Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.C(=O)=O>CCOCC>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 64 h
Yield: 52 %

Procedure:
Bis{di(1H,1H,2H,2H-perfluorooctyl)phenylphosphino}palladium dichloride (89 mg, 0.05 mmol), iodobenzene (0.11 ml, 1 mmol), phenylboronic acid (122 mg, 1 mmol) and triethylamine (0.15 ml, 1.1 mmol) were placed in a 10 ml stainless steel cell. The cell was sealed and pressurised to approximately 5520 kPa (800 psi) (i.e. full of carbon dioxide). The cell was then heated to 100 C. for 64 hrs and then allowed to cool. When the pressure had dropped below 13800 kPa (2000 psi) the cell was vented into ether (100 ml), the cell was opened once atmospheric pressure was reached and washed out with dichloromethane (20 ml). The organic fractions were combined and concentrated in vacuo to give the crude product. The product was purified by flash column chromatography on silica gel, eluting with hexane to give a white crystalline solid (80 mg, 0.52 mmol, 52%); δH (250 MHz; CDCl3) 7.34-7.65 (10H, m, aryl).
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.[Fe]>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: [Fe]
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
To 270 g of polyphosphoric acid (117.4% phosphoric acid) heated at 80°-95° C. was added 0.75 g (2.7 mmole) of ferrous sulfate heptahydrate followed by 60 g (0.17 mole) of 2,5-dianilinoterephthalic acid containing about 583 ppm (about 0.63 mmole) of iron. The total iron content, relative to 2,5-dianilinoterephthalic acid, was about 1.9 mole percent. The mixture was heated at 120°-125° C. for four hours. After the viscous solution was cooled to 90°-95° C., the acid strength was adjusted to 107% by the dropwise addition of 75% phosphoric acid (65 g). The resultant melt was stirred for 20 minutes and then slowly poured into a mixture of 360 g of methanol and 40 g of water at 35° C. The temperature of the resultant slurry was allowed to rise during the addition to about 64° C., with the temperature being controlled during addition by external cooling and adjustment of melt addition rate. The slurry was heated at reflux (68°-72° C.) for one hour and diluted with 600 g of water. After the resultant slurry was stirred for 30 minutes, the solid component was collected by filtration and washed with water until acid-free. The resultant presscake was reslurried in 1000 g of water and 5 g of 50% sodium hydroxide, then heated for 85° C. for two hours. After being cooled to 60° C., the slurry was filtered and washed with water until free of alkali. After the presscake was reslurried in 800 g water, a solution containing 37 g of water, 1.6 g of 50% sodium hydroxide, and 3.15 g of naphthenic acid was added. The slurry was heated to 140°-145° C. for two hours in a closed system (e.g., a pressure reactor). After the slurry was cooled to 60°-70° C., the pH was adjusted to 4.5-5.0 with phosphoric acid, stirred for one hour, collected by filtration, and washed with water. The wet cake can be oven dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give about 50 g of quinacridone as a brilliant violet solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:10]([O:11][C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)=[O:13])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:20]1([CH3:28])[CH:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[O:21]1.I([O-])(=O)(=O)=[O:30].[Na+]>O1CCOCC1.O.C(OCC)C>[CH3:1][O:2][CH:3]1[CH:10]([O:11][C:12]([N:14]2[CH2:19][CH2:18][S:17](=[O:30])[CH2:16][CH2:15]2)=[O:13])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:20]1([CH3:28])[CH:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[O:21]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC1C(OC(=O)N2CCSCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: COC1C(OC(=O)N2CCS(=O)CC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
To a solution of 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(thiomorpholin-4-ylcarbonyloxy)-1-oxaspiro[2,5]octane (41 mg) in 1,4-dioxane (2 ml) and water (0.2 ml) was added sodium periodate (21 mg) at ambient temperature. After stirring at the same temperature for 18 hours, the reaction mixture was diluted with diethyl ether. The precipitates were filtered off by celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by ethyl acetate) to yield 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(1-oxothiomorpholin-4-ylcarbonyloxy)-1-oxaspiro[2,5]octane (25 mg) as an oil.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[C:20]([CH3:28])[N:19]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[C:20]([CH3:28])[N:19]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: COC(=O)c1cc(C)nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: [Pd]
Product: COC(=O)c1cc(C)nc(N2CC[C@H](N)[C@H](OC)C2)c1
Yield: 91.2 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-6-methylpyridine-4-carboxylate obtained in Example (166a) (38.8 mg) and a 10% palladium-carbon catalyst (40 mg), to obtain 23.9 mg of the title compound as a colorless oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.F[C:25]1[C:30]([C:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:25]2[C:30]([C:31]3[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH:32]=3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:19][CH:18]=1
Reactant: OC1CC=C(c2cccnc2F)CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: OC1CC=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 200 °C
Yield: 6.3 %

