Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:13]([O:20][N:21]=[C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2C1=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a suspension of 5.0 g of isatin in 200 ml of ethanol was added a solution of 9.75 g of O-benzylhydroxylamine hydrochloride and 4.18 g of sodium acetate in 50 ml of water at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated. The concentrate was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. Recrystallization of the crude product from ethanol gave 6.06 g (71%) of 3-(benzyloxyimino)indolin-2-one as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([C@@H:13]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH2:14][N+:15]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O>O1CCCC1>[NH2:15][CH2:14][C@H:13]([C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[OH:24])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: O=C1CCCC[C@H]1[C@@H](C[N+](=O)[O-])c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H](c1ccc(OCc2ccccc2)cc1)[C@@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 9.5 g of (-)-(S)-[(R)-4-(benzyloxy)-α-(nitromethyl)benzyl]cyclohexanone in 150 ml of dry tetrahydrofuran is added dropwise at room temperature while stirring to a suspension of 2.5 g (67.2 mmol) of lithium aluminium hydride in 80 ml of dry tetrahydrofuran under argon and the mixture is stirred at room temperature for 16 hours. The reaction mixture is treated with 20 ml of tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The residue is dissolved in ether, the ethereal phase is extracted with 1N hydrochloric acid, the acidic phase is made alkaline with 3N sodium hydroxide solution and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated. There is obtained (+)-(1S)-cis-2-[(R)-α-(aminomethyl)-4-(benzyloxy)benzyl]cyclohexanol in the form of a colourless oil; [α]D20 =+14.7° (c=0.7, chloroform).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[C:11]3[CH:22]=[C:21]([C:23]([O:25]C(C)(C)C)=[O:24])[S:20][C:12]=3[N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)=[O:8])=[CH:5][CH:4]=1.Cl>O1CCOCC1>[CH2:18]([O:17][C:15]([N:13]1[C:12]2[S:20][C:21]([C:23]([OH:25])=[O:24])=[CH:22][C:11]=2[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][Cl:1])=[CH:31][CH:30]=2)=[N:14]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(CCl)cc2)c2cc(C(=O)OC(C)(C)C)sc21
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(CCl)cc2)c2cc(C(=O)O)sc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
5-tert-butyl 1-ethyl 3-[(4-chloromethyl-benzoyl)amino]-1H-thieno[2,3-c]pyrazole-1,5-dicarboxylate (8.2 g) was added to a solution of hydrochloric acid in dioxane (88 mL, 4N solution). The resulting mixture was stirred at 50° C. for 2 hours. Afterward, volatiles were removed by evaporation under reduced pressure and the residue triturated with diethyl ether, filtered, extensively washed with diethyl ether and dried under vacuum at 40° C. to give 5.7 g of the title compound, used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH:23][C:24](=[O:27])[CH2:25]Cl)[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[O-][C:29]#[N:30].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O>[NH2:30][C:29]1[N:13]2[C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:3]([CH3:5])([CH3:4])[CH3:2])=[CH:7][CH:8]=3)=[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:15][C:14]2=[N:23][C:24](=[O:27])[CH:25]=1
Reactant: N#C[O-]
Reactant: CC(C)(C)c1ccc(-c2nc(NC(=O)CCl)sc2-c2ccncc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(-c2c(-c3ccncc3)sc3nc(=O)cc(N)n23)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 15.7 %

Procedure:
To a solution of N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-2-chloroacetamide hydrochloride (1.0 g) in dimethylsulfoxide (5 mL) was added sodium cyanate (0.24 g). The mixture was stirred at room temperature for 14 hours. An aqueous solution of sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (1:1). The extract was washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure and the residue was purified with silica gel column chromatography (hexane-tetrahydrofuran, 1:1) and recrystallized from ethyl acetate to obtain the title compound (0.14 g, yield 24%).
