Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[C:32]([CH3:39])[CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][C:32]=3[CH3:39])[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: Cc1cc(F)ccc1C(=O)O
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(F)cc3C)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(4-fluoro-2-methyl-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-fluoro-2-methylbenzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown oil. MS m/e: 549.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13](=[O:16])[CH:12](C)[NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC(N2C(=O)C(=O)C(C3C=CC=CC=3)N2)=CC=1)([O-])=O.[N+](C1C=CC(N2C(=O)C(=O)C(C3C=CC(C)=CC=3)N2)=CC=1)([O-])=O.[N+](C1C=CC(N2C(=O)C(=O)C(C3C=CC=C(OC)C=3)N2)=CC=1)([O-])=O.[N+](C1C=CC(N2C(=O)C(=O)C(C3C=CC(OC)=CC=3)N2)=CC=1)([O-])=O.[N+](C1C=CC(N2C(=O)C(=O)C(C3C=CC=C([N+]([O-])=O)C=3)N2)=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[O:16])[CH2:12][NH:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1NN(c2ccc([N+](=O)[O-])cc2)C(=O)C1=O
Agent: COc1ccc(C2NN(c3ccc([N+](=O)[O-])cc3)C(=O)C2=O)cc1
Agent: COc1cccc(C2NN(c3ccc([N+](=O)[O-])cc3)C(=O)C2=O)c1
Agent: Cc1ccc(C2NN(c3ccc([N+](=O)[O-])cc3)C(=O)C2=O)cc1
Product: O=C1CNN(c2ccc([N+](=O)[O-])cc2)C1=O

Procedure:
1-(4′-nitrophenyl)-3-methyl-4,5-pyrazolinedione; 1-(4′-nitrophenyl)-3-phenyl-4,5-pyrazolinedione; 1-(4′-nitrophenyl)-3-(4′-methylphenyl)-4,5-pyrazolinedione; 1-(4′-nitrophenyl)-3-(3′-methoxyphenyl)-4,5-pyrazolinedione; 1-(4′-nitrophenyl)-3-(4′-methoxyphenyl)-4,5-pyrazolinedione; 1-(4′-nitrophenyl)-3-(3′-nitrophenyl)-4,5-pyrazolinedione;
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:12]4[S:13][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][N:11]=4)[N:15]=[CH:16]3)[N:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.088 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (THF/hexane) to yielded the title compound as a light brown solid (0.03 g, 14%). MS (ISN) 485.2 [(M−H)−]; mp 263° C.
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][CH2:6][C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CO.C(OCC)C>[Br:5][CH2:6][CH:7]([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)C(O)CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of sodium cyanoborohydride (17.72 g, 282.0 mmol) in anhydrous MeOH (160 mL) under an atmosphere of nitrogen was added ethyl bromopyruvate (32.25 mL, 256.4 mmol, 80-85%) in anhydrous MeOH (160 mL). The mixture was treated with 1N HCl in diethyl ether to pH 4 and stirred for 1 h at 0° C. The solvent was removed in vacuo, and the resulting slurry was partitioned between diethyl ether and saturated aqueous NH4Cl solution. The aqueous layer was extracted several times into diethyl ether, and the organic extracts were combined, dried over Na2SO4 and concentrated to a pale yellow oil. The oil was diluted with diethyl ether (300 mL) and chilled to −78° C. for 1 hour. The resulting precipitate was collected by filtration to afford the alcohol as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 5.99 (dd, J=1.2, 6.0 Hz, 1H), 4.43-4.39 (m, 1H), 4.21-4.08 (m, 2H), 3.69 (d, J=0.8 Hz, 2H), 1.23-1.18 (m, 3H).
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1.C(O)(=O)C.Cl>O>[C:2]([N:1]=[C:4]([NH2:5])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)#[N:3]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(NC(N)=NC#N)cc1
Yield: 24.8 %

