Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:21](=[O:22])[C:20]4[C:19]([C:23](O)=[O:24])=[CH:18][CH:17]=[CH:16][C:15]=4[C@@H:14]3[CH3:26])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].OC1C2N=N[NH:34]C=2C=CC=1.C(N(CC)CC)C>O1CCCC1>[CH:1]1([N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:21](=[O:22])[C:20]4[C:19]([C:23]([NH2:34])=[O:24])=[CH:18][CH:17]=[CH:16][C:15]=4[C@@H:14]3[CH3:26])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1cccc2[nH]nnc12
Reactant: C[C@H]1c2cccc(C(=O)O)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1c2cccc(C(N)=O)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Reaction time: 16 h
Yield: 40.2 %

Procedure:
(1S)-2-(1-Cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (0.15 gr, 0.42 mmol), hydroxybenzotriazole ammonium salt (0.13 gr, 0.84 mmol) and 1-ethyl-3-(3′-dimethylamino) carbodiimide hydrochloric acid salt (0.16 gr, 0.84 mmol) were dissolved in a mixture of tetrahydrofuran (6 mL) and triethylamine (0.23 mL, 1.68 mmol) and stirred under nitrogen atmosphere for 16 hours. Volatiles were evaporated and the crude was dissolved in dichloromethane and washed with 15% ammonium hydroxide. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (dichloromethane/methanol/7N ammonia in methanol 100:3:1) to afford the title compound (0.060 g, 40%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:8][C@H:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:6]1)[CH3:3].N1CC[CH2:34][CH2:33]1>>[O:25]([C:22]1[CH:21]=[CH:20][C:19]([C:11]2[N:10]=[C:9]([CH:7]3[CH2:6][CH:5]([CH2:4][N:2]4[CH2:1][CH2:34][CH2:33][CH2:3]4)[CH2:8]3)[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=23)=[CH:24][CH:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)C[C@H]1C[C@@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Reactant: C1CCNC1
Product: Nc1nccn2c(C3CC(CN4CCCC4)C3)nc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
Prepared according to the procedure described above for cis-3-(3-dimethylaminomethylcyclobutyl)-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine, except using pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[CH:7]=1
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cnc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a stirred solution of 3-chloro-2-hydroxypyridine-5-carboxylic acid (1 g, 5.762 mmol) in benzene (16 mL) and MeOH (4 mL) was added dropwise TMSCHN2 (3.17 mL, 6.338 mmol) at 0° C., and the resulting mixture was stirred overnight at room temp. The reaction mixture was quenched by the addition of AcOH and the mixture was evaporated off. The residue was suspended in water and precipitate was collected. The crude solid was washed with Et2O, and dried under a reduced pressure to give 728.1 mg (67%) methyl 3-chloro-2-hydroxypyridine-5-carboxylate as a white crystalline powder. IR (KBr) 1655, 1282, 1245, 769 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ3.79 (s, 3H), 8.01 (s, 1H), 8.06 (s, 1H); MS (FAB) m/z 188 (M++1); Anal. Calcd. for C7H6ClNO3: C, 44.82; H, 3.22; Cl, 18.90; N, 7.47. Found: C, 44.74; H, 3.22; Cl, 19.00; N, 7.34.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]Cl)[CH:2]=1.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>C1(C)C=CC=CC=1.O>[C:1]1([CH2:9][S:11]([O-:14])(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:11]([O-:14])(=[O:13])=[O:12])[CH:2]=1.[Na+:15].[Na+:15]
Reactant: ClCc1cccc(CCl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=S(=O)([O-])Cc1cccc(CS(=O)(=O)[O-])c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
In a 300-ml egg-plant type flask provided with cooling pipe for reflux, 17.5 g (0.1 mol) of m-xylylene dichloride was dissolved in 40 ml of toluene, and a solution of 28.0 g (0.22 mol) of sodium sulfite in 40 ml of distilled water was put into the flask. The mixture in the flask was heated in an oil bath kept at 130° C. under refluxing for 24 h, while the mixture was vigorously stirred with a magnetic stirrer using teflon-coated stirring pieces. After that the reaction mixture was cooled to room temperature, and a white precipitate was collected by filtration. The precipitate was dried under reduced pressure and purified by well washing with diethyl ether and then recrystallizing in a 2:1 mixture of water and methanol. The purified product was 16.5 g of sodium m-xylylenedisulfonate (53% yield). The sodium salt was dissolved in distilled water and passed through a column of an ion-exchange resin (Duolite C-20 of Wako Junyaku Co.) to obtain the aimed disulfonic acid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[N:8]=1)=O.[Cl:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=4)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(=O)N(C)C)c2)ccc1=O
Product: CN(C)C(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(Cl)c3)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzamide (A-20) and 3-chloro-phenylhydrazine according to the method described for example 91. MS: M=420.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][OH:18])[CH2:7][CH2:6][CH2:5]2.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CN(CCO)CCCN1CCCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(CCO)CCCN1CCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-((3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl)(methyl)amino)ethanol (67 mg, 0.254 mmol) in ethanol (4 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (145 mg, 0.509 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then diluted with water and aqeuous sodium carbonate (sat.) then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed on silica gel eluting with ethyl acetate, followed by 5-10% (2M NH3 in methanol) in a 1:1 mixture of ethyl acetate and dichloromethane. 1H NMR (DMSO-d6) δ 7.67 (d, J=3.3 Hz, 1H), 7.55 (d, J=5.1 Hz, 7.07 (t, J=4.4 Hz, 1H), 6.55 (m, 2H), 6.48 (s, 1H), 6.23 (brs, 2H), 4.35 (t, J=5.4 Hz, 1H), 3.51-3.44 (m, 2H), 3.24-3.17 (m, 4H), 2.66 (t, J=6.45, 2H), 2.41-2.33 (m, 4H), 2.17 (s, 3H), 1.89-1.81 (m, 2H), 1.63 (quint, J=7 Hz, 2H). ESI-MS (m/z, %) 373 (MH+, 100), 258 (31), 187 (49), 127 (42). ESI-HRMS calculated for C20H29N40S (MH+), calculated: 373.2056, observed: 373.2052.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].[C:16](=O)([O-])[O-].[Na+].[Na+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH3:16]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Reaction time: 10 h

