Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)#[N:2].O.O[Li].O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)#[N:2]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(C#N)cc(-c3cccc(F)c3)c2)c1F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 40 °C
Yield: 25 %

Procedure:
Ethyl 2-[3-[[3-cyano-5-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenoxy]acetate (300 mg, 0.68 mmol, 1.0 eq) was dissolved in THF (20 mL). Water (10 mL) and LiOH.H2O (110 mg, 2.7 mmol, 4 eq) were added and the solution heated at 40° C. overnight. The THF was removed in vacuo and the aqueous phase acidified to pH 6 by addition of diluted HCl. The precipitate that formed was collected by filtration, washed with water and dried to give the title compound as a white solid (70 mg, 25%).
Reaction SMILES: [C@H:1]12[CH2:23][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:17](Cl)[C:12]4=[N:11][N:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2.CC1(C)C(C)(C)OB([C:32]2[O:36][C:35]([Si](C(C)C)(C(C)C)C(C)C)=[N:34][CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C@H:1]12[CH2:23][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:17]([C:32]5[O:36][CH:35]=[N:34][CH:33]=5)[C:12]4=[N:11][N:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2
Reactant: O=C(c1nnc2c(Cl)cc(C(F)(F)F)cn12)N1C[C@@H]2C[C@H]1CO2
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: O=C(c1nnc2c(-c3cnco3)cc(C(F)(F)F)cn12)N1C[C@@H]2C[C@H]1CO2
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A mixture of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl(8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanone (46 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (51 mg), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg) and potassium carbonate (37 mg) in DME/water (2/0.5 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (2 mL), and 1N hydrochloric acid (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 1 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (16 mg).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].Cl[C:11]1[N:12]=[N:13][C:14]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[CH:15][CH:16]=1.O.C(=O)([O-])O.[Na+]>C(O)CCC.C(OC(=O)C)C>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[N:13]=[N:12][C:11]([NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:16][CH:15]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)cn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
tert-butyl carbazate, 8.98 g (67.3 mmol) and 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (11.9 g, 61.1 mmol) were mixed in 1-butanol (245 mL). This mixture was heated till 90° C. and stirred at that temperature for 16 h. The reaction mixture was cooled and water (250 mL) and ethylacetate (250 mL) were added. The biphasic mixture was neutralised with sodium hydrogencarbonate till the pH is 7. Then the organic layer was separated and the water layer was extracted with ethylacetate (250 mL). The combined organic layers were washed once with water (250 mL) and evaporated. The residue was stirred in isopropylether, filtered off and dried under vacuum. Yield: 5.9 g (20.3 mmol; 33%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC=CC=1CCC(O)=O.CC1C=CC=CC=1CCC(Cl)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][CH:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][C:45]=1[F:51].[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59][CH2:60][C:61]([N:63]=[C:64]=[S:65])=[O:62]>C1(C)C=CC=CC=1.C(O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][CH:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][C:64]([NH:63][C:61](=[O:62])[CH2:60][CH2:59][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[CH3:52])=[S:65])=[CH:46][C:45]=1[F:51]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1ccccc1CCC(=O)N=C=S
Agent: Cc1ccccc1CCC(=O)Cl
Agent: Cc1ccccc1CCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCc4ccccc4C)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methylphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methylphenyl)propanoyl isothiocyanate was prepared using the resultant 3-(2-methylphenyl)propanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(2-methylphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (45 mg, yield 54%).
Reaction SMILES: C(O[C:4](=[O:26])[C:5]([N:7]([C:14]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:23]([CH3:25])[CH3:24])C1C=CC=CC=1)=[O:6])C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:20]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:23]([CH3:24])[CH3:25])[C:14]=1[NH:7][C:5](=[O:6])[C:4]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])=[O:26])([CH3:21])[CH3:22]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C(C)C)cccc1C(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(=O)Nc1ccccc1O
Yield: 85 %

