Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]=2[C:7](=[O:10])[NH:8][CH:9]=1.I[CH3:25].O>CN(C)C=O>[Br:3][C:4]1[C:5]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]=2[C:7](=[O:10])[N:8]([CH3:25])[CH:9]=1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)c[nH]c(=O)c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(C)c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil dispersion) was added to a stirring solution of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (11.2 g, 30.4 mmol) in dimethylformamide (217 mL) under nitrogen. After 30 minutes, iodomethane (2.27 mL, 36.5 mmol) was added and the solution was stirred at room temperature for 3 h. Upon addition of water (250 mL) a precipitate formed. The precipitate was collected by vacuum filtration, rinsed with water (50 mL) and dried in a vacuum oven at 55° C. overnight to provide 11.2 g of 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (96%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:7]([C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=1)=[O:8]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Clc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2Cl)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
A mixture of m-toluoyl chloride (22 g, 0.17 mol) and 1,4-dichlorobenzene (120 g, 0.82 mol) was heated to 100° C. in a flask. Aluminum chloride (60 g, 0.45 mol) was added in one portion. Hydrogen chloride started to evolve from the solution. The mixture was heated to 170° C. in 30 min. and stirred at this temperature for 3 hours. The resulting brownish solution was cooled to about 80° C. and poured onto ice. Ether (50 ml) was added. The organic layer was separated and distilled under vacuum after the removal of ether. The residue from distillation was recrystallized twice from hexane to give 20 g of white crystals (53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccc(F)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(F)c(F)c1
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-(3,4-difluorophenyl)acetate (1.20 g, 5.99 mmol), N-bromosuccinimide (1.17 g, 6.59 mmol), and 2,2′-azobis(isobutyronitrile) (0.148 g, 0.899 mmol) in CCl4 (20 mL) was gradually heated to reflux and stirred at this temperature overnight. The solvent was removed in vacuum. The residue was purified by flash column chromatography (100% hexanes for 5 minutes, then 0 to 5% of EtOAc in hexanes over 23 minutes). The desired product was obtained as a colorless oil (1.14 g, 68%). 1H NMR (300 MHz, CDCl3) δ 1.31 (d, J=6.0 Hz, 3H), 4.17-4.35 (m, 2H), 5.27 (s, 1H), 7.11-7.20 (m, 1H), 7.24-7.30 (m, 1H), 7.42-7.52 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:13][C:14]([C@@H:16]([NH2:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].[C:22]([CH2:26][C:27](O)=O)([CH3:25])([CH3:24])[CH3:23].CC(C)(C)CC=O>CO>[CH3:23][C:22]([CH2:26][CH2:27][NH:21][C@H:16]([C:14]([NH:13][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([OH:20])=[O:19])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: CC(C)(C)CC(=O)O
Agent: CC(C)(C)CC=O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.6 %

Procedure:
Aspartame (11.76 g), tertbutylacetic acid (4.64 g) and methanol (100 ml) were charged to a hydrogenation vessel. 3,3-Dimethylbutyraldehyde (4.0 g) was added. The vessel was pressure purged with nitrogen (4×), and 0.48 g of 4% palladium on carbon (containing 50% water) was added. After pressure purging the reactor with nitrogen (4×), followed by hydrogen (4×), the mixture was hydrogenated at 50 psig for 12 hours at room temperature. After completion of the reaction, the vessel was pressure purged with nitrogen (4×). The catalyst was removed from the reaction mixture by filtration through powdered cellulose. Methanol (50 ml) was used to rinse the reaction vessel and the filter cake. The filtrate and wash were combined, and methanol was evaporated under reduced pressure. The solution was reduced to 75 ml total volume, and 75 g of deionized water was added. The remaining methanol was evaporated from the solution under reduced pressure. The resulting solution was stirred at room temperature for 12 hours. Hexane (75 ml) was added, and the solution was stirred for 3 hours at room temperature. The crystallized solid was isolated by filtration and washed with 50 ml deionized water and 50 ml of hexane. The wet product was dried in air to give 8.1 g of neotame (>98% by HPLC).