Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[C:6]([F:19])[C:5]([CH3:20])=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:20][C:5]1[C:6]([F:19])=[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(CBr)ccc(Cl)c1Oc1cccc2ccccc12
Yield: 45.5 %

Procedure:
To a solution of 1-[(6-chloro-2-fluoro-3-methylphenyl)oxy]naphthalene (1.69 g, 5.89 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (1.154 g, 6.48 mmol) and AIBN (0.048 g, 0.295 mmol). The mixture was heated at reflux overnight. The reaction mixture was filtered through Celite and the solvent was evaporated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the desired product (0.98 g, 45.5%) as a light yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.43-8.51 (m, 1H), 7.84-7.92 (m, 1H), 7.53-7.64 (m, 3H), 7.23-7.34 (m, 3H), 6.50 (d, 1H), 4.50 (d, 2H).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][CH:15]1[CH2:20][CH:19]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH:17]([CH3:26])[CH:16]1[OH:27].C(O)(C)C>CC(C)=O>[CH3:14][CH:15]1[CH2:20][CH:19]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH:17]([CH3:26])[C:16]1=[O:27]
Reactant: CC(C)CCC1CC(C)C(O)C(C)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(C)CCC1CC(C)C(=O)C(C)C1
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Jones reagent (150 mL) was added dropwise at room temperature to a solution of 2,6-dimethyl-4-(3-methylbutyl)cyclohexanol (100 g. 0.5 mol, produced according to Example 4) in acetone (3,000 mL). The reaction mixture was stirred for 1 h and isopropanol added to decompose excess Jones reagent. The salts were removed by filtration and the solution concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with water (400 mL), 5% sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was dried, the solvent evaporated, and the residue fractionated to yield 71 g of the ketone, bp 96°-100° C. (3 mm). NMR (CDCl3) δ0.8-1.1 (12H, m), 1.1-3.2 (12H, m). IR (film) 1725, 1140, 990 cm-1. MS (m/e) 196 (M+), 69, 82, 97, 41.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.[Ag-]=O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Reactant: BrCc1ccccc1
Agent: O=[Ag-]
Solvent: CN(C)C=O
Product: O=C(CCOCCc1ccc2sccc2c1)N1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 31 h

Procedure:
In 8 mL of N,N-dimethylformamide was dissolved 1.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-1-azetidinyl)-1-propanone, and 1.90 g of silver(I) oxide and 0.97 mL of benzyl bromide were added to the solution, after which the resulting mixture was stirred at room temperature for 31 hours. The insoluble materials were filtered off and water and ethyl acetate were added to the residue, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene:ethyl acetate=3:1 to 1:4) to obtain 1.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-[3-(benzyloxy)-1-azetidinyl]-1-propanone as an oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[N:6].[CH2:7](Cl)[C:8]1[CH:16]=[CH:15][C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=1>C(#N)C>[O:13]1[C:14]2[CH:15]=[CH:16][C:8]([CH2:7][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH2:6])=[CH:9][C:10]=2[O:11][CH2:12]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CNCCC#N
Solvent: CC#N
Product: CN(CCCN)Cc1ccc2c(c1)OCO2
Reaction time: 18 h