Procedure:
A solution of sodium dicyanamide (0.5 g) in water (20 ml) was added to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (1.0 g) in a mixture of aqueous acetic acid (20 ml) and 10M hydrochloric acid (0.5 ml). The resultant solution was stirred at room temperature for 3 days. A precipitate formed which was collected, washed with water and then with ethanol, and dried to give the title compound (0.33 g), thin layer chromatography and nuclear magnetic resonance spectroscopy showed this to be consistent with the product of Example 6, m.p. 257°-260° C. (decomp).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[CH3:30][S:31][CH2:32][CH2:33][CH2:34][NH2:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:35][CH2:34][CH2:33][CH2:32][S:31][CH3:30])=[O:17])=[N:14][CH:15]=1
Reactant: CSCCCN
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CSCCCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.3 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (222 mg, 0.527 mmol) obtained in Example 12 in methylene chloride (5 ml), 3-methylthiopropylamine (66 mg, 0.632 mmol), 1-hydroxybenzotriazole (71 mg, 0.527 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.632 mmol) and 4-methylmorpholine (69 μl, 0.632 mmol) were added. The reaction solution was stirred for 3 days at room temperature, and was concentrated under reduced pressure. The concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with ethyl acetate:methylene chloride (=1:20) was concentrated under reduced pressure, to obtain the title compound (253 mg, 0.497 mmol, 94%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Cl.[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23])([O-:18])=[O:17].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc([N+](=O)[O-])c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a round bottom flask was added 4-chloro-3-(trifluoromethyl)-phenyl isocyanate (443 mg, 2.0 mmol, 1.0 eq.) and acetonitrile (3.0 mL). The solution was cooled to 0° C. before a mixture of 3-nitrobenzylamine HCl (377 mg, 2.0 mmol, 1.0 eq.), DMP (1.0 mL), and triethyl amine (0.27 mL, 2.0 mmol, 1.0 eq.) was added dropwise. The reaction was then allowed to warm to RT slowly, and then stirred for an additional 2 h. The reaction was then concentrated to remove acetonitrile. EtOAc and water were added, and the mixture was extracted, washed with brine, dried with Na2SO4, and concentrated to give an oil. Upon sitting at RT, the oil crystallized to give urea 26 (728 mg, 97% yield). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 374.1 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 9.23 (br. s, 1H), 8.14 (m, 1H), 8.09 (m, 1H), 8.04 (d, 1H), 7.74 (d, 1H), 7.62 (m, 2H), 7.52 (d, 1H), 7.04 (br t, 1H), 4.40 (s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([OH:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CC(C)([O-])C.[K+].Br[CH2:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[N:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)C(=O)CBr
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)n(-c2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1

Procedure:
Crude (S)-2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester (44 g) was dissolved in DMF and treated with 12.2 g potassium tert-butoxide and 14.7 ml 1-bromopinacolone. After 2 h the solvent was removed in vacuo, the residue taken up in DCM and extracted with water. The crude product obtained after evaporation of the solvent was purified by flash column chromatography on silica eluting with heptane/ethyl acetate giving the title compound as colorless oil (45 g).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1.[Li]CCCC.[NH4+].[Cl-].[CH3:18][CH2:19][O:20]CC>CCCCCC>[Br:10][C:8]1[CH:9]=[C:4]([C:19](=[O:20])[CH3:18])[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCOCC
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 3,5-dibromopyridine (2.39 g, 10.00 mmol) in ether (70.0 mL) was treated at −78° C. with n-BuLi (4.0 mL of a 2.5M solution in hexane, 10.00 mmol). The reaction mixture was stirred for 30 min before N,N-dimethylacetaminde (1.50 mL, 16.13 mmol) was added and the solution was then allowed to warm to rt over 1 h. Sat. aq. NH4Cl was then added and the aq. layer was extracted with Et2O (2×50 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 hept-EA) gave the title compound as a white solid. TLC: rf (19:1 CH2Cl2-MeOH)=0.57. LC-MS-conditions 02: tR=0.80 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1Br.[CH:10]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)=[O:11]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:10]=[O:11])[CH:17]=1
Reactant: Fc1cccc(F)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Product: O=Cc1cccc(-c2c(F)cccc2F)c1