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]2)=[C:17]=[O:18].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:17]([NH:16][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]4)=[O:18])=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(N2CCCCCC2)cc1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-azepanyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.53 (s, 1H), 8.28 (d, 1H, J=8 Hz), 7.74 (s, 1H), 7.67 (d, 1H, J=8 Hz), 7.50 (t, 1H, J=8 Hz), 7.14 (d, 2H, J=9 Hz), 6.84 (t, 1H, J=6 Hz), 6.66 (d, 2H, J=9 Hz), 4.20 (d, 2H, J=6 Hz), 3.44 (m, 4H), 2.63 (s, 3H), 1.71 (m, 4H), 1.45 (m, 4H). MS (ESI) 389 (M+H)+; Anal. Calcd for C24H28N4O.0.3H2O: C, 73.18; H, 7.32; N, 14.22. Found: C, 73.08; H, 7.38; N, 14.22.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:27][C:28](=O)[CH2:29][CH3:30].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:29]([C:28]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH2:10][N:11]([C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:12][CH2:13]3)=[N:6][N:7]2[CH:27]=1)[CH3:30]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCc1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 69 %

Procedure:
A mixture of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone (0.120 g, 0.342 mmol), 1-bromobutan-2-one (0.077 g, 0.512 mmol) and sodium bicarbonate (0.016 g) in ethanol was refluxed over night. The reaction mixture was concentrated in vacuo, then diluted with 10 mL of water, extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by column chromatography. The title compound was obtained as a white solid in 69% yield (0.095 g). 1H NMR (300 MHz, CDCl3) δ 7.73-7.47 (m, 4H), 7.43 (s, 1H), 7.33 (d, J=7.5 Hz, 1H), 6.71 (d, J=7.5 Hz, 1H), 4.02-3.82 (m, 2H), 3.58-3.5 (m, 2H), 3.4-3.25 (m, 4H), 2.78 (q, 2H), 1.29 (m, J=7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 154.4, 148.1, 135.7, 134.44, 134.41, 132.3, 129.4, 127.2, 126.9, 126.8, 126.7, 125.4, 125.34, 121.8, 113.1, 109.4, 46:6, 46.4, 46.2, 41.2, 22.4, 13.5. MS (ES+)m/z 404 (M+1).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:2].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+].O>C1COCC1.C(OCC)(=O)C>[OH:2][CH:1]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (500 mg, 2.51 mmol) in dry THF (7 mL) at −78° C. was added 1 M phenylmagnesium bromide solution in THF (7.5 mL, 7.5 mmol, 3 eq.). After stirring the reaction mixture for 2 h, saturated aqueous ammonium chloride (1.5 mL) was added. The mixture was warmed to room temperature, and water (50 mL) and ethyl acetate (25 mL) were added. The phases were separated, and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic phases were washed with 10% citric acid, brine, saturated aqueous sodium bicarbonate, and dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel chromatography (pentane/ethyl acetate, 7:3) to give tert-butyl (2R)-2-[hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate a colorless oil. Subsequent BOC deprotection was carried out by dissolving the intermediate in ethyl acetate (3 mL) and leading a stream of HCl (g) through the solution for 20 min. The solvent was evaporated to give the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:22](O)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:22]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2cnc(F)c(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cnc(F)c(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
16 mg (0.04 mmol) of the compound of Example 62A is reacted analogously to the synthesis of the compound of Example 1 with 6 mg (0.05 mmol) of 4-imidazolinone-hydrochloride. 11 mg (55% of theory) of the title compound is obtained.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:20]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH3:28][O:27][C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][S:17][C:9]1[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)=[O:26]