Procedure:
5.2 g (0.02 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 1.3 g (0.012 M) of sodium carbonate, 1.5 ml (0.024 M) of methyliodide and 200 ml of acetone are boiled under energetic shaking for 10 hours. The acetone is distilled off and the residue is washed and then filtered. After drying 4.9 g (88.5% from the theoretical yield of N-(2,6-dichlorophenyl)-N'-acetyl-S-methylisothiourea are obtained with a melting point 135-139° C. After recrystallization from ethanol, the melting point of the product is 139°-141° C.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)[CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5].Br[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CCOCCO.[Cu]>[O:1]=[C:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5]
Reactant: CCC(C(=O)c1ccc2c(c1)CCC(=O)N2)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCCO
Product: CCC(C(=O)c1ccc2c(c1)CCC(=O)N2)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
1.8 Grams of 6-(1-oxo-2-piperazinylbutyl)-3,4-dihydrocarbostyril, 2.0 g of p-bromonitrobenzene, 1.2 g of potassium carbonate and 0.1 g of copper powder were dispersed in 80 ml of ethyl cellosolve and stirred at 120°-150° C. by heating for 5 hours. The reaction mixture was concentrated under a reduced pressure and the residue thus obtained was added water and extracted with chloroform. The chloroform layer was washed with water, dried and the chloroform was removed by distillation. The residue thus obtained was separated and purified by a separative thin layer chromatography and recrystallized from ethanol to obtain 0.2 g of 6-{1-oxo-2-[4-(4-nitrophenyl)-1-piperazinyl]-butyl}-3,4-dihydrocarbostyril in yellow powdery crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10].CS(O[CH:19]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]1)(=O)=O>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: CN1CCC(OS(C)(=O)=O)C1
Reactant: NC(=O)c1cc(F)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(F)cc2C(N)=O)C1
Temperature: 60 °C
Yield: 42 %

Procedure:
To a suspension of 0.44 g (60% in oil, 0.011 mole) of sodium hydride in 10 ml of dimethylformamide was added 1.55 g (0.01 mole) of 5-fluoro-2-hydroxybenzamide in 10 ml of dimethylformamide under nitrogen atmosphere at room temperature. The reaction mixture was heated to 60° C. and 1.80 g (0.01 mole) of 1-methyl-3-pyrrolidinol methane sulfonate (ester) was added. The reaction mixture was then heated to 100° C. for 18 hr. The dimethylformamide was removed by rotary evaporation at 70° C., 0.5 mm Hg. The residue was taken up in 200 ml of methylene chloride, washed with 2×50 ml of 1N sodium hydroxide and 50 ml of water. The organic phase was extracted with 2×50 ml of 1N hydrochloric acid. The combined aqueous extracts were washed with 50 ml of methylene chloride, made basic with concentrated sodium hydroxide and extracted into 2×50 ml of methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residual oil was crystallized from hexane to give 1.0 g of off-white crystals, m.p. 90°-93° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1.CCO.[H][H].[Pd]>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([OH:19])[CH2:16][O:17][CH2:18]2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: OC1(c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2)COC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(C2(O)COC2)cc1
Yield: 127.6 %