Procedure:
To N-methyl-β-alaninenitrile (50 g, mmol in acetonitrile was added piperonyl chloride (50 g, mmol). After stirring for 18 h, the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with aqueous carbonate, dried (MgSO4), and the solvent was removed in vacuo. The residue was dissolved in methanol saturated with ammonia (600 mL) and Raney nickel (10 g) was added. After shaking under an atmosphere of hydrogen at 20 psi for 6 h, the reaction was filtered through celite and the solvent was removed in vacuo to give 65 g of N-(1,3-benzodioxol-5-ylmethyl)-N-methyl-1,3-propanediamine.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][C:31]#[C:32][C:33]([O:36][Si](CC)(CC)CC)([CH3:35])[CH3:34])[CH2:12][C@@H:11]([O:44][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][C:31]#[C:32][C:33]([OH:36])([CH3:35])[CH3:34])[CH2:12][C@@H:11]([OH:44])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)C#CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 91.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(4-triethylsilyloxy-4-methyl-2-pentynyloxymethyl)androsta-5,7,16-triene (480 mg, 0.635 mmol) and 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (6 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (4 hours), worked up and purified by column chromatography (ethyl acetate:dichloromethane=4:1 followed by ethyl acetate) to give the titled compound (240 mg, 92%) as a pale yellow foam.
Reaction SMILES: C1(N2C(=O)C3=CNC4C=[CH:15][C:16]([N:19]5[CH2:24]CN[CH2:21][CH2:20]5)=CC=4C3=N2)C=CC=CC=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:48])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[N:40]=[C:31]3[C:30]=2[CH:29]=1.CN1CCNCC1>>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([N:39]2[C:38](=[O:48])[C:32]3=[CH:33][NH:34][C:35]4[CH:36]=[CH:37][C:28]([N:27]5[CH2:21][CH2:20][N:19]([CH3:24])[CH2:16][CH2:15]5)=[CH:29][C:30]=4[C:31]3=[N:40]2)=[CH:46][CH:45]=1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Reactant: Nc1ccc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2c1
Agent: CN1CCNCC1
Product: CN1CCN(c2ccc3[nH]cc4c(=O)n(-c5ccc(Cl)cc5)nc-4c3c2)CC1

Procedure:
The title compound was prepared following the procedure described for 7a using 6b and 1-methyl-piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.50 (7H, br), 3.75 (3H, s), 7.00 (1H, d, J=9.06 Hz), 7.40 (1H, m), 7.48 (1H, br), 7.68 (1H, d, J=9.06 Hz), 7.92 (1H, d, J=8.79 Hz), 8.05 (2H, d, J=8.79 Hz), 8.56 (1H, br), 9.12 (1H, br). m/z 394.9 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:10][O:11][C:7]=2[C:6]([OH:17])=[C:5]([C:18]([O:20]CC)=O)[N:4]=1)#[N:2].[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+].Cl>>[C:1]([C:3]1[C:8]2[C:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:10][O:11][C:7]=2[C:6]([OH:17])=[C:5]([C:18]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20])[N:4]=1)#[N:2]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(-c3cccs3)noc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3cccs3)c12
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Ethyl 4-cyano-7-hydroxy-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (136 mg, 0.432 mmol) and glycine (648 mg, 8.63 mmol) were added to sodium methoxide solution (13 mL, 6.48 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and 0.25 M hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 101 mg of the title compound. MS: (−) m/z 343.28 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:26][CH:27]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CO)cc3)c2CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(COS(C)(=O)=O)cc3)c2CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (170 mg, 0.391 mmol) in anhydrous DCM under nitrogen, add methanesulfonyl chloride (33 μL, 0.426 mmol) and triethylamine (61 μL, 0.44 mmol) and continue stirring for 2 h. Dilute with water (5 mL) and extract three times with DCM. Wash the combined organic extracts with brine, dry over anhydrous Na2SO4, and concentrate in vacuo to obtain the desired intermediate that was used without purification.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH3:26])[CH3:25])=[CH:22][CH:23]=1)[C:7]([NH:9][NH2:10])=[O:8]
Reactant: CN(C)c1ccc(C(CCCCl)C(=O)NNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(CCCCl)C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (2.64 mL) was added to tert-butyl N′-[5-chloro-2-(4-dimethylaminophenyl)pentanoyl]hydrazinecarboxylate (106.9 mg), and the reaction solution was stirred at room temperature for four hours. The reaction solution was concentrated under reduced pressure to obtain 5-chloro-2-(4-dimethylaminophenyl)pentanoic acid hydrazide hydrochloride. A solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate hydrochloride (77.6 mg) and triethylamine (0.16 mL) in ethanol (1.25 mL) was added to a solution of the resulting 5-chloro-2-(4-dimethylaminophenyl)pentanoic acid hydrazide hydrochloride and triethylamine (0.291 mL) in ethanol (1.25 mL), and the reaction solution was stirred at 80° C. in a nitrogen atmosphere for 22 hours. The reaction solution was cooled to room temperature, and then the solvent was evaporated from the reaction solution under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=9:1) and further purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=9:1) to obtain 26.6 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:9](=[O:13])[CH2:10][CH2:11][I:12])[C:5]([F:8])=[CH:6][CH:7]=1.[Na+].[I-]>C(#N)C.O>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C@H:9]([OH:13])[CH2:10][CH2:11][I:12])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C(CCI)c1c(F)ccc(Cl)c1F
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O[C@H](CCI)c1c(F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
1-(3-Chloro-2,6-difluorophenyl)-3-iodopropan-1-one: (Ref: Synthesis, 366-399 (1998)) To a stirred solution of NaI (0.153 g, 1.019 mmol) in ACN (0.637 ml) was added TMS-CI (0.130 mL, 1.019 mmol) dropwise. A precipitate was formed, and the mixture turned yellow. Water (0.015 mL, 0.849 mmol) was added (which re-dissolved the precipitate), followed by addition of Intermediate 2B (0.172 g, 0.849 mmol). The mixture was diluted with additional ACN (0.637 mL), and stirred at rt under argon for 15 min. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with 10% Na2S2O3 and brine, dried over anhydrous MgSO4, filtered, and concentrated to yield the desired product as a light yellow oil (0.265 g, 94%), MS (ESI) m/z: 330.7 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.50 (ddd, J=8.9, 8.1, 5.7 Hz, 1H), 6.96 (td, J=8.8, 1.8 Hz, 1H), 3.59-3.53 (m, 2H), 3.45-3.40 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[C:18]([O:24][CH3:25])[CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(OCC)C.C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:18]([O:24][CH3:25])[CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)c(OC)c2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNCC(=O)OC(C)(C)C)c(OC)c2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.6 %