Procedure:
N-(2,6-Diisopropylphenyl)-oxanilic acid ethyl ester (2.78 g, 10 mmol, 1 eq) and 2-aminophenol (1.31 g, 12 mmol, 1.2 eq) were dissolved in toluene (50 ml), forming a suspension. To this suspension was added triethylamine (2.78 ml, 20 mmol, 2 eq). The suspension was then heated to reflux, causing the solids to dissolve. After heating at reflux overnight, the product precipitated. At this point, ethyl acetate was added until the precipitate redissolved. The solution was then washed with 2 M HCl solution (2×100 ml). The aqueous layer was then washed with ethyl acetate, and the combined organic layers were washed with brine (100 ml), and dried over MgSO4. The solvent was then removed under reduced pressure, leaving a yellowish solid. The yellowish solid was then recrystallized from toluene, producing a product, white crystalline solid (2.9 g, 8.5 mmol, 85% yield). 1H NMR (300 MHz, CDCl3) δ 9.67 (s, 1H), 8.84 (s, 1H), 8.12 (s, 1H), 7.50 (dd, J=8.25, 1.8 Hz 1H), 7.37 (t, J=7.2 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.16 (dt, J=7.7, 1.5 Hz, 1H), 6.95 (comp m, 2H), 3.03 (septet, J=6.6 Hz, 2H), 1.22 (d, J=6.9, 12H); 13C NMR (75 MHz, CDCl3) δ 158.9, 158.2, 148.2, 146.1, 129.4, 127.9, 124.2, 124.0, 122.3, 121.2, 119.1, 29.2, 23.9. Anal. Calcd for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23; O, 14.10. Found: C, 34.90; H, 4.64; N, 5.79.
Reaction SMILES: C=O.O=[C:4]([CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])C(OCC)=O>>[Cl:22][C:18]1[CH:17]=[C:16]([C:10](=[CH2:4])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(=O)C(C(=O)OCC)c1cccc(Cl)c1
Agent: C=O
Product: C=C(C(=O)OCC)c1cccc(Cl)c1

Procedure:
This compound is prepared according to the method of Klioze and Ehrgott (U.S. Pat. No. 4,216,218) from formaldehyde and diethyl 2-oxo-3-(3-chlorophenyl)succinate (Example 26, Part A).
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[NH:15][N:14]=2)=[CH:10][C:9]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1)=[O:27].Cl.Cl[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1>O1CCCC1>[F:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[NH:15][N:14]=2)=[CH:10][C:9]=1[C:26]([N:28]1[CH2:29][CH2:30][CH:31]([O:34][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[CH2:32][CH2:33]1)=[O:27]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(O)CC1
Reactant: Clc1ccncn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(Oc2ccncn2)CC1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
Sodium tert-butoxide (125 mg, 1.30 mmol) was added in one portion to 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2a) (150 mg, 0.39 mmol) in tetrahydrofuran (2 ml) at 20° C. The resulting suspension was stirred at 20° C. for 10 minutes. 4-chloropyrimidine hydrochloride (49.5 mg, 0.43 mmol) was added in one portion and the resulting mixture was stirred at 50° C. for 2 hours. Sodium tert-butoxide (41 mg, 0.43 mmol) was added in one portion followed by 4-chloropyrimidine hydrochloride (65 mg, 0.43 mmol) and the mixture heated at 50° C. for 2 hours and then stirred at ambient temperature overnight. The crude product was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. This was purified by preparative HPLC (Sunfire column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a solid (91 mg, 50.4%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.61 (1H, m), 1.66-1.73 (1H, m), 1.88-1.94 (1H, m), 2.02-2.09 (1H, m), 3.14-3.25 (1H, m), 3.32-3.48 (2H, m), 3.98-4.07 (1H, m), 4.34 (2H, s), 5.33-5.39 (1H, m), 6.95 (1H, d), 7.21-7.25 (1H, m), 7.37-7.44 (2H, m), 7.80-7.84 (1H, m), 7.87-7.90 (1H, m), 7.97 (1H, d), 8.26 (1H, d), 8.54 (1H, d), 8.79 (1H, s), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.69 (M+H 460.6).
Reaction SMILES: C([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[C:11]([NH:29][NH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]1=[O:36])C1C=CC=CC=1>C(O)C.CN(C)C=O.[Pd]>[CH2:34]([O:33][C:31]([NH:30][NH:29][C:11]1[C:10](=[O:36])[N:9]([OH:8])[C:18]2[C:13]([N:12]=1)=[CH:14][C:15]([N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH3:28])=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=2)=[O:32])[CH3:35]
Reactant: CCOC(=O)NNc1nc2cc(-n3ccnc3C)c(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)NNc1nc2cc(-n3ccnc3C)c(C(F)(F)F)cc2n(O)c1=O