Procedure:
To a vial containing cesium carbonate (1391 mg, 4.27 mmol) was added 4-(benzo[d]thiazol-2-ylamino)phenol (1035 mg, 4.27 mmol), and 4-(2-fluoropyridin-3-yl)cyclohex-3-enol (330 mg, 1.708 mmol) followed by NMP (2.2 mL). The reaction was heated at 200° C. for 2 h with microwave irradiation. The black mixture was diluted with ethyl acetate and washed with 5N NaOH before drying over sodium sulfate, filtering, and concentrating under reduced pressure to a brown residue. Purification by column chromatography (ethyl acetate/dichlormethane) afforded 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)cyclohex-3-enol (44.8 mg, 0.108 mmol, 3, steps, 6.31% yield) as a pale brown oil. MS (ESI, pos. ion) m/z: 416.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[NH:19][C:18]4[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15](=[O:24])[N:14]([CH2:25][CH2:26][CH3:27])[C:13]=4[N:12]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:24]=[C:15]1[N:14]([CH2:25][CH2:26][CH3:27])[C:13]2[N:12]=[C:11]([C:6]34[CH2:7][CH2:8][C:3]([CH:2]=[O:1])([CH2:10][CH2:9]3)[CH2:4][CH2:5]4)[NH:19][C:18]=2[C:17](=[O:20])[N:16]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 0.092 g (0.246 mmol) of 8-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 15) in 5 ml of CH2Cl2 was added 0.125 g (0.295 mmol) Dess-Martin periodinane. The reaction mixture was stirred at rt until the oxidation was complete. The reaction solution was filtered through a plug of basic alumina, washed with sat'd NaHCO3, brine, and dried over Na2SO4. The CH2Cl2 solution was conc'd in vacuo to give 0.057 g (62% yield) of an off-white solid.(MH+=373.30)
Reaction SMILES: [C:1]([N:18]1[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:19]1[C:20](O)=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].B.CSC.CO>C1COCC1>[C:1]([N:18]1[CH:19]([CH2:20][OH:21])[CH2:23][CH:24]([OH:26])[CH2:25]1)([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CC(O)CC1CO
Temperature: 25 °C

Procedure:
To a solution of N-fmoc-trans-4-hydroxy-L-proline (13.4 g, 38.1 mmol) in 250 ml THF was added borane-methyl sulfide (78 mmol, 5.78 g, 7.22 ml) dropwise at room temperature. After the evolution of H2 had ceased, the solution was heated to reflux with mechanical stirring. After 1 hour a white precipitate had formed. Methanol was carefully added, and the resulting solution refluxed for a further 15 minutes. The solution was cooled to room temperature, the solvents evaporated under reduced pressure, and the residual gum coevaporated with 2×100 ml methanol (MeOH). The resulting crystalline product weighed 12.0 g (35.3 mmol, 93%). 1H NMR: (CDCl3, 200 MHz) δ7.85-7.25 (8H, m, ArH) , 4.50-4.10 (5H, m, ArCHCH2, H3, H5), 3.80-3.40 (4H, m, 2 H2, 2 H6), 2.15-1.95 (1H, m, H2a), 1.80-1.60 (1H, m, H2b).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26](N)=[O:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.[OH-:32].[K+].Cl>C(O)C.O>[OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26]([OH:27])=[O:32])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: [OH-]
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(N)=O)cn5)cc4)CC3)n2CCS1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixed solution of the compound (200 mg, 0.458 mmol) obtained in Example 65 and potassium hydroxide (129 mg) in ethanol (5.00 mL) and water (1.50 mL) was stirred at 100° C. for 9 h. The reaction mixture was cooled to room temperature, poured into 0.05 N hydrochloric acid (50.0 mL) with ice cooling, extracted with dichloromethane/2-propanol (4/1), and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the white precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (166 mg, 83%) as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][CH2:11][CH2:12][O:13][C:14]1[C:23]([O:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>>[Br:10][CH2:11][CH2:12][O:13][C:14]1[C:23]([O:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:22][C:21]([N+:1]([O-:4])=[O:2])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cccc(OC(=O)c2ccccc2)c1OCCBr
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc(OC(=O)c2ccccc2)c1OCCBr
Yield: 87 %