Reactant: COC(=O)c1cccc(CSc2nc3ccccc3n2CC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(CSc2nc3ccccc3n2CC(=O)O)c1
Yield: 73.3 %

Procedure:
A solution of tert-butyl[2-(3-methoxycarbonyl-benzylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor H-01b, 31 mg, 0.075 mmol) in TFA/dichloromethane (1:1, 2 ml) is stirred at rt for 4 h. The solvents are removed under a stream of air. The solid residue is suspended in Et2O (2 ml) and sonicated. Filtration, rinsing with Et2O and drying under high vacuum, yields the title compound (19.6 mg) in 73% as a white solid: tR=5.52 min (LC-1), ESI-MS (pos.): m/z 357.25 [M+H]+, ESI-MS (neg.): m/z 355.29 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 3.83 (s, 3H, OMe), 4.65 (s, 2H, SCH2), 4.92 (s, 1H, CH2CO2), 7.15-7.21 (m, 2Harom), 7.42-7.48 (m, 2Harom), 7.57 (m, 1Harom), 7.72 (d, 1Harom), 7.81 (d, 1Harom), 8.05 (s, 1Harom).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl.O>[C:52]([O:51][C:49]([N:43]1[CH2:48][CH2:47][N:46]([C:10]([CH:8]2[CH2:7][C:6]3[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:9]2)=[O:12])[CH2:45][CH2:44]1)=[O:50])([CH3:55])([CH3:53])[CH3:54]
Reactant: O=C(O)C1Cc2cc(F)ccc2O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2Cc3cc(F)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
In a 250 ml round-bottomed flask containing a solution of 5-fluoro-2,3-dihydro-benzofuran-2-carboxylic acid (1.8 g, 9.9 mmol) in 100 ml of dichloromethane was added EDAC.HCl (2.85 g, 14.9 mmol, 1.5 eq), HOBt (2.00 g, 14.8 mmol, 1.5 eq), triethylamine (2.00 g, 19.8 mmol, 2.0 eq), and t-butyl piperazine-1-carboxylate (2.20 g, 11.8 mmol, 1.2 eq). The solution was stirred overnight at room temperature before diluting with 50 ml of water. The crude product was then extracted from the mixture using 3×50 ml of dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1.8 grams of the desired amide as a light yellow solid (52%); 1H NMR (300 MHz, CDCl3): δ 6.92 (dd, J=2.4 Hz, 7.8 Hz, 1H), 6.79 (m, 1H), 6.69 (dd, J=4.2 Hz, 8.7 Hz, 1H), 5.40 (dd, J=7.2 Hz, 9.9 Hz, 1H), 3.78-3.91 (m, 3H), 3.46-3.67 (m, 5H), 3.26-3.39 (m, 2H), 1.49 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 40.2 %

Procedure:
To a solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (6.79 g) in methylene chloride (68 ml) were added trifluoroacetic acid (29.1 g) and anisole (11.02 g) at 0° C., and the mixture was stirred at ambient temperature for 65 minutes. After the reaction mixture was evaporated, to the residue were added ethyl acetate and water, followed by adjusting to pH 7 with an aqueous solution of sodium bicarbonate. The separated aqueous solution was adjusted to pH 3.0 with 10% hydrochloric acid, and the precipitated substance was collected by filtration to give 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (1.88 g), mp 104°-116° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CCNCC
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(/C=C1/C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@]2(C)[C@@H](O)CC[C@@H]12)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 50 mg (0.116 mmol) 17-hydroxywortmannin in 1 mL CH2Cl2 is added 22.5 mL (0.217 mmol) diethylamine. The reaction mixture is stirred at room temperature for 2 hours 30 minutes and then concentrated in vacuo to give an orange paste. The residue is dissolved in ethyl actate (EtOAc) and precipitated with hexane. The precipitate is washed two times with hexane to give 45 mg (77%) product as an orange solid. HRMS (ESI) m/z calcd for C27 H37NO8 503.25206, found: 504.25747 (M+H)+1.