Procedure:
A solution of 1.4 g (~2.8 mmol) 1-benzyloxy-3-(2-ethoxycarbonylhydrazino)-6-(2-methyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one in a mixture of 100 ml ethanol and 50 ml N,N-dimethylformamide was hydrogenated at atmospheric pressure by using 0.15 g 5% Pd-C as a catalyst. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to give the title compound as a crude product (1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])C3C([C:13]=2[CH:14]=1)=CC(Br)=CC=3.[CH3:22][N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[Sn](CCCC)(CCCC)CCCC>>[CH3:22][N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:14]=[C:13]2[C:5](=[CH:4][CH:3]=1)[N:6]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: CCCCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Product: CCCCCCn1c2ccc(Br)cc2c2cc(-c3cccn3C)ccc21

Procedure:
As shown in scheme 3, 3,6-dibromo-9-hexyl-9H-carbazole (31) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32). Then, in the presence of sodium tert-butoxide, Pd(dba)2, and tri-tert-butyl phosphine, N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32) is reacted with diphenylamine to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33). n-butyl lithium is reacted with N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33), and then tributylstannylchloride is added thereto to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributyl-stannylpyrrole (34). N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributylstannylpyrrole (34) is reacted with 5-bromo-2-thiophene-carboxaldehyde by Stille coupling reaction to obtain 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35). Finally, 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9y-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[5-(N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl)thiophen-2-yl]acrylic acid (36) is obtained.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:49]([OH:51])=[O:50])[CH2:20][CH2:21][C:22](=[O:48])[NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([P:40]([CH2:45][CH:46]=[CH2:47])([CH2:42][CH:43]=[CH2:44])=[O:41])[P:32]([CH2:37][CH:38]=[CH2:39])([CH2:34][CH:35]=[CH2:36])=[O:33])=[CH:26][CH:25]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[CH2:37]([P:32]([CH:31]([P:40]([CH2:42][CH:43]=[CH2:44])([CH2:45][CH:46]=[CH2:47])=[O:41])[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:22](=[O:48])[CH2:21][CH2:20][C@@H:19]([C:49]([OH:51])=[O:50])[NH2:18])=[CH:25][CH:26]=1)([CH2:34][CH:35]=[CH2:36])=[O:33])[CH:38]=[CH2:39]
Reactant: C=CCP(=O)(CC=C)C(Cc1ccc(NC(=O)CC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1)P(=O)(CC=C)CC=C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C=CCP(=O)(CC=C)C(Cc1ccc(NC(=O)CC[C@H](N)C(=O)O)cc1)P(=O)(CC=C)CC=C
Reaction time: 2.5 h

