Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:25][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][C:6]1=O)C.C(O)(=O)C.Cl.[C:32]([NH:36][NH2:37])([CH3:35])([CH3:34])[CH3:33]>C(O)C>[C:32]([N:36]1[C:6]2[CH:7]=[CH:8][C:9]3([CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:13][CH2:14]3)[CH2:25][C:5]=2[CH:4]=[N:37]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CN(C)C=C1CC2(C=CC1=O)CCN(C(=O)OCc1ccccc1)CC2
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)n1ncc2c1C=CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Temperature: 25 °C
Yield: 78.9 %

Procedure:
Benzyl 10-((dimethylamino)methylene)-9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (59.2 g, 167 mmol) was dissolved in ethanol (835 mL). To the solution was added acetic acid (20 mL, 345 mmol) and tert-butylhydrazine hydrochloride (29.1 g, 234 mmol). The reaction was heated to reflux for 1 hour. The reaction was cooled to room temperature and concentrated to an orange oil. Purification by flash column chromatography (20-40% ethyl acetate/heptanes) afforded the title compound (50 g, 79%) as a pale yellow solid. +ESI (M+H) 380.5; 1H NMR (400 MHz, CDCl3, δ): 7.26-7.40 (m, 5 H), 7.17 (s, 1 H), 6.66 (d, J=9.95 Hz, 1 H), 5.77 (d, J=10.15 Hz, 1 H), 5.12 (s, 2 H), 3.38-3.64 (m, 4 H), 2.58 (s, 2 H), 1.60 (s, 12 H), 1.50 (br. s., 1 H).
Reaction SMILES: [N:1]([C@H:4]([C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[C:2]=[S:3].[C:26]([NH:29][NH2:30])(=O)[CH3:27]>CCO>[CH3:27][C:26]1[S:3][C:2]([NH:1][C@H:4]([C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:18][CH:19]=2)[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[N:30][N:29]=1
Reactant: CC(=O)NN
Reactant: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Solvent: CCO
Product: Cc1nnc(N[C@@H](Cc2ccc([N+](=O)[O-])cc2)c2csc(-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A solution of (S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole, 53, (332 mg, 0.876 mmol) and acetic hydrazide (65 mg, 0.876 mmol) in EtOH (5 mL) is refluxed for 2 hours. The solvent is removed under reduced pressure, the residue is dissolved in POCl3 (3 mL) and the resulting solution is stirred at room temperature for 18 hours after which the solution is heated to 50° C. for 2 hours. The solvent is removed in vacuo and the residue is dissolved in EtOAc (40 mL) and the resulting solution is treated with 1N NaOH until the pH remains approximately 8. The solution is extracted with EtOAc. The combined aqueous layers are washed with EtOAc, the organic layers combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford 0.345 g (93% yield) of the desired product as a yellow solid. 1H NMR (CDCl3) 8.09 (d, J=8.4 Hz, 2H), 7.91 (m, 2H), 7.46 (m, 4H), 7.44 (s, 1H), 5.23 (m, 1H), 3.59 (m, 2H), 2.49 (s, 3H). ESI+MS 424 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].COCCN(S(F)(F)[F:33])CCOC>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cn2)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(C#N)cn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a solution of tert-butyl 4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound 26.2, 1 g, 3.13 mmol, 1.00 equiv, 95%) in dichloromethane (50 mL) under nitrogen at −78° C. was added dropwise a solution of bis(2-methoxyethyl)aminosulfur trifluoride (830 mg, 3.75 mmol, 1.20 equiv) in dichloromethane (10 mL) during the course of 1 min. The resulting mixture was stirred for 1 h at −78° C. The reaction was then carefully quenched by dropwise addition of water and washed with 2×20 mL of sodium bicarbonate(aq) followed by 3×20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10) to yield 0.38 g (38%) of the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C@H:7]2[C@H:8]([O:16][CH3:17])[O:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:6]2[CH2:5][CH:4]=1.C(N(CC)CC)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].Cl>CN(C)C=O>[Si:25]([O:1][CH2:2][C:3]1[C@H:7]2[C@H:8]([O:16][CH3:17])[O:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:6]2[CH2:5][CH:4]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO)=CC[C@H]12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO[Si](C)(C)C(C)(C)C)=CC[C@H]12
Reaction time: 1 h
Yield: 93.9 %

Procedure:
3 g (12.5 mmol) of methyl (1R,4aS,7aS)-7-hydroxymethyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran4-carboxylate was dissoved in 50 ml of dimethylformamide and 1.9 ml (13.8 mmol) of triethylamine was added thereto under nitrogen atmosphere. The reaction solution was stirred for one hour and then 2.07 g (13.8 mmol) of t-butyldimethylsilylchloride dissolved in 10 ml of dimethylformamide was added dropwise thereto. After stirring for 3 hours, 1N-aqueous hydrochloric acid solution was added in order to stop the reaction. Organic layer was extracted by the addition of diethylether and then it was washed with saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 4.16 g (Yield 94%) of methyl (1R,4aS,7aS)-7-(t-butyldimethylsilyloxymethyl)-1 -methoxy-1,4a,5,7a-tetrahydrocyclo penta[c]pyran-4-carboxylate as a colorless oil.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]=[CH:10][CH:11]=[N:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([Li])[CH2:24][CH2:25][CH3:26].[CH3:28][CH2:29][CH2:30][CH2:31]CC.C(OCC)C>C1COCC1.O>[C:1]1([CH3:22])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][CH:10]([CH:11]([NH:12][C:13]1[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=1[CH3:19])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Cc1cc(C)c(N=CC=Nc2c(C)cc(C)cc2C)c(C)c1
Reactant: CCCCCC
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(Nc1c(C)cc(C)cc1C)C(CCCC)Nc1c(C)cc(C)cc1C
Temperature: -78 °C
Yield: 65 %

Procedure:
In a 150 ml Schlenk vessel, N,N′-dimesitylethanediimine (2.92 g; 10 mmol) was dissolved in 30 ml of THF under nitrogen as protective gas and the solution was cooled to −78° C. 1.6 M Butyllithium in hexane (13.8 ml; 22 mmol) was then slowly added to the resulting suspension at −78 ° C. The reaction mixture was warmed to −10° C. over a period of one hour and was stirred at this temperature for a further hour. The solvent was then taken off and 15 ml of diethyl ether and 10 ml of water were then added on an ice bath. The aqueous layer was extracted with 2×5 ml of ether and the combined extracts were dried over powdered NaOH. Taking off the solvent left an orange oil. The crude product was chromatographed on a silica gel column (50 g) and eluted with petroleum ether/toluene (1:1). Taking off the solvent gave yellow crystals of dl-N,N′-dimesityldecane-5,6-diamine (2.67 g; 65%).
Reaction SMILES: [Si](O[C@@H](CC)C(O)=O)(C(C)(C)C)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][C@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH3:36])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1>>[NH2:25][CH2:26][CH2:27][CH2:28][C@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH2:36][CH3:2])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Product: CC[C@H](OC)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as in Example 71 using (S)-2-(tert-butyldiphenylsilyloxy)butanoic acid in place of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 434 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 3H), 7.35 (app t, 2H, J=8 Hz), 7.28 (m, 1H), 7.13 (m, 2H), 4.53 (dd, 1H, J=7 Hz, 4 Hz), 3.40 (s, 3H), 3.26 (m, 1H), 2.86 (m, 2H), 2.42 (m, 1H), 1.94 (m, 2H), 1.74 (m, 2H), 0.96 (t, 3H, J=8 Hz). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]3[N:10](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=[C:12]([C:13]4[C:14]([CH3:27])=[N:15][N:16]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=5)[C:17]=4[CH3:18])[C:7]3=[CH:6][C:5]=2[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]3)=[CH:40][CH:39]=2)[CH2:3][CH2:2]1.[OH-].[Li+]>CO.O>[CH:1]1([C:4]2[N:9]=[C:8]3[NH:10][CH:11]=[C:12]([C:13]4[C:14]([CH3:27])=[N:15][N:16]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=5)[C:17]=4[CH3:18])[C:7]3=[CH:6][C:5]=2[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:45][CH2:46][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:48][CH2:49]3)=[CH:40][CH:39]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)c(C4CC4)nc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2nc(C3CC3)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 16.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(6-cyclopropyl-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (111 mg, 0.14 mmol) was hydrolyzed by lithium hydroxide (17.6 mg, 0.42 mmol), in methanol/water (3/2 ml) to afford 14 mg of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 8.7 (b, 1H), 7.52 (s, 1H), 7.40-7.37 (m, 2H), 7.107-7.099 (d, 1H), 7.002-6.9 (m, 3H), 6.9-6.8 (m, 1H), 5.26 (s, 2H), 3.62-3.59 (t, 3H), 3.209-3.117 (t, 3H), 2.22 (s, 1H), 3.12 (s, 3H), 1.496 (s, 9H), 1.16-1.15 (m, 2H), 0.91-0.87 (m, 2H). MS: m/z=621.3 (M+1).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[C:17](=[O:22])[O:18][CH:19]([OH:21])[CH:20]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[C:29](Cl)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>O1CCCC1>[C:29]([O:21][CH:19]1[O:18][C:17](=[O:22])[C:16]([CH2:15][O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:20]1)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCC(=O)OCC1=CC(O)OC1=O
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)OCC1=CC(OC(=O)CCCCCCCCCCC)OC1=O