Procedure:
To a stirred solution of 3-(4-(dibenzylamino)phenyl)oxetan-3-ol (1.5 g, 5.217 mmol, 1.0 eq) in THF (50 mL) and EtOH (50 mL) was added 10% Pd/C (300 mg) and the mixture was stirred in hydrogen atmosphere at 40 psi H2 for 5 h. The mixture was passed through celite, the filtrate concentrated under reduced pressure to get 3-(4-aminophenyl)oxetan-3-ol (1.1 g, 77%; TLC system: EtOAc/PE (7:3), Rf: 0.55).
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]([F:30])([F:29])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:19]=1)[CH:9]([CH3:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[F:29][C:17]([F:30])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:19]=1)[CH2:16][NH:8][CH:9]([CH3:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11]
Reactant: CCCCOc1cccc(C(F)(F)CN(C(=O)OC(C)(C)C)C(C)C(=O)N(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCOc1cccc(C(F)(F)CNC(C)C(=O)N(C)C)c1
Reaction time: 8 h

Procedure:
84 mg (0.196 mmol) of 2-[N-tert-butoxycarbonyl-2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylpropanamide are dissolved in 3 mL of DCM and 0.49 mL (1.96 mmmol; 10 eq) of a 4M HCl solution in dioxane are added. After 8 hours, further 10 eq (0.49 mL) of 4M HCl 1 dioxane are added and the mixture is stirred overnight. Further 5 eq (0.245 mL) of 4M HCl in dioxane are the added and the mixture stirred for further 24 hours. The solution is evaporated, the white residue suspended in diethyl ether and then evaporated twice. The residue is flash-chromatographed on silica gel (DCM/MeOH 1/1 as an eluant followed by MeOH/conc. NH3 95/5). and the free base 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylpropanamide is isolated as a pale yellow fluid. The compound is dissolved in DCM (3 mL) and 4M HCl in dioxane is added to bring the solution to pH 2. The mixture is stirred for 10 minutes and then evaporated. The white residue is taken up with ether and evaporated twice. 45 mg (49%) of 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylpropanamide, hydrochloride (Example 2-1) are obtained.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1>[OH:14][C@@H:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: COP([O-])OC
Agent: Cl
Solvent: C1CCOC1
Product: COP(=O)(OC)[C@H](O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The solution of the Al--Li--(R)-binaphthol complex (hereinafter abbreviated as ALB) obtained in Example 1 in tetrahydrofuran (0.1M, 0.36 ml) was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C. After it was maintained at this temperature for 15 minutes, benzaldehyde (0.48 mmol) was added thereto. After reacting for 90 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2 SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxyphenylmethylphosphonate as a final product in a yield of 95%. The chemical reaction in this Example is shown in chemical formula 26.
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].[CH3:32][N:33]([CH3:39])[CH2:34][CH2:35][NH:36][CH2:37][CH3:38]>C(Cl)Cl>[CH3:32][N:33]([CH3:39])[CH2:34][CH2:35][N:36]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:37][CH3:38]
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
Reactant: CCNCCN(C)C
Solvent: ClCCl
Product: CCN(C=C1C(=O)OC(COC)C2(C)C1=C(O)C(=O)C1=C2C(OC(C)=O)CC2(C)C(O)CCC12)CCN(C)C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
17-Hydroxywortmannin (129 mg, 0.3 mmol) is dissolved in 5 ml methylene chloride and stirred at room temperature under nitrogen atmosphere as N,N-dimethyl-N′-ethyl-ethylenediamine (0.31 mmol, 56 μl) is added. The reaction solution turns orange immediately. After 30 min, the solvent is evaporated and the solid is recrystallized from ethyl acetate/hexane (3:1). After filtration, the solid is washed with hexane and dried under vacuum to yield 115 mg of the title compound as an orange powder. UV λmax (CH3CN/H2O): 250 nm, 320 nm, 397 nm; Positive ESI-MS: m/z 547 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].[CH:13]#[C:14][CH2:15][CH3:16]>C(NCC)C.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12])#[C:14][CH2:15][CH3:16]
Reactant: C#CCC
Reactant: COCOc1cc(F)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CCOCC
Product: CCC#Cc1ccc(F)cc1OCOC
Temperature: 70 °C
Yield: 91 %