Reaction SMILES: [Br:1]B1C2CCCC1CCC2.C(Cl)Cl.[C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)#[CH:15].C(O)(=O)C.[OH-].[Na+].OO>>[Br:1][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH2:15]
Reactant: C#CC1CCCCC1
Reactant: BrB1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=C(Br)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9-bromo-9-bora-bicyclo[3.3.1]nonane 1 M in DCM (33 mL, 33 mmol) at 0° C. was added ethynylcyclohexane (3.6 mL, 28 mmol) under argon via syringe slowly dropwise in portions over 10 min. The reaction mixture was allowed to stir 3 h, at which point acetic acid (4.8 mL, 83 mmol) was added dropwise in portions over 20 min. After 1 h additional, sodium hydroxide (17 mL, 166 mmol) was added slowly, followed by cautious addition of hydrogen peroxide (8.5 mL, 83 mmol). The reaction mixture was allowed to stir rapidly 1 h, then was warmed to ambient temperature. The reaction mixture was partitioned between hexanes and water, and the organic layer was washed with saturated aq. Sodium bicarbonate, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting liquid was filtered through a 3 cm pad of silica gel, rinsing with 200 mL hexanes, and the filtrate was concentrated in vacuo to give crude (1-bromovinyl)-cyclohexane as a clear/colorless oil which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].O1CCCC1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[Cl:30].C(N(CC)CC)C>O>[Cl:30][C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[C:21]([NH:20][S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH:22]=2)[NH:26][N:25]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(Cl)c2c1
Yield: 9.9 %

Procedure:
N-(3-Chloro-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained in the following way: a solution of 0.36 g of 2-methylsulfonylbenzenesulfonyl chloride and of 3.6 ml of tetrahydrofuran is added dropwise to a solution, cooled to 0° C., of 0.22 g of 5-amino-3-chloro-1H-indazole, of 15 ml of tetrahydrofuran and of 0.37 ml of triethylamine. After reacting for 30 minutes at a temperature in the region of 0° C. and 18 hours at a temperature in the region of 20° C., 30 ml of distilled water are added to the reaction medium. The medium is extracted with 30 ml and 15 ml of ethyl acetate. The organic phase is subsequently dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture as eluent. The solid thus obtained is recrystallized from 45 ml of isopropanol. After drying under reduced pressure at 60° C., 0.05 g of N-(3-chloro-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide is thus obtained in the form of a white solid melting above 260° C. (analysis C14H12ClN3O4S2 % calculated C, 43.58; H, 3.13; Cl, 9.19; N, 10.89; O, 16.59; S, 16.62. % found C, 43.72; H, 2.88; Cl, 7.94; N, 10.63; S, 16.80).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([NH2:11])[CH:10]=[C:5]2[CH:4]=[N:3]1.BrC1C=C2C=NN(C)C2=NC=1.[C:23]1([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:23]1([C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:11][C:9]2[CH:10]=[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]3=[N:7][CH:8]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cn1ncc2cc(N)cnc21
Agent: CC(C)(C)[O-]
Agent: Cn1ncc2cc(Br)cnc21
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1ncc2cc(N=C(c3ccccc3)c3ccccc3)cnc21
Temperature: 115 °C

Procedure:
1-Methyl-1H-pyrazolo[3,4-b]pyridin-5-amine. A degassed mixture of 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (880 mg, 4 mmol), diphenylmethanimine (1.08 g, 6 mmol), tris(dibenzylideneacetone)palladium (0) (734 mg, 0.8 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.24 g, 2 mmol), and sodium tert-butoxide (576 mg, 6 mmol) in toluene (18 mL) was heated at 115° C. under nitrogen overnight. The reaction mixture was purified by column chromatography on silica gel (eluting with 4% ethyl acetate in petroleum ether) to give N-(diphenylmethylene)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine (1.2 g, crude). The crude N-(diphenylmethylene)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine was dissolved in tetrahydrofuran (10 mL), and hydrochloric acid (2 N, 5 mL) was added. The mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH=8 with saturated sodium carbonate solution, and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography on silica gel (eluting with 33% ethyl acetate in petroleum ether) to give 1-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine (420 mg, 68.4% yield) as an off-white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH:12]([C:15]#[N:16])[C:13]#[N:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CS(C)=O>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][CH2:20][C:12]([CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:13]#[N:14])[C:15]#[N:16]
Reactant: BrCCC1OCCO1
Reactant: N#CC(C#N)CCOCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCOCCc1ccccc1)CCC1OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A solution of the compound from step b) (1.53 g) in dry dimethyl sulphoxide (20 ml) was added to a suspension of sodium hydride (prewashed with diethyl ether) in dimethyl sulphoxide (20 ml). The mixture was stirred for 2 hours at room temperature. 2-[2-Bromoethyl]-1,3-dioxolane (0.920 ml) was then added and the whole heated at 60° for a further 2 hours. The cooled mixture was then quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to yield the crude final product. This material was purified by flash chromatography over silica using ethyl acetate in dichloromethane as eluant to yield a pure sample of the subtitled compound (0.56 g, 25%).