Temperature: 25 °C

Procedure:
To a stirred solution of 3-dodecoyloxymethyl-5-hydroxy-2(5H)-furanone (0.098 g., 0.313 mmol) and pyridine (0.026 g., 0.313 mmol) in 3 ml anhydrous tetrahydrofuran at 0° was added lauroyl chloride (0.082 g., 0.376 mmol). The solution was allowed to warm to room temperature, stirred until starting material was no longer visible by TLC, and partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed twice with 5% sodium bicarbonate solution, twice with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a solid residue. This material was further purified by recrystallization (acetone/methanol) to give the desired ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].Cl>O1CCOCC1.O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(I)cc1C(=O)O)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To an ice cooled solution of 2-amino-5-iodobenzoic acid (540 mg, 2.03 mmol) and sodium bicarbonate (170 mg, 2.03 mmol) in 9 mL of dioxane/water (2:1) was added 2,6-dichlorophenylisocyanate (468 mg, 2.44 mmol). The reaction was slowly warmed to room temperature while stirring overnight. The reaction mixture was acidified with 2N HCl and extracted with EtOAc. The product, which partially precipitated from the organic layer, was filtered and washed with EtOAc (173 mg). The filtrate was dried (MgSO4) and evaporated under reduced pressure. Trituration of the residue with Et2O afforded an additional 543 mg of 2-[3-(2,6-dichlorophenyl)ureido]-5-iodobenzoic acid: 1H-NMR (300 MHz, d6-DMSO) δ 7.37 (t, J=8 Hz, 1H), 7.58 (d, J=8 Hz, 2H), 7.84 (dd, J=8 Hz, 4 Hz, 1H), 8.19 (d, J=4 Hz, 1H), 8.28 (d, J=8 Hz, 1H), 9.60 (s, 1H, exchangeable), 10.50 (s, 1H, exchangeable).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[SH:25])[C@@H:20]([NH:26][C:27](=[O:57])/[C:28](/[C:50]2[N:51]=[C:52]([NH2:56])[S:53][C:54]=2[Cl:55])=[N:29]\[O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]3=[O:58])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:59]([O:63][C:64]([NH:66][CH2:67][CH2:68][S:69][CH2:70][C:71]1[CH:72]=[N:73][CH:74]=[CH:75][C:76]=1Cl)=[O:65])([CH3:62])([CH3:61])[CH3:60].O>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[S:25][C:76]2[CH:75]=[CH:74][N:73]=[CH:72][C:71]=2[CH2:70][S:69][CH2:68][CH2:67][NH:66][C:64]([O:63][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:65])[C@@H:20]([NH:26][C:27](=[O:57])/[C:28](/[C:50]2[N:51]=[C:52]([NH2:56])[S:53][C:54]=2[Cl:55])=[N:29]\[O:30][C:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:19]3=[O:58])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S)CCC23)c(Cl)s1
Reactant: CC(C)(C)OC(=O)NCCSCc1cnccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCSCc1cnccc1SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3nc(N)sc3Cl)C2CC1
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]-acetamido]-3-mercapto-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (3.0 g, 0.0036 mol) in dimethylformamide (30 mL) was added 3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4-chloropyridine (1.3 g, 0.0043 mol) at room temperature. After stirring overnight, the reaction mixture was treated with water (200 mL), and the solid that formed was filtered and dried to afford the crude title compound (2.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27]C=1)[C:23](O)=[O:24].C1C=[N:35]C2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][N:35]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:21]=2)=[CH:4][C:3]=1[B:9]1[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[O:13]1
Reactant: On1nnc2cccnc21
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(C(F)(F)F)c2)cc1B1OC(C)(C)C(C)(C)O1
Yield: 91 %

Procedure:
To a mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 equiv.) and 3-(trifluoromethyl)benzoic acid (1.1 equiv.) in DMF (0.27 M) was added HOAt (1.3 equiv.) and EDC (1.3 equiv.) After 3 h the reaction mixture was diluted with water and then extracted with EtOAc. The organic phase was washed sequentially with 1 M aqueous sodium hydroxide and brine and was then dried over sodium sulfate. The solution was concentrated and dried under vacuo to give N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide in 91% yield. LCMS (m/z) (M+H)=407.1, Rt=1.13 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])[CH:7]=1)=[O:19]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)ccn1
Solvent: c1ccncc1