Procedure:
1-Bromo-4-fluoro-2-methoxymethoxy-benzene (7.6 g, 32 mmol) is placed in a pressure flask, dissolved in diethylamine (65 mL) and degassed with nitrogen for 15 min. An excess of butyne is bubbled through the solution, CuI (1.9 g, 10 mmol) and PdCl2(PPh3)2 (2.3 g, 3.3 mmol) are added, and the flask is heated to 70° C. for 44 h. The mixture is diluted with ether, then washed with saturated aqueous NH4Cl and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage® Si65M, 3% THF/hexane) to provide 6.12 g (91%) of the title compound as an orange solid. GCMS m/e 208 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11][CH:10]([C:17]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OC(=O)C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:11][CH:12]([C:14](=[O:16])[O:19][C:17]2=[O:18])[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC(C1)C(=O)OC2=O

Procedure:
A suspension of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester (1 g, 3.6 mmol) in acetic anhydride (20 mL) is heated at reflux for 2 h. The reaction mixture is evaporated three times with toluene before it is dried under high vacuum at rt overnight to give a yellow solid. MS (LC-MS): 278 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].C(N(CC)CC)C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(#N)C>[CH3:8][Si:9]([CH3:11])([CH3:10])[C:12]#[C:13][C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1
Reactant: Cc1cc(Br)cs1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)cs1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-bromo-2-methylthiophene (1.00 g), trimethylsilyl acetylene (1.17 mL), bis(triphenylphosphine) palladium(II) dichloride (119 mg), copper(I) iodide (65 mg), triethylamine (1.57 mL), and acetonitrile (15 mL) was stirred at 80° C. for 4 hours under an argon atmosphere. The reaction mixture was left to be cooled and filtrated through a Celite (registered trademark) pad. To the filtrate was added saturated brine, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (605 mg). 1H-NMR (CDCl3) δ ppm: 0.23 (9H, s), 2.44 (3H, d, J=1.0 Hz), 6.75-6.80 (1H, m), 7.21-7.25 (1H, m).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1Nc1ccc(Br)nc1
Temperature: 130 °C
Yield: 34.5 %

Procedure:
A mixture of 6-bromopyridin-3-amine (27.27 mmol, 4.70 g), 2,5-dichlorobenzoic acid (54.34 mmol, 10.38 g), Cu (2.71 mmol, 0.2 g), Cu2O (1.36 mmol, 0.2 g) and K2CO3 (54.27 mmol, 7.5 g) in 1,2-dimethoxiethane (40 ml) was heated in a microwave oven at 130° C. for 14 hours, under nitrogen atmosphere. Water was added and the mixture was filtered through celite and extracted with AcOEt. The organic phase was washed with saturated K2CO3 aqueous solution and brine. The solvent was evaporated to afford 3.08 g (yield 31%) of the expected product.
Reaction SMILES: [SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][SH:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[C:22]([CH3:30])([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH3:23])=[CH:17][CH:16]=1>CC(N(C)C)=O.C(OCC)(=O)C>[SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][S:7][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:31])[C:22]([CH3:23])([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH3:30])=[CH:19][CH:20]=1
Reactant: SCCSCCS
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)c1ccc(SCCSCCS)cc1)N1CCOCC1
Reaction time: 5 h

Procedure:
25.7 g (0.15 mol) of 2-mercaptoethylsulfide (purity 90%) are added to a suspension of 8.3 g (0.06 mol) of potassium carbonate in 50 ml of dimethylacetamide. A solution of 8.0 g (0.03 mol) 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one in 25 ml of dimethylacetamide is added dropwise at 85° C. over 60 min. After stirring for 5 h, the reaction mixture is cooled, diluted with ethyl acetate (100 ml), extracted with water (3×100 ml) to remove the carbonate and dimethylacetamide, dried over MgSO4, and concentrated under vacuum. The resulting yellow liquid (stench) is purified by flash chromatography on silica gel (hexane/ethyl acetate 85:15) to yield a pale yellow oil. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.750 (t, SH), 2.57 (t, 4H), 2.71-2.85 (m, 6H), 3.20 (t, 2H), 3.70 (t, 4), 7.31 (d, 2H), 8.51 (d, 2H).