Procedure:
A solution of fuming nitric acid (55 mL) and concentrated sulfuric acid (11 mL) was cooled to −5° C. Powdered methyl 2-[(2-bromoethyl)oxy]-3-[(phenylcarbonyl)oxy]benzoate (30 g, 79.1 mmol) was slowly added over a period of 30 min. After an additional stirring time of 30 min., the reaction mixture was quickly poured over ice, which was then extracted with dichloromethane (2×400 mL). The combined organic layers were washed with water (400 mL) and aqueous saturated sodium bicarbonate (200 mL). The organic solution was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The crude precipitate was triturated with diethyl ether (200 mL) to give 29.1 g (87%) of methyl 2-[(2-bromoethyl)oxy]-5-nitro-3-[(phenylcarbonyl)oxy]benzoate as an off-white powder: 1H NMR (400 MHz, CDCl3): 9.06 (t, J=2.2 Hz, 1H), 8.72 (d, J=3.2 Hz, 1H), 8.57-8.53 (m, 3H), 8.32 (d, J=3.2 Hz, 1H), 7.79 (t, J=8.0 H, 1H), 4.43 (t, J=5.8 Hz, 2H), 4.00 (s, 3H), 3.57 (t, J=5.6 Hz, 2H).
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OC(=O)C)(=O)C>[C:1]1([CH2:11][CH:12]2[CH2:16][C:17](=[O:18])[O:19][C:13]2=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=Cc1cccc2ccccc12)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(Cc2cccc3ccccc23)C(=O)O1
Yield: 69.7 %

Procedure:
A solution of 24.5 g of 2-(1-naphthylmethylene)succinic acid in 260 ml of acetic anhydride was heated at 60° C. for 1 hour, and the reaction mixture was evaporated under reduced pressure. A mixture of benzene and hexane (1:1) was added to the residue, and the precipitated crystals were collected by filtration to obtain 16.0 g of 2-(1-naphthylmethyl)succinic anhydride as orange yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1C=C[C:14]2N(O)N=[N:17][C:15]=2[CH:16]=1.C(N)(C)C.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[CH:15]([NH:17][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[CH3:1])([CH3:16])[CH3:14]
Reactant: Cc1ncccc1C(=O)O
Reactant: On1nnc2ccccc21
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ncccc1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methyl nicotinic acid (2.5 g, 18 mmol), HOBT (3.7 g, 27 mmol), isopropylamine (3.1 mL, 36 mmol), and triethylamine (7.5 mL, 54 mmol) in 150 mL of DMF is added EDC (5.2 g, 27 mmol). The reaction is allowed to stir at room temperature for 24 hours and is then concentrated under reduced pressure. Ethyl acetate and brine is added and the layers are separated. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude residue by silica gel flash column chromatography gives the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:37]1[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][CH:40]1[CH2:41][CH2:42][N:37]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:38][CH2:39]1
Reactant: OCCC1CCNCC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(CCO)CC3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (50 mg, 0.20 mmol), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol), DIPEA (78 μL, 0.47 mmol), 4-piperidineethanol (30 mg, 0.23 mmol) and EDAC (45 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on column chromatography (eluent: dichloromethane/MeOH, 95/5) to give a white solid. This solid was triturated in MeOH, filtered, washed with MeOH and diethyl ether and dried to give the title compound (35 mg, 55%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCOC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCCO
Product: CCOC(=O)Cc1ccccc1-c1ccc(-c2onc(C)c2NC(C)CCCO)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 4-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamino]-pentan-1-ol and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)=O.CO.[Li]CCCC.Br[CH2:46][C:47]([CH3:70])=[CH:48][CH2:49][CH2:50][C:51]([CH3:69])=[CH:52][CH2:53][C:54]1[C:63]([CH3:64])=[C:62]([O:65][CH3:66])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]=1[O:67][CH3:68]>C1COCC1>[C:8]1([S:5]([CH:4]([CH:3]=[C:2]([CH3:1])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:46][C:47]([CH3:70])=[CH:48][CH2:49][CH2:50][C:51]([CH3:69])=[CH:52][CH2:53][C:54]2[C:63]([CH3:64])=[C:62]([O:65][CH3:66])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]=2[O:67][CH3:68])(=[O:6])=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCS(=O)(=O)c1ccccc1
Reactant: COc1c(C)c(CC=C(C)CCC=C(C)CBr)c(OC)c2ccccc12
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C)c(CC=C(C)CCC=C(C)CC(C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)S(=O)(=O)c2ccccc2)c(OC)c2ccccc12
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 135.9 %

