Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:31][CH2:32][CH2:33][OH:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:31][CH2:32][CH2:33][OH:34])=[O:18])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
5-[(2,5-Difluorophenyl)[(4-fluoro-3-methylphenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (300 mg, 0.69 mmol), 2-aminoethanol (60 μl, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1.0 mmol), 1-hydroxybenzotriazole (93 mg, 0.69 mmol), and triethylamine (292 μl, 2.1 mmol) were dissolved in methylene chloride (60 ml), and the solution was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (developed with 5% methanol/methylene chloride, eluted with 30% methanol/methylene chloride), to obtain the title compound (190 mg, 0.39 mmol, 58%) as a white amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=4[CH:34]=3)[CH2:19]2)=[N:14]1.ClC(Cl)C.[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH4-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:39]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]2[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1)[CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][N:13]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=4)[N:9]=[CH:8][CH:7]=3)[N:14]=2)[CH2:19]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(N(Cc3ccccc3)Cc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.9 %

Procedure:
To a mixture of 6-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one (30 mg, 0.06 mmol) and 4 Å molecular sieves (30 mg) was added dichloroethane (0.4 mL) and benzaldehyde (13 μL, 0.13 mmol). The solution was stirred for 1 h, after which NaB(OAc)3H (27 mg, 0.13 mmol) was added. After stirring overnight at RT, the reaction mixture was heated at 60° C. for 7 h. DMF (0.5 mL), NaBH4 (30 mg, 0.8 mmol) and CH2Cl2 (0.2 mL) were then added, and the reaction mixture was heated at 60° C. overnight. The mixture was diluted with satd. aq. NaHCO3 (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude was purified directly by basic reverse phase HPLC to afford 2 mg (5%) of the title compound. MS (ESI): exact mass calculated for C32H30N6O2S, 562.22; m/z found, 563.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[I-].[Na+].[H-].[Na+].[I-].Cl[CH2:19][CH2:20][S+](C)C>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:20][CH2:19]3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: C[S+](C)CCCl
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1c2cc(Br)ccc2CCC12CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
To a solution of 7-bromo-1-tetralone (1.03 g, 4.58 mmol) in tert-butanol (10 mL) was added sodium iodide (0.131 g, 0.872 mmol) and sodium hydride (0.349 g, 60% suspension in mineral oil, 8.72 mmol). The reaction mixture was stirred at r.t. for 20 min. Then (2-chloroethyl)dimethylsulfonium iodide (Intermediate 5, 1.10 g, 4.36 mmol) was added portionwise over 1 h. After the reaction had reached completion, water (15 mL) was added and the resulting mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography using 5% EtOAc in heptanes as eluent to give the title compound (0.789 g, 78%). 1H NMR (400 MHz, CDCl3) δ ppm 0.84 (dd, 2 H), 1.40 (dd, 2 H), 1.95 (t, 2 H), 2.93 (t, 2 H), 7.14 (d, 1 H), 7.55 (dd, 1 H), 8.11 (d, 1 H); MS (ES+) m/z 250.98, 253.03 [M+H]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10]C(C)(C)C)=O)#[N:2].[CH2:15]([C:23]1[CH:31]=[CH:30][C:26](C(O)=O)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:15]([C:23]1[CH:24]=[CH:25][C:26]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][CH:3]2[C:1]#[N:2])=[O:10])=[CH:30][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCCC1C#N
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Product: CCCCCCCCc1ccc(C(=O)N2CCCC2C#N)cc1

Procedure:
General procedure D was used to deprotect 19 (1.2 mmol, 0.24 g). The product was immediately carried on and coupled to 2 (1.2 mmol, 0.281 g) using general procedure F. After standard work up procedures the title product was recovered from flash chromatography to yield 0.238 g (0.76 mmol) after two steps. 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J=8.1, 2H), 7.21 (dd, J=7.9, 14.6, 2H), 4.91 (s, 0.5H), 4.66 (s, 0.5H), 3.67 (s, 1H), 3.56 (s, 1H), 2.66-2.60 (m, 2H), 2.32 (s, 1H), 2.17 (s, 1H), 2.01 (s, 1H), 1.88 (s, OH), 1.60 (d, J=7.5, 2H), 1.28 (dd, J=7.5, 14.4, 10H), 0.87 (t, J=6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 173.09, 146.33, 133.26, 132.60, 128.43, 128.21, 127.64, 127.44, 118.72, 59.24, 52.28, 50.05, 46.85, 35.84, 31.85, 31.19, 29.41, 29.22, 25.42, 22.64, 14.11.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:39]=[CH:38][C:21]([O:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]5)=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:41][C:2]([F:1])([F:40])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:13][CH2:14][CH:15]([C:18]4[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]5[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:29][CH2:30]5)=[CH:38][CH:39]=4)[CH2:16][CH2:17]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
10% Palladium on carbon (0.924 g, 0.87 mmol) was added to tert-butyl 4-[2-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazine-1-carboxylate (2.5 g, 4.34 mmol) and ammonium formate (2.74 g, 43.43 mmol) in ethanol (100 mL). The resulting mixture was stirred at 78° C., with further portions of ammonium formate being added every 5 hours until the reaction was complete. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was evaporated to dryness, redissolved in DCM (100 mL) and the solution was washed with water (100 mL) followed by brine (50 mL), then the solvents were evaporated to afford tert-butyl 4-[2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]ethyl]piperazine-1-carboxylate (2.020 g, 81%) as a solid.
Reaction SMILES: O[C:2]1([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:7]1([C:4]2[CH:3]=[C:2]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[O:6][N:5]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(O)CC(c3ccccc3)=NO2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccc3)no2)CC1
Yield: 86 %