Procedure:
Fmoc-protected compound 105 (431 mg, 0.51 mmol) was treated with a 5% v/v solution of piperidine in DMF (2.5 mL). After stirring for 2.5 h, the reaction mixture was concentrated to dryness and purified by silica gel chromatography on a Biotage™ flash chromatography system using a gradient of 0-10% methanol in CH2Cl2. Compound 106 was obtained as a colorless oil (246 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.82-1.91 (m, 1H), 2.16-2.24 (m, 1H), 2.45-2.60 (m, 2H), 2.71 (tt, J=23.9, 6.2 Hz, 1H), 3.24 (dt, J=16.6, 6.2 Hz, 2H), 4.42 (dd, J=8.8, 4.5 Hz, 1H), 4.47-4.61 (m, 8H), 5.19-5.22 (m, 4H), 5.29-5.35 (m, 4H), 5.83-5.94 (m, 4H), 7.21 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 8.57 (bs, 1H).
Reaction SMILES: CC[O:3][CH2:4][CH3:5].[CH3:6]/[C:7](/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8]\[CH2:9]CC#N.CC(C[AlH]CC(C)C)C>CCCCCC>[CH3:6]/[C:7](/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8]\[CH2:9][CH2:5][CH:4]=[O:3]
Reactant: CCCCCCCCC/C(C)=C/CCC#N
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Product: CCCCCCCCC/C(C)=C/CCC=O
Temperature: -60 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a cooled and stirred ether (700 ml) solution of the (E)-5-methyl-4-tetradecenenitrile (4) (30.0 g, 136 mmols), an n-hexane solution of DIBAL-H (1.7 M, 123 ml, 209 mmols) was added dropwise at −60° C. under an argon gas. The mixture was stirred for 1 hour at −60° C. and for 3 hours at room temperature. The excess reagent was quenched with the addition of HCO2Et (5 ml). After 30 minutes of stirring, the mixture was poured into a saturated aqueous solution of NH4Cl (1.5 L). The resulting mixture was stirred for 20 minutes, acidified with a 20% aqueous solution (1 L) of H2SO4, and extracted with ether. The ether solution was washed with water, dried (MgSO4), and concentrated in a vacuum. The oily residue was subjected to chromatography on Florisil (450 g), and eluted with n-hexane-ether (50:1) to obtain 29.0 g (95.4%) of (E)-5-methyl-4-tetradecenal (5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:21]([O:24][C@@H:25]([CH2:27][CH2:28][CH:29]=[CH2:30])[CH3:26])[CH2:22][CH3:23])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](O)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:38][C@:39]1([C:44]([NH:46][S:47]([C:50]2([CH3:53])[CH2:52][CH2:51]2)(=[O:49])=[O:48])=[O:45])[CH2:41][C@H:40]1[CH:42]=[CH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:26][C@@H:25]([O:24][C@@H:21]([CH2:22][CH3:23])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](=[O:19])[NH:38][C@:39]1([C:44](=[O:45])[NH:46][S:47]([C:50]2([CH3:53])[CH2:52][CH2:51]2)(=[O:49])=[O:48])[CH2:41][C@H:40]1[CH:42]=[CH2:43])=[O:11])[CH2:27][CH2:28][CH:29]=[CH2:30]
Reactant: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Reaction time: 16 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,4R)-1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-((R)-hex-5-en-2-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (all material from step 3, 489 mg, 1.14 mmol), (1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide-trifluoroacetic acid salt (450 mg, 1.26 mmol), HATU (456 mg, 1.20 mmol) and DCM (10 mL). To the stirred solution was added N,N-diisopropylethylamine (0.80 mL, 4.56 mmol). The mixture was stirred for 16 h and then was transferred to a separatory funnel. The mixture was thrice washed with aq. 1N HCl; then brine. The solution was dried over MgSO4; filtered; then concentrated in vacuo to afford tert-butyl ((2S,3S)-3-((R)-hex-5-en-2-yloxy)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-1-oxopentan-2-yl)carbamate as a light-orange solid foam (569 mg).
Reaction SMILES: Br[C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([Br:7])[N:6]=1.[O-]S([O-])=O.[Na+].[Na+]>O>[Br:7][C:5]1[N:6]=[CH:2][NH:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1[nH]c(Br)nc1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1[nH]cnc1Br
Temperature: 90 °C
Reaction time: 10 h
Yield: 60.4 %

