Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20])(C)(=O)=O.[I-:35].[Na+].O.C(Cl)(Cl)Cl>CC(C)=O>[I:35][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: [I-]
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCOS(C)(=O)=O)cn2)CC1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCI)cn2)CC1
Yield: 90.1 %

Procedure:
To a solution of 72 mg of N-(12-mesyloxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in acetone was added 130 mg of sodium iodide and the mixture was heated under reflux for 10 hours. To the reaction solution were added water and chloroform and extracted with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford 69.0 mg of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]1[N:16](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:15][CH2:14][N:13]([CH:29]([CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[C:30]([NH:32][CH3:33