Procedure:
Prepared using General Procedure 12: A suspension of 4-formyl-3-methoxyphenyl 4-(heptyloxy)benzoate (340 mg, 0.918 mmol) INT-25, tert-butyl 2-aminoacetate HCl (154 mg, 0.918 mmol), TEA (128 μL, 0.918 mmol) and magnesium sulfate (500 mg) in diethyl ether (20 mL) was stirred vigorously for 18 h. The reaction mixture was filtered and solvent removed under vacuum. Crude material was taken up into THF/MeOH (10 mL, 10 mL) and sodium borohydride (34.7 mg, 0.918 mmol) added with cooling to 0° C. After stirring for 1 h at room temperature the reaction was quenched with NaHCO3 (10 mL) and the solvent removed under vacuum. The residue was diluted with NaHCO3 (50 mL) and the product extracted with EA (100 mL). The organic extracts were combined and washed with brine (100 mL) and pre-absorbed onto silica gel then purified by chromatography (EA/isohexanes) to afford 270 mg (58%) of 4-(((2-(tert-butoxy)-2-oxoethyl)amino)methyl)-3-methoxyphenyl 4-(heptyloxy)benzoate INT-26 as a white solid. LCMS-ESI (m/z) calculated for C28H39NO6: 485; found 486 [M+H]+, tR=2.23 min (Method 10).
Reaction SMILES: C([Si]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])[CH:24]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:31]1([S:29]([C:25]2[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][OH:18])[CH:28]=[CH:27][CH:26]=2)=[O:30])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)[Si](OCCCCc1cccc(S(=O)C2CCCC2)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=S(c1cccc(CCCCO)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl{4-[3-(cyclopentylsulfinyl)phenyl]butoxy}diphenylsilane (690 mg) in dry THF (10 ml) was treated with a solution of tetra-n-butylammonium fluoride in THF (1M; 3 ml) and the resultant reaction mixture stirred at room temperature for 5 h prior to concentration in vacuo. The residue was purified by chromatography (SPE, Gradient between cyclohexane and EtOAc) to give the title compound. LCMS RT=2.64 min.
Reaction SMILES: [C:1]([C:3]([C:35]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:36])=[CH:4][C:5]1[CH:34]=[CH:33][C:8]([NH:9][C:10]2[N:11]=[C:12]3[C:18]([C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][N:16](COCC[Si](C)(C)C)[C:13]3=[N:14][CH:15]=2)=[CH:7][CH:6]=1)#[N:2].C(O)(C(F)(F)F)=O.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[C:1]([C:3]([C:35]([N:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1)=[O:36])=[CH:4][C:5]1[CH:34]=[CH:33][C:8]([NH:9][C:10]2[N:11]=[C:12]3[C:18]([C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCOCC4)cc3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)NC(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCOCC4)cc3)nc12
Reaction time: 8 h