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[C:23]([CH:33]=1)[CH2:24][NH:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:17])([C:10]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C:26]([NH:25][CH2:24][C:23]1[CH:33]=[C:19]([Cl:18])[CH:20]=[CH:21][C:22]=1[N:34]1[CH:38]=[N:37][N:36]=[N:35]1)=[O:32])=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)CC(C)(NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)C[C@](C)(NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-tert-butyloxycarbonylamino-2,4-dimethylpentanoic acid (120 mg, 0.49 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (150 mg, 0.49 mmol, 1.0 equiv), EDC (141 mg, 0.73 mmol, 1.5 equiv) and HOAt (33 mg, 0.24 mmol, 0.5 equiv) in DMF (1 ml) was brought to pH 8 by dropwise addition of Hünig's Base and stirred at room temperature for 18 h. The solvent was removed in vacuo, and the resulting oil was purified by silica gel chromatography (50% EtOAc-hexanes to 70% EtOAc-hexanes to EtOAc) to afford the two separate diastereomers as white solids. Diastereomer A (less polar): 1H NMR (300 MHz, CDCl3): δ 9.32 (s, 1 H), 8.10 (t, J=5.4 Hz, 1 H), 7.72 (d, J=2.1 Hz, 1 H), 7.40 (dd, J=2.1, 8.1 Hz, 1 H), 7.27 (d, J=8.1 Hz, 1 H), 5.03 (s, 1 H), 4.55–4.50 (m, 1 H), 4.23 (dd, J=6.3, 15.3 Hz, 1 H), 4.01 (dd, J=5.1, 15.3 Hz, 1 H), 3.84–3.79 (m, 1 H), 3.55–3.52 (m, 1 H), 2.22–2.12 (m, 1 H), 1.95–1.68 (m, 5 H), 1.59 (s, 3 H), 1.51–1.45 (m, 1 H), 1.34 (s, 9 H), 0.98 (d, J=6.6 Hz, 3 H), 0.85 (d, J=6.3 Hz, 3 H). Diastereomer B (more polar): 1H NMR (300 MHz, CDCl3): δ 9.29 (s, 1 H), 8.11–8.08 (m, 1 H), 7.70 (d, J=2.1 Hz, 1 H), 7.39 (dd, J=2.1, 8.4 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 5.21 (s, 1 H), 4.59–4.54 (m, 1 H), 4.25 (dd, J=6.3, 15.3 Hz, 1 H), 4.00 (dd, J=4.8, 15.3 Hz, 1 H), 3.85–3.79 (m, 1 H), 3.53–3.49 (m, 1 H), 2.24–2.22 (m, 1 H), 1.97–1.83 (m, 5 H), 1.66–1.60 (m, 1 H), 1.39 (s, 3 H), 1.36 (s, 9 H), 0.97 (d, J=6.3 Hz, 3 H), 0.91 (d, J=6.6Hz, 3 H). Diastereomeric mixture: LCMS (M+H): 534.0.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]=[O:19])=[C:12]([Br:20])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][Si:22]([CH2:25][Mg]Cl)([CH3:24])[CH3:23]>C1COCC1>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]([OH:19])[CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[C:12]([Br:20])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=CCCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Solvent: C1CCOC1
Product: C[Si](C)(C)CC(O)CCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 3-(4-benzenesulfonyl-2-bromo-phenyl)-propionaldehyde (4.77 g, 13.5 mmol) in THF (40 mL) was added trimethylsilylmethylmagnesium chloride (1M in Et2O, 27.3 mL) at −78° C. under Argon atmosphere. The reaction was allowed to reach 0° C. and was stirred for 3 hours, then quenched by addition of buffer pH=2 KHSO4/Na2SO4 (10%) at 0° C. The mixture was extracted 3 times with EtOAc and the combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 8/2) to afford 4-(4-benzenesulfonyl-2-bromo-phenyl)-1-trimethylsilanyl-butan-2-ol (4.60 g, 77% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH:27][C@H:28]3[CH2:33][CH2:32][C@@H:31]([CH3:34])[CH2:30][CH2:29]3)[N:10]=2)[CH2:3][CH2:2]1.Cl[C:36]([O:38][CH3:39])=[O:37]>>[CH3:34][C@@H:31]1[CH2:30][CH2:29][C@H:28]([NH:27][C:11]2[N:10]=[C:9]([O:8][CH2:7][CH:4]3[CH2:3][CH2:2][N:1]([C:36]([O:38][CH3:39])=[O:37])[CH2:6][CH2:5]3)[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:12]=2)[CH2:33][CH2:32]1
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CCNCC3)n2)CC1
Reactant: COC(=O)Cl
Product: COC(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)CC1

Procedure:
Using the procedure of Example 1 Step 5, 4-((piperidin-4-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine was reacted with methyl chloroformate to provide the title compound. 1H NMR (CDCl3, 400 MHz) 8.07 (s, 1H), 7.37 (d, 2H), 6.93 (d, 2H), 5.19 (sb, 1H), 4.19 (d, 2H), 4.07 (m, 3H), 3.88 (m, 4H), 3.69 (s, 3H), 3.20 (m, 4H), 2.77 (m, 2H), 1.97-1.57 (m, 11H), 1.26 (m, 3H), 0.94 (d, 3H); MS (ESI) m/z: Calc: 523.3 (M+). Found. 524.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[B:31](OC)([O:34]C)[O:32]C.Cl>C1COCC1.O>[F:1][C:2]1[C:7]([B:31]([OH:34])[OH:32])=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)[N:3]=1
Reactant: COB(OC)OC
Reactant: CCCCCCCCCc1ccc(-c2cccc(F)n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.8 %

Procedure:
A solution of 100 mol of 2-fluoro-6-(4-nonylphenyl)pyridine in 500 ml of dry THF is added dropwise to a solution of 110 mmol of lithium diisopropylamide in 100 ml of dry tetrahydrofuran at −70° C. under a protective gas atmosphere. The mixture is stirred for an additional 4 h at this temperature. A solution of 200 mmol of trimethyl borate in 40 ml of dry tetrahydrofuran is then added dropwise at a temperature of less than −60° C. The reaction mixture is then slowly warmed up to room temperature, admixed with a solution of 60 ml of water and 20 ml of concentrated hydrochloric acid while cooling with ice, and stirred for another hour at room temperature. The reaction mixture is extracted with tert-butyl methyl ether, the combined organic extracts are washed with water and saturated sodium chloride solution and dried with sodium sulfate, and the solvents are removed under reduced pressure. The raw product is crystallized from n-heptane/acetone 4:1, giving 19.8 g (58%) of 2-fluoro-6-(4-nonylphenyl)pyridine-3-boronic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][CH2:8][C:9]([CH2:11][C:12](OC)=[O:13])=O>C(O)(=O)C>[CH2:8]([C:9]1[CH:11]=[C:12]([OH:13])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1)[CH3:7]
Reactant: Nc1nc[nH]n1
Reactant: CCC(=O)CC(=O)OC
Solvent: CC(=O)O
Product: CCc1cc(O)n2ncnc2n1

Procedure:
33.6 g (0.4 mmol) of 3-amino-1H-1,2,4-triazole and 52 g (0.4 mol) of methyl 3-oxo-n-valerate were heated in 130 ml acetic acid for 70 min. After cooling crystals precipitated, which were filtered by suction and dissolved in 1 l water. After several extractions with dichloromethane the combined organic layers were dried over sodium sulfate, and the solvent distilled off in vacuo. The title compound crystallized during the evaporation in colorless crystals,
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1>CN(C=O)C>[OH:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH:63][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1
Reactant: Nc1cccc(-c2ccc(O)nc2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(O)nc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 18 %

Procedure:
DIEA (0.008 mL, 0.048 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.009 g, 0.043 mmol) and HATU (0.018 g, 0.048 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-hydroxy-pyridin-3-yl)-phenylamine (0.008 g, 0.043 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.003 g of product in 21% yield: LCMS (ESI) m/z 389 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([Si](C)(C)C)[N:11]=[N:10]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][N:11]=[N:10]1
Reactant: C[Si](C)(C)c1cn(-c2cc(F)ccc2Br)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Fc1ccc(Br)c(-n2ccnn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
1-(2-Bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (0.800 g, 2.55 mmol) was dissolved in THF (10 mL) and tetrabutylammonium fluoride (2.8 mL, 2.80 mmol, 1.0 M in THF) was added dropwise and the reaction mixture was stirred at 25° C. for 4 h. The resulting mixture was concentrated in vacuo and the residue was purified with a Biotage system on silica gel with hexanes:ethyl acetate (8:2 to 7:3) gradient as the eluent to afford the title compound as a white solid (0.36 g, 58% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 8.06 (1H, d, J=1.0 Hz), 7.90 (1H, d, J=1.3 Hz), 7.76 (1H, dd, J=8.8, 5.3 Hz), 7.39 (1H, dd, J=8.3, 2.8 Hz), 7.19 (1H, ddd, J=8.9, 7.5, 3.0 Hz), LCMS (+ESI, M+H+) m/z 242/244.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[C:8]([OH:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:14])[CH:4]=1)[NH2:2].C(O[CH:18]=[CH:19][C:20](=O)[C:21]([F:24])([F:23])[F:22])C.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[CH3:14][C:5]1[CH:4]=[C:3]([N:1]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[N:2]2)[C:12]2[C:7](=[C:8]([OH:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: Cc1cc(NN)c2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-n2nccc2C(F)(F)F)c2cccc(O)c2n1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of 4-hydrazino-2-methyl-quinolin-8-ol (21 mg, 0.11 mmol) and 4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (16 μL, 0.11 mmol) in ethanol (0.5 mL) was heated to 75° C. for 30 min. The solvent was than removed in vacuo and the residue was redissolved in acetic acid (0.5 mL). After the addition of concentrated H2SO4 (20 μL) and stirring for 1 h at 100° C., the reaction mixture was cooled to room temperature and a mixture of Na2CO3 (0.40 mg, 3.8 mmol) in water (1 mL) was added. The reaction mixture was then concentrated in vacuo and the residue was partitioned between DCM (10 mL) and water (5 mL). The pH of the aqueous layer was adjusted to 10 by the addition of saturated aqueous NH3 solution and the aqueous layer was extracted with DCM (1×320 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS (m/z): 294.