Procedure:
9.06 g (18.76 mmol) (3,7,11,15,19-pentamethyl-eicosa-2,6,10,14,18-pentaene-1-sulfonyl)-benzene were dissolved in 80 ml of dry THF and the solution was cooled to −78° C. with CO2/MeOH. At −78° C., 11.80 ml (18.88 mmol) BuLi (1.6 M solution in hexane) was added drop wise via septum and syringe over 10 min. The orange solution was stirred for 2.5 h at −78° C. 6.07 g (14.56 mmol) 2-(8-bromo-3,7-dimethyl-octa-2,6-dienyl)-1,4-dimethoxy-3-methyl-naphtalene dissolved in 30 ml of dry THF was added via dropping funnel over 10 min. The brown reaction mixture was stirred at −78° C. for 1.5 h. At −78° C., the reaction was quenched by addition of 50 ml of a Et2O/MeOH mixture (1:1 v/v). The mixture was allowed to reach room temperature and after that 100 ml of saturated NH4Cl solution was added. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo by rotary evaporation at 30° C. to give 16.21 g of 2-(9-benzenesulfonyl-3,7,11,15,19,23,27-heptamethyl-octacosa-2,6,10,14,18,22,26-heptaenyl)-1,4-dimethoxy-3-methyl-naphtalene as a brownish yellow oil, which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7])C.O=P1(C)CCC=C1.[Cl-].[Na+]>O>[CH:8]([CH:5]([CH:11]([CH3:13])[CH3:12])[C:6]#[N:7])([CH3:10])[CH3:9]
Reactant: CCOC(=O)C(C#N)(C(C)C)C(C)C
Agent: CP1(=O)C=CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C(C#N)C(C)C
Yield: 85 %

Procedure:
98.5 g (0.5 mol) of diisopropyl-cyanoacetic acid ethyl ester (prepared according to J. Chem. Soc., 1930, page 2,758), 300 ml of 1-oxo-1-methyl-phospholine, 31 g of sodium chloride and 22 g of water were heated to 160°-170° C. for 9 hours. After cooling, the mixture was diluted with 1,000 ml of water and extracted by shaking four times with 150 ml of petroleum ether each time. The combined petroleum ether phases were washed twice with 200 ml of water each time and dried with Na2SO4 and the petroleum ether was distilled off under normal pressure. The residual crude product was then purified by vacuum distillation. 53.2 g (85% of theory) of diisopropyl-acetonitrile of boiling point 60° C./14 mm Hg were obtained. Refractive index nD20 =1.4190.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: N[C@@H]1CC[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2S(=O)(=O)c1ccccc1
Yield: 97 %

Procedure:
(1R*,2R*,5S*,6R*)-2-benzylamino-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane (Description 4; 1.73 g, 3.3 mmol) was dissolved in a mixture of methanol (30 mL) and acetic acid (20 mL), then treated with 10% palladium on charcoal (500 mg). The suspension was hydrogenated at 50 psi hydrogen for 16 hours, then filtered and concentrated. The residue was basified with saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (2×100 mL). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the title compound as a gum (1.10 g, 3.2 mmol).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].O.O.[C:9]([O-:14])(=[O:13])[CH:10]([CH3:12])[OH:11].C[N+](C)(C)C>CN(C)C=O>[C:9]([O:14][CH2:2][C:3]([O:5][CH3:6])=[O:4])(=[O:13])[CH:10]([CH3:12])[OH:11]
Reactant: COC(=O)CBr
Reactant: CC(O)C(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC(=O)C(C)O

Procedure:
Methyl bromoacetate (4.73 mL, 50 mmol) was added to a stirring solution of tetramethylammonium lactate dihydrate (11.0 g, 55 mmol) in 20 mL dimethylformamide at room temperature. Tetramethylammonium bromide separated from the reaction mixture as a white solid and the title compound was formed quantitatively within 60 min as determined by CG (Method A). The reaction mixture was filtered, the solids were washed with ethyl ether, and the combinated filtrate and ether solution was washed with 5% NaCl/5% NaHCO3. Sufficient ethyl ether was added to effect rapid separation of the phases, the aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgSO4. The solvent was removed and the resulting residue was distilled under reduced pressure to give the title compound: b.p. 79° C./0.15 mm Hg.