Procedure:
A mixture of ethyl 2,4-dibromo-1H-imidazole-5-carboxylate (9 g, 30.21 mmol, 1.00 equiv) and Na2SO3 (7.2 g, 2.00 equiv) in water (80 mL) was stirred at 90° C. for 10 h. The reaction was cooled to room temperature and the solid was collected by filtration, washed with 4×20 mL of water then air-dried to afford 4.0 g (60%) of ethyl 4-bromo-1H-imidazole-5-carboxylate as a white solid. 1H-NMR (300 MHz, CD3OD): δ 7.80 (s, 1H), 4.42-4.35 (m, 2H), 1.40 (t, J=9.6 Hz, 3H) ppm. LCMS (method A, ESI): RT=1.13 min, m/z=219.0 [M+H]+.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[ClH:1].[C:16]([O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13]2)=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(CN2CC=CCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(CN2CC=CCC2)cc1
Reaction time: 17 h

Procedure:
A mixture of 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride (1.0 g.), pyridine (7 ml.) and acetic anhydride (7 ml.) was kept at 20°-25° C. for 17 hours. The solid which formed was collected and washed with ether (50 ml.) to yield 1-(4-acetoxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride (1.1 g.), m.p. 220°-222° C.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][C:12]#[N:13]>>[C:1]1([N:7]2[C:12]([NH2:13])=[CH:11][C:10]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)c1cccs1
Product: Nc1cc(-c2cccs2)nn1-c1ccccc1

Procedure:
Phenyl hydrazine and 3-oxo-3-(thiophen-2-yl)propanenitrile were combined according to literature procedures to yield 1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-5-amine. See WO 2006/071940.
Reaction SMILES: [Br-].C([O:6][C:7](=[O:54])[C:8]([O:11]/[N:12]=[C:13](/[C:41]1[N:42]=[C:43]([NH:46]C(OC(C)(C)C)=O)[S:44][CH:45]=1)\[C:14]([NH:16][C@@H:17]1[C:20](=[O:21])[N:19]([S:22]([OH:25])(=[O:24])=[O:23])[C@@H:18]1[CH2:26][N:27]1[CH:31]=[C:30]([CH2:32][NH:33][C:34](=[O:40])[CH2:35][N+:36]([CH3:39])([CH3:38])[CH3:37])[N:29]=[N:28]1)=[O:15])([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:46][C:43]1[S:44][CH:45]=[C:41](/[C:13](=[N:12]/[O:11][C:8]([C:7]([OH:54])=[O:6])([CH3:9])[CH3:10])/[C:14]([NH:16][C@H:17]2[C@@H:18]([CH2:26][N:27]3[CH:31]=[C:30]([CH2:32][NH:33][C:34](=[O:40])[CH2:35][N+:36]([CH3:37])([CH3:38])[CH3:39])[N:29]=[N:28]3)[N:19]([S:22]([O-:25])(=[O:24])=[O:23])[C:20]2=[O:21])=[O:15])[N:42]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cc(CNC(=O)C[N+](C)(C)C)nn2)cs1
Agent: CC[SiH](CC)CC
Agent: [Br-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1Cn1cc(CNC(=O)C[N+](C)(C)C)nn1)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
To a slurry of 2-(((1-(((2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxo-1-sulfoazetidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-N,N,N-trimethyl-2-oxoethanaminium bromide (50 mg, 0.0635 mmol) In DCM (640 μL) at 0° C. was added TFA: DCM (1:1, 1.92 mL) followed by triethylsilane (31 μL, 0.19 mmol). The reaction mixture was stirred at 0° C. for 30 min and slowly warmed to room temperature. After 2 h at rt, it was concentrated in vacuo and triturated with MTBE:Heptane (1:2) whereupon a solid was observed. The crude solid was purified by reverse phase prep HPLC (C18 column, acetonitrile: water solvent system with 0.1% formic acid modifier) to afford the title compound (11 mg, 27%). LCMS: m/z=630.9 (M−1); 1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J=8.6 Hz, 1H), 9.06 (t, J=5.6 Hz, 1H), 8.06 (s, 1H), 7.32 (s, 2H), 6.71 (s, 1H), 5.28 (dd, J=8.6, 5.5 Hz, 1H), 4.89-4.64 (m, 2H), 4.38 (t, J=5.1 Hz, 2H), 4.22 (q, J=5.3 Hz, 1H), 4.08 (s, 2H), 3.22 (s, 9H), 1.33 (s, 3H), 1.26 (s, 3H).