Procedure:
tert-Butyl 4-(5-hydroxy-3-phenyl-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate (320 mg, 0.92 mmol) was dissolved in methanol (10 mL). A solution of sodium carbonate (200 mg, 1.9 mmol) in water (10 mL) was added to the mixture. Reaction was stirred at reflux for 2 hours. Methanol was removed from the reaction mixture in vacuo. Remaining aqueous was extracted 2× ethyl acetate. Combined extracts were washed with brine. Organic layer was dried (magnesium sulfate), filtered, and concentrated. Title compound was obtained as off-white solid in 86% yield. (M−C4H8+H)+=273.1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:39])([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:28]=[CH:29][C:30]([C:33]([OH:39])([CH3:38])[C:34]([F:35])([F:36])[F:37])=[CH:31][N:32]=3)=[CH:14][CH:13]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)OC1(C)C
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(O)(c1cnc(-c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)nc1)C(F)(F)F
Temperature: 100 °C
Yield: 37.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (318 mg, 0.88 mmol), 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (100 mg, 0.44 mmol, Intermediate E), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (18 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (431 mg, 1.32 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.5 mL), and water (0.2 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 45 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 3% 2M NH3.MeOH in DCM, to provide 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (70 mg) as an off-white solid and a mixture of enantiomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:24][CH:23]=[CH2:22])[C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2cc(Br)ccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
((R)-6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (3.26 g, 10 mmol) was dissolved in dimethylformamide (30 ml). Sodium hydride (50% in oil) (528 mg, 11 mmol) was added and stirred for 15 minutes at room temperature. Allyl bromide (0.95 ml, 11 mmol) was added and the reaction mixture was stirred at room temperature overnight. To the reaction mixture was added H2O (400 ml) and extracted twice with 150 ml diethylether. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product (3.25 g). The crude product was purified with silica gel chromatography with cyclohexane/ethyl acetate (9:1) as eluent, yielding the purified product (2.7 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH:14]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])[CH3:15].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:17]([CH:14]([CH3:16])[CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: CC(C)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COc1ccc(C(=O)N(c2ccccc2)C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2,4-dimethoxybenzoic acid (4.31 g, 23.7 mmol) in 35 mL of dichloromethane is treated with N-isopropylaniline (3.07 mL, 21.33 mmol), hydroxybenzotriazole (3.2 g, 23.7 mmol), and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (4.54 g, 23.7 mmol). This solution is stirred at room temperature for 18 hours and the resulting solution is partitioned between ethyl acetate and 1N hydrochloride solution. The organic layer is washed with water, dried over sodium sulfate and concentrated. The resulting material is purified by chromatography on silica gel (150 g) with 40-60% ethyl acetate/hexane as the eluent to afford 2,4-dimethoxy-N-(1-methylethyl)-N-phenylbenzamide as a colorless foam.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][NH:32]3)O1>>[NH:32]1[C:33]2[C:29](=[C:28]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=4[N:7]=3)[CH:36]=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Yield: 28 %

Procedure:
1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 55 from Example 11a was reacted with 0.18 g (1.3 eq) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure A to give 18 mg of 389 after RP-HPLC purification (28% yield). MS (Q1) 381.2 (M)+
Reaction SMILES: COC(=O)[CH2:4][S:5][CH2:6][CH:7]([NH:15][C:16]([O:18]C(C)(C)C)=O)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1>FC(F)(F)C(O)=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[NH:15][C:16](=[O:18])[CH2:4][S:5][CH2:6]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CSCC(NC(=O)OC(C)(C)C)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CSCC(c2ccc(F)cc2)N1
Yield: 100.7 %