Procedure:
The title compound was synthesized in the same manner as in Reference Example 206 from 1,3-difluoro-2-bromobenzene and 3-formylphenylboronic acid. colorless oil (3.0 g, yield 93%).
Reaction SMILES: CC1C=CC(S([CH2:11][N+:12]#[C-:13])(=O)=O)=CC=1.[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH3:15].CCOCC.CS(C)=O.[H-].[Na+]>CCOCC.O>[CH2:14]([O:16][C:17]([C:18]1[C:19]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:13][NH:12][CH:11]=1)=[O:27])[CH3:15]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c[nH]cc1-c1ccc(C)cc1
Reaction time: 3 h
Yield: 74.5 %

Procedure:
A solution of TosMIC (15.7 g, 80.5 mmol) and 5 (14.6 g, 76.7 mmol) in a dry ether/DMSO (2:1) (154 mL) solution was added dropwise under argon to a stirred solution of NaH (2.39 g, 99.7 mmol) in ether (70 mL). The mixture started to reflux due to the exothermic reaction. After 3 h, water (200 mL) was carefully added to the mixture and the aqueous phase was extracted with ether and CH2Cl2. The combined organic extracts were dried (Na2SO4), concentrated, and chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to give a light brown solid (13.1 g, 74%): mp 154-155° C.; 1H NMR δ 1.25 (t, J=7.2 Hz, 3H), 2.36 (s, 3H), 4.22 (q, J=7.2 Hz, 2H), 6.75-6.77 (m, 1H), 7.16 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.46-7.48 (m, 1H), 8.38-8.54 (br, 1H); 13C NMR δ 14.5, 21.4, 59.8, 113.9, 118.3, 125.4, 126.8, 128.6, 129.4, 132.0, 136.3, 165.2; Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.11; H, 6.59; N, 6.12.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][CH2:21][CH3:22])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1>CO>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][CH2:21][CH3:22])[CH:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[OH:12])=[CH:6][CH:5]=1
Reactant: CCCC(C(=O)c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(c1ccc(Br)cc1)C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (917 mg, 24.25 mmol) was added to a MeOH solution (25 ml) containing the intermediate from Step C (6.53 g, 18.66 mol). After stirring for 1 hour at room temperature the solution was concentrated and the residue partitioned between water and EtOAc. The organic phase was washed with water, brine and dried over Na2SO4. The filtered solution was concentrated to give the title compound as an 8:1 mixture of diastereomers which was used in the next step without further purification. 1H NMR for major diastereomer (500 MHz, CDCl3): δ 7.44 (d, J=8.1 Hz, 2H); 7.30 (d, J=8.5 Hz, 2H); 7.19 (d, J=8.5 Hz, 2H); 7.07 (d, J=8.1 Hz, 2H); 4.71-4.68 (m, 1H); 2.81-2.74 (m, 1H); 1.56-1.48 (m, 1H); 1.42-1.32 (m, 1H); 1.12-0.95 (m, 2H); 0.75 (t, J=7.3 Hz, 3H). LC1 4.00 min. (M−OH)=335
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.[C:43]([O:48][CH2:49][O:50][C:51](=[O:71])[C@H:52]([OH:70])[CH2:53][C@H:54]([NH2:69])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[CH:63]=2)=[CH:58][CH:57]=1)(=[O:47])[CH2:44][CH2:45][CH3:46].CCN(C(C)C)C(C)C>>[C:43]([O:48][CH2:49][O:50][C:51](=[O:71])[C@H:52]([OH:70])[CH2:53][C@H:54]([NH:69][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[CH:63]=2)=[CH:58][CH:57]=1)(=[O:47])[CH2:44][CH2:45][CH3:46]
Reactant: CCCC(=O)OCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)OCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.8 %

Procedure:
HATU (37.9 mg, 99.6 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (14.9 mg, 83 μmol) in DMF (0.5 mL, 6.4 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. (2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid butyryloxymethyl ester (27.9 mg, 66.4 mol) was added to the mixture, followed by DIPEA (35 μL, 0.2 mmol) dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to yield a yellow liquid, which was purified by preparative HPLC to yield the title compound as a white solid (5.2 mg, purity 98.2%). MS m/z [M+H]+ calc'd for C29H29ClN4O7, 581.17. found 581.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.[ClH:13]>>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: Cl
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Product: Cc1cc(Cl)c(Br)c[n+]1[O-]
Temperature: 25 °C