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[Cl:31][C:32]1[S:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][C:36]=1[Cl:37]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:37][C:36]1[CH:35]=[C:34]([S:38]([NH:1][C:2]2[CH:30]=[CH:29][C:5]3[NH:6][C:7]([C:12]4[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]5[C:20]([C:21]=4[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=5)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=3[CH:3]=2)(=[O:40])=[O:39])[S:33][C:32]=1[Cl:31]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cc(Cl)c(Cl)s4)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 49 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 2,3-dichlorothiophene-5-sulfonyl chloride (0.015 g, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 15 minutes. The reaction was diluted with ethyl acetate (40 mL), washed with 1 N hydrochloric acid, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99:1 dichloromethane:methanol to give the title compound (14.8 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.69 (m, 1 H) 4.47 (m, 2 H) 7.50 (m, 2 H) 7.56 (s, 1 H) 7.71 (d, J=8.82 Hz, 1 H) 7.76 (s, 1 H) 8.55 (dd, J=7.91, 2.02 Hz, 1 H) 8.88 (dd, J=4.60, 1.65 Hz, 1 H) 11.28 (s, 1 H) 14.19 (br s, 1 H). MS (ESI−) m/z 640 (M−H)−.
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][NH:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1>C(Cl)Cl>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:18][N:33]([CH3:32])[CH2:34][CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]1)[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: CNCCCN1CCN(C)CC1
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
Product: COCC1OC(=O)C(=CN(C)CCCN2CCN(C)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added methyl-[3-(4-methyl-piperazine-1-yl)propyl]amine (80 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 603 (M+H).
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([O:9][CH2:10][C:11]([O:13]CC)=[O:12])[CH:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:27]([N:30]1[C:37]([NH2:38])=[C:36]([NH2:39])[C:34](=[O:35])[N:33]([CH2:40][CH2:41][CH3:42])[C:31]1=[O:32])[CH2:28][CH3:29]>CO>[CH2:40]([N:33]1[C:34](=[O:35])[C:36]2[NH:39][C:1]([C:4]3[O:8][N:7]=[C:6]([O:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=3)=[N:38][C:37]=2[N:30]([CH2:27][CH2:28][CH3:29])[C:31]1=[O:32])[CH2:41][CH3:42]
Reactant: CCOC(=O)COc1cc(C(=O)O)on1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)no3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxyisoxazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yloxy]acetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.I[C:38]1[S:39][CH:40]=[CH:41][CH:42]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Ic1cccs1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 2-iodothiophene according to the general procedure C. Obtained as a yellow solid (91 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30]([C:28]3[S:29][C:25]([CH3:24])=[CH:26][CH:27]=3)=[O:31])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: Cc1ccc(C(=O)O)s1
Product: Cc1ccc(C(=O)Nc2ccc(F)c([C@]3(C)CCOC(N)=N3)c2)s1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 5-methyl-thiophene-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH2:23])=O)(C)(C)C.FC(F)(F)C(O)=O.CC(OC)(C)C.C1CCCCC1.C(O)C.C(NC(C)C)(C)C>C(Cl)Cl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[C:16]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH2:23])[CH:17]=1
Reactant: C=C(c1ccccc1)c1cc(C)ccc1OCC1CCCN1C(=O)OC(C)(C)C
Solvent: C1CCCCC1
Solvent: CCO
Solvent: ClCCl
Product: C=C(c1ccccc1)c1cc(C)ccc1OCC1CCCN1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1.76 g (4.5 mmole)2-[4-methyl-2-(1-phenyl-vinyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tertiary butylester in 22 ml abs. CH2Cl2 at 0° C. 5.4 ml trifluoroacetic acid are added and the reaction solution is agitated for 1 h at the same temperature. Then the reaction mixture is reduced on the rotary evaporator and the residue is absorbed in 20 ml dichloromethane. The solution is displaced with 20 ml concentrated ammonia solution and the organic phase is separated off. The aqueous phase is extracted twice with 10 ml dichloromethane in each case and the purified organic phases are dried through MgSO4. The solvent is removed on the rotary evaporator and the raw product obtained in this way is cleaned by column chromatography on silica gel with MTBE/cyclohexane/ethanol/diisopropylamine (ratio of volumes=3/1/1+Vo.−%) as the eluant. 1.31 g (4.5 mmole, 100%)2-[4-methyl-2-(1-phenyl-vinyl)-phenoxymethyl]-pyrrolidine are obtained.