Procedure:
A solution of [2-tert-butoxycarbonylamino-2-(4-fluoro-phenyl)-ethylsulfanyl]-acetic acid methyl ester (3.23 g, 9.4 mmol) in trifluoroacetic acid (10 mL) was stirred at 50° C. for 10 hours. The solution was then concentrated under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give 2.0 g of 5-(4-fluoro-phenyl)-thiomorpholin-3-one, MP=111-112° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([CH2:48][O:49][CH2:50][C@H:51](O)[CH2:52][O:53]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>N1C=CC=CC=1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:48][O:49][CH2:50][C@H:51]2[CH2:52][O:53]2)[C@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](COC[C@H](O)COS(=O)(=O)c3ccc(C)cc3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](COC[C@H]3CO3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1

Procedure:
In analogy to the procedure described in example 1) (h)-(l), (R)-3-[(3S,4R,5R)-4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol was treated with di-tert-butyl-dicarbonate in dioxane/water in the presence of sodium hydrogencarbonate to yield the (3S,4R,5R))-3-[(2R)-2,3-dihydroxy-propoxymethyl]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester. Subsequent mono-tosylation of the aforementioned diol by toluene-4-sulfochloride in pyridine led to the (3S,4R,5R)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxymethyl]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester which after treatment with NaOH in DMSO yielded (3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester. Further reaction of the epoxide with sodium methylate in a mixture of N,N-dimethylformamide and methanol gave the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxymethyl]-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester which was finally deprotected by treatment with hydrochloric acid in methanol to yield the (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol as a colorless foam; MS: 660 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].[F:35][C:36]([F:43])([F:42])[CH2:37][NH:38][CH2:39][CH2:40][NH2:41].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:41][CH2:40][CH2:39][NH:38][CH2:37][C:36]([F:43])([F:42])[F:35])=[O:33])[C:25]=1[CH3:34])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: NCCNCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCNCC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.2 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (267 mg, 0.51 mmol), N-(2,2,2-trifluoro-ethyl)-ethane-1,2-diamine (123 mg, 0.86 mmol), HOBt (104 mg, 0.77 mmol), EDAC (154 mg, 0.81 mmol) and TEA (0.14 mL, 1 mmol) in DMF (3 mL) was stirred At rt for 48 hours. The reaction was concentrated, diluted with sat. sodium bicarbonate and extracted with DCM. The organic layer was washed with brine, dried and purified on a silica gel column to give 237 mg (72%) of the titled compound.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[O-2].[Mg+2:14]>O>[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[Mg+2:14].[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O

Procedure:
Iceberg lettuce was preserved as in Example 10, except that the lettuce slices were dipped into a preservative solution containing 4.0 grams ascorbic acid and 0.30 grams magnesium oxide in 100 ml water, to provide a magnesium ascorbate solution having an ascorbate ion to magnesium ion molar ratio of 3:1, and a pH of 4.15. The results are shown in Table 5.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH3:31])[N:25]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[N:25]=3)[CH3:31])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CNc1cccc(OC)n1
Product: COc1cccc(N(C)C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)n1

Procedure:
The crude product was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and and 2-methoxy-6-methylaminopyridine. The reaction mixture was evaporated to dryness, dissolved in dichloromethane (100 ml) and extracted with a aqueous phosphate buffer, pH 7. The aqueous phase was extracted with dichloromethane (100 ml×2) and the combined organic phases were dried and evaporated to dryness. The product was subjected to flash chromatography, ethyl acetate/heptane (1:7) to give the titlew product (86%, white crystals). HPLC-MS m/z=420.4 (M+1), Rt: 5.23 min.
Reaction SMILES: CSC.B(F)(F)F.C[N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32]C)=[CH:25][C:24]=2[Br:34])=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12]>ClCCl>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:35])[C:18]=1[O:22][C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([OH:32])=[CH:25][C:24]=1[Br:34])[C:14]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:36]
Reactant: COc1cc(Br)c(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)c(Br)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Boron trifluoride dimethyl sulfide (10 μL, 80 μmol) was added at room temperature to a stirred solution of methyl-N-[3,5-dichloro-4-(2-bromo-4-methoxy-5-isopropylphenoxy)benzoyl]glycine (1.0 mg, 2.0 μmol) and dichloromethane (0.50 mL). The reaction mixture was stirred at room temperature for 8 hours and then treated with ice-water, extracted with ethyl acetate and washed with water. The organic phase was dried over sodium sulphate and concentrated to give a light yellow solid. The solid was purified on column (MPLC, silica gel, chloroform/methanol/acetic acid, gradient elution from 1/0/0 to 95/5/0.5) to give 0.90 mg (94%) of N-[3,5-dichloro-4-(2-bromo-4-hydroxy-5-isopropylphenoxy)benzoyl]glycine. LC-MS (ES−1): m/z 476.