield: 81.6 %

Procedure:
To a mixture of ethyl (dimethoxyphosphoryl)(fluoro)acetate (1.46 g) and magnesium bromide (1.33 g) in THF (20 ml) was added dropwise to a Et3N (0.92 ml) with stirring at 0-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at same condition for an hour. A solution of 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinaldehyde (1.36 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at 0-15° C. for 4 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4— The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (3:7). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2Z)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridinyl)-2-fluoroacrylate (1.42 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][C@@H:16](O)[CH2:15][N:14]3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:39])CCOC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][C@H:16]([F:39])[CH2:15][N:14]3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@@H](F)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
(2S,4R)-benzyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (1.5 g, 3.4 mmol) was added as a solid to a solution of bis(2-methoxyethyl)aminosulfur trifluoride (0.98 mL, 5.1 mmol) in 15 mL CH2Cl2 cooled to −78° C. Reaction was stirred at −78° C. for two hours and then warmed to room temperature and stirred for 2 hours. Reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. Layers were separated and aqueous layer washed one time with CH2Cl2. Combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give a yellow oil. The oil was triturated with CH2Cl2 and pentane to yield (2S,4S)-benzyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate JG-20 as a yellow solid (0.96 g, 62%).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12](=[NH:18])[S:13][C:14]=2[CH2:15]OC)[N:9]=1)[NH2:3].[S:19]([NH2:23])([NH2:22])(=[O:21])=[O:20]>COCCO>[NH2:18][C:12]1[S:13][C:14]([CH:15]=[N:22][S:19]([NH2:23])(=[O:21])=[O:20])=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[N:11]=1
Reactant: NS(N)(=O)=O
Reactant: COCc1sc(=N)[nH]c1-c1csc(N=C(N)N)n1
Solvent: COCCO
Product: NC(N)=Nc1nc(-c2nc(N)sc2C=NS(N)(=O)=O)cs1
Temperature: 70 °C
Yield: 28.7 %

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-[2-(imino)(methoxy)methylthiazol-4-yl]thiazole (1.0 g) and sulfamide (1.36 g) in a 2-methoxyethanol (10 ml) was heated at 70° C. for 7 hours. The resulting precipitate was removed by filtration. The filtrate was chromatographed on a silica gel column eluting with ethyl acetate:methanol=3:1. Recrystallization from a mixture of N,N-dimethylformamide and water afforded 4-[2-(amino)(aminosulfonylimino)methylthiazol-4-yl]-2-(diaminomethyleneamino)thiazole (0.35 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[O:31][CH3:32]>>[CH3:32][O:31][C:25]1[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: COc1ccc(C)cc1Br
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: COc1ccc(C)cc1N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 2-bromo-4-methylanisole. Light yellow solid. MS (ESI): 435.3 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=1)[C:20]([O:22]C)=[O:21])=[O:14].C1COCC1.[OH-].[Li+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=1)[C:20]([OH:22])=[O:21])=[O:14]
Reactant: COC(=O)c1cc(C(=O)Nc2cc(C(F)(F)F)ccc2F)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2F)cc1C(=O)O
Temperature: 25 °C

Procedure:
A solution of methyl 5-((2-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-2-methylbenzoate 35 (0.904 g, 2.5 mmol), THF (20 mL), lithium hydroxide (0.18 g, 7.6 mmol), and water (5 mL) was heated at 55° C. for 24 hours and then cooled to room temperature. The aqueous layer was separated, cooled in an ice-water bath, and acidified with 6 M HCl (aq) to pH 1. This solution was extracted with ethyl acetate (3×10 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 5-((2-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-2-methylbenzoic acid 36.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][C@H:26]5[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]5)=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:38])C=CC=CC=1>CO>[O:38]=[C:9]1[C:10]2([C:20]3[CH:21]=[CH:22][C:23]([O:25][C@H:26]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]4)=[CH:24][C:19]=3[O:18][CH2:17]2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)OCC32C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)OCC32C(=O)Nc3ccccc32)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 69.6 %

Procedure:
A suspension of tert-butyl (3S)-3-{[1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl]oxy}pyrrolidine-1-carboxylate (0.50 g, 0.85 mmol) in methanol (20 mL) was degassed by bubbling through nitrogen for one hour before palladium hydroxide on carbon (20%, 0.084 g) was added. The mixture was stirred under 120 psi hydrogen at 60° C. for 48 h. The mixture was filtered through a pad of celite, the filtrate was concentrated in vacuo. The obtained residue was recrystallized from ethyl acetate and hexanes to afford tert-butyl (3S)-3-[(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate (0.25 g, 70%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.01 (br s, 1H), 7.29-7.09 (m, 1H), 7.12 (d, J=7.0 Hz, 1H), 7.02 (dd, J=7.5, 0.8 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 6.47 (d, J=2.1 Hz, 1H), 6.33 (dd, J=8.3, 2.1 Hz, 1H), 4.96 (d, J=9.1 Hz, 1H), 4.81 (s, 1H), 4.69 (d, J=9.1 Hz, 1H), 3.64-3.37 (m, 4H), 2.22-1.96 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 445.0 (M+23).
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([C@@H:10]1[CH2:14][C:13](=[N:15][O:16][CH3:17])[CH2:12][N:11]1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19])=[O:9])(=O)C.[OH-].[Na+]>CO>[C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][C:20]([C:18]([N:11]2[CH2:12][C:13](=[N:15][O:16][CH3:17])[CH2:14][C@H:10]2[C:8]([NH:7][CH2:6][CH2:5][OH:4])=[O:9])=[O:19])=[CH:25][CH:24]=1
Reactant: CON=C1C[C@@H](C(=O)NCCOC(C)=O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C1C[C@@H](C(=O)NCCO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.4 %

Procedure:
A solution was made containing the side-chain protected compound from the previous step, e.g. 2-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl acetate (450 mg, 10.6 mmol) in TBF (10 ml). An aqueous solution (10 ml) of sodium hydroxide (75 mg, 19 mmol) with methanol (5 ml) was added and the reaction stirred at room temperature for three hours. The solvent was removed in vacuo and the crude purified by column chromatography using THF (100%) to give the expected final product, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide (300 mg, 75%) as a white solid.