Procedure:
5-Bromo-2-methyl-4-nitropyridine oxide (7.0 g, 30 mmol) was refluxed in conc. HCl (80 mL) for 16 hrs. The mixture was allowed to cool to room temperature, partially concentrated and then neutralized by NaOH (10N) to pH 7. The crude was partitioned between CHCl3 and water. The organic solution was separated, dried and concentrated to yield 5-bromo-4-chloro-2-methylpyridine oxide as a white solid (6.71 g). MS [M+H]+: 223.7; tR=1.91 min. (method 1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:32]#[C:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:23][C@H:22]([O:24][CH2:25]C2C=CC=CC=2)[CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].ClC1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(#N)C.FC(F)(F)C(O)=O>O>[CH3:36][C:34]([CH3:35])([CH3:37])[C:33]#[C:32][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C@H:20]2[CH2:21][C@H:22]([O:24][C:25]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH2:23]2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1C[C@H](OCc2ccccc2)C1
Reactant: Clc1ncccn1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2C[C@H](Oc3ncccn3)C2)c(C(=O)O)s1

Procedure:
The title compound was synthesized in a manner analogous to Example 20, using 3-[(trans-3-benzyloxy-cyclobutyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester in place of 3-[(cis-3-benzyloxy-cyclobutyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester and 2-chloro-pyrimidine in place of 3-fluoro-pyridine: MS (m/z): 493.8 [M−H]−; HPLC retention time: 3.53 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: C(OC(=O)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[N:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][N:25]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:8]([NH:7][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[N:25]=[CH:26][C:27]([C:30]([NH2:31])=[O:32])=[N:28][CH:29]=2)=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(Oc2cnc(C(N)=O)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cnc(Oc2ccc(CNCCc3ccccc3)cc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.8 %

Procedure:
Dissolve [4-(5-carbamoylpyrazin-2-yloxy)benzyl]phenethylcarbamic acid tert-butyl ester (0.015 g, 0.0334 mmol) in dichloromethane (1 mL). Add TFA (1 mL). Stir at room temperature for 6 hours. Load directly onto an SCX (5 g) column. Wash the column with methanol thien elute with 2.0 M NH3 in methanol to give the title compound (11.5 mg, 98%): MS ES+ 348.9 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.4 min, 98.4 purity.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH2:22][C:23](Cl)=[N:24][OH:25])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.[C:27]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)#[CH:28]>O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[CH2:22][C:23]1[CH:28]=[C:27]([C:29]2[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[O:25][N:24]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)c(F)c2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (3-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Manufacturing Example 94-1-3 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added tiethylamine (142 μL, 1.02 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (18.0 mg, 13.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][C:9]=2[C:13]([O:15]CC)=O)=[CH:4][CH:3]=1.C(OCC)(=O)C.O.[NH2:25][NH2:26]>O1CCOCC1.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][C:9]=2[C:13]([NH:25][NH2:26])=[O:15])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1occc1-c1ccc(N)cc1
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NNC(=O)c1occc1-c1ccc(N)cc1

Procedure:
After ethyl 3-(4-aminophenyl)-2-furan carboxylate (7 g) was dissolved in a mixed solvent of 1,4-dioxane (7 mL) and ethanol (3 mL), hydrazine monohydrate (11.4 mL) was added. The mixture was heated at reflux for 6 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with a saturated sodium chloride solution. Thereafter, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure, thereby giving 3.8 g of the target compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[Cl:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:17]([CH3:18])[C:16]([Cl:15])=[C:20]([CH3:21])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(=O)C(Cl)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2nc(SCc3ccccc3)nn2c(C)c1Cl
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To a suspension of 153 g (0.74 mol) 3-amino-5-benzylthio-1,2,4-triazole in 250 ml of glacial acetic acid was added to 100 g (0.74 mol) of 3-chloro-2,4-pentanedione in a dropwise manner. The reaction mixture was heated at reflux for 18 hours and cooled to room temperature. The reaction mixture was poured over ice and the oil which separated solidified upon stirring. The solid was collected by filtration and recrystallized from methanol to yield 116 g (79%) of the desired product as an off white solid, m.p. 164°-166° C. IR and 1H NMR spectra were in agreement with the assigned structure.