Product: O=C(Nc1ccnc(NC(=O)C2CC2)c1)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a cooled (0° C.) solution of N-(2-aminopyridin-4-yl)-2,4,6-trichlorobenzamide (82 mg, 0.26 mmol) in pyridine (5 mL) under nitrogen atmosphere was added cyclopropanecarbonyl chloride (41 mg, 0.39 mmol) dropwise. The mixture was allowed to warm to room temperature, stirred overnight, and then quenched with water (15 mL). The reaction was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford the desired product (10 mg, 17% yield). 1H NMR (500 MHz, CDCl3): δ 8.19 (d, J=1.5 Hz, 1H), 8.13 (d, J=6.0 Hz, 1H), 7.52 (s, 2H), 7.49-7.47 (m, 2H) 1.78 (s, 1H), 0.88-0.86 (m, 2H), 0.81-0.78 (m, J=9.5 Hz, 2H). LCMS (ESI) m/z: 367.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([OH:22])[CH:21]=1)=[O:15].[OH-].[K+].Cl>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:13][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:22])[CH:21]=2)=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CC(=O)c1cccc(O)c1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=CC(=O)c2cccc(O)c2)cc1OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
A solution of 3,4-Dimethoxybenzaldehyde (16.6 g, 100 mmol) in EtOH (75 mL) was treated with 3-Hydroxyacetophenone (13.6 g, 100 mmol) and the resulting solution cooled to 0° C. in an ice bath. A 200 mL solution of aqueous KOH (28 g, 500 mmol) was added slowly and the resulting bright red solution was allowed to stir overnight (16 h) at room temperature. The mixture was then acidified to pH 5 by the dropwise addition of concentrated HCl and the resulting suspension extracted with EtOAc (2×200 mL). The combined organic extract was washed with a saturated NaCl solution (2×100 mL), dried over MgSO4, filtered, evaporated, and flash chromatographed (silica gel, 30% 50% EtOAc/hexanes) to give crude material. The crude solid was crystallized from EtOAc to afford 13.9 g (49%) of a yellow colored solids: IR (neat) 3420, 1650, 1575, 1510, 1265, 1140 cm−1; 1H NMR (CDCl3, 300 MHz) 7.80 (d, J=15.6 Hz, 1H), 7.68 (s, 1H), 7.59, (d, J=7.7 Hz, 1H), 7.42-7.36 (m, 2H), 7.24 (dd, J=8.3, 1.8 Hz, 1H), 7.16-7.13 (m, 2H), 6.90 (d, J=8.3 Hz, 1H), 6.82 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H); 13C NMR (CDCl3, 75 MHz) 191.3, 157.0, 152.0, 149.7, 146.1, 140.1, 130.2, 128.2, 123.8, 121.2, 120.7, 120.3, 115.7, 111.6, 110.7, 56.4.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH3:19])[C:8]=2[CH:20]=O)=[C:5]([CH3:22])[O:4][N:3]=1.Cl.[NH2:24][OH:25].N1C=CC=CC=1.Cl>C(O)C.C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH3:19])[C:8]=2[CH:20]=[N:24][OH:25])=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: NO
Reactant: Cc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C=O
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C=NO
Temperature: 150 °C
Yield: 50 %

Procedure:
The semi-crude 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde was mixed with hydroxylamine hydrochloride (100 mg, 0.014 mmol) and pyridine (0.15 mL) in dry ethanol (1.5 mL) and heated at 150° C. for 10 min in the microwave. 1 M HCl and CH2Cl2 were added and the phases were separated. The oxime was purified on preparative IIPLC to give E3 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde oxime (37 mg, 50%). Identification of the title compound by 1H-NMR showed that the product was an approximately 1:1 mixture of the (E) and (Z) oxime isomers. ES/MS m/z: 313.17 (M+H), 311.19 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.83 s 1H; 7.13 m 2H, 6.87 m 2H, 2.41 s 3H, 1.88 s 3H.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C)C=O.[CH:21]1([CH2:27][CH:28]([OH:43])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:39]([CH3:42])([CH3:41])[CH3:40])=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C1C=CN=CC=1)C.O>[CH:21]1([CH2:27][CH:28]([O:43][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:39]([CH3:41])([CH3:40])[CH3:42])=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1ccc(CC(O)CC2CCCCC2)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(CC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
973 mg (6.46 mmol) of t-butyldimethylsilyl chloride, 0.90 ml (6.46 mmol) of triethylamine and 67 mg (0.55 mmol) of 4-(N,N-dimethylamino)pyridine were added to 10 ml of a dimethylformamide solution containing 1.74 g of 5-(3-cyclohexyl-2-hydroxypropyl)-2-t-butyl-1-nitrobenzene [prepared as described in step (i) above]. The mixture was then stirred for 1 hour and 20 minutes at room temperature, and then for 2.5 hours at 40° C. At the end of this time, the reaction solution was poured in water and extracted with a 3:1 by volume mixture of hexane and ethyl acetate. The organic layer was washed with dilute aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 75 g of silica gel. Elution with a 1:9 by volume mixture of diethyl ether and hexane afforded 2.22 g (yield 96% over the 2 steps) of the title compound as an oily substance.