Procedure:
To a 20 ml vial 2-[4-(2-cyano-3-morpholino-3-oxo-prop-1-enyl)anilino]-N-isopropyl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-carboxamide (65 mg, 0.11 mmol was dissolved in DCM (3 ml) added TFA (3 ml, 0.11 mmol) was added. The reaction mixture was stirred overnight. HCl (1 ml, 0.11 mmol) and methanol (3 ml) were added and the reaction mixture was stirred at overnight and then neutralized to pH 6-7 with NaHCO3. The organics were extracted with EtOAc, washed with water, dried with Na2SO4, filtered and evaporated solvent to give 45 mg of 2-[4-(2-cyano-3-morpholino-3-oxo-prop-1-enyl)anilino]-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:11][N:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cccc(Cl)c1
Reaction time: 8 h

Procedure:
3-Chlorobenzoyl chloride (30 mg, 0.17 mmol, CAS RN 618-46-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (20 mg, 0.10 mmol, example 1, intermediate a) and DIPEA (30 μL, 0.17 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the title product as a waxy solid (12 mg, 36%). MS (ESI): m/z=337.0 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23]C)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC2CCCCC=2C=1C(OC)=O.[Cl:39]C1C=C(S(Cl)(=O)=O)C=CC=1>>[Cl:39][C:3]1[CH:2]=[C:1]([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: COC(=O)c1c(N)sc2c1CCCC2
Product: COC(=O)c1c(NS(=O)(=O)c2cccc(Cl)c2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from methyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and 3-chlorobenzene-sulfonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@H]1CO)=O)(C)(C)C.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][SH:40])=[CH:37][CH:36]=1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][S:40][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1

Procedure:
The procedure described in Preparation 5-(2) was repeated, but using 12.16 g of (2S)-1-t-butoxycarbonyl-2-methanesulfonyloxymethylpyrrolidine [prepared by the methanesulfonylation of (2S)-1-t-butoxycarbonyl-2-hydroxymethylpyrrolidine], 7.3 ml of 4-methoxybenzyl mercaptan and 2.3 g of sodium hydride (as a 55% w/w suspension in mineral oil) in 100 ml of dry dimethylformamide, to afford 13.93 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18]/[C:16](=[N:23]\[OH:24])/[CH:15]=3
Reactant: NO
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C/C(=N/O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Yield: 179.2 %

Procedure:
An oxime of testosterone was prepared in accordance with the following procedure. A dry pyridine solution of testosterone (6.95 mmoles) and hydroxylamine hydrochloride (17.4 mmoles) was stirred at room temperature for 48 hours. The pyridine was removed in vacuo and the crystalline residue was recrystallized from methanol-water and from ethanol to yield 1.89 g (89%) of testosterone oxime, mp 207-210, indicated by tlc to be a mixture of the syn and anti oxime isomers.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:25])[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=O.O.[NH2:28]N.C(O)(=O)C>C(O)C>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13](=[O:25])[CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[N:28]1
Reactant: CN(C)/C=C/C(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(Cc1cccc2ccccc12)Nc1ccsc1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
To a solution of (E)-N-(2-(3-(dimethylamino)acryloyl)thiophene-3-yl)-2-(naphthalen-1-yl)acetamide (185 mg, 0.51 mmol) in abs. ethanol (2 mL) was added hydrazine hydrate (0.2 ml, 4.11 mmol) and acetic acid (0.5 mL, 8.73 mmol). The reaction mixture was stirred at room temperature overnight under N2 (g) inlet and then concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and H2O. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The precipitate that formed was washed with methanol and collected filtration to afford N-(2-(1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (50 mg, 30%). Method [7] m/z 334.0 (M+H); retention time=5.887. 1H-NMR (DMSO-d6) δ 12.92 (broad s, 1H), 10.37 (s, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.92 (d, J=6.9 Hz, 2H), 7.86 (d, J=7.7 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J=5.3 Hz, 1H), 7.61-7.47 (m, 4H), 7.36 (d, J=5.3 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 4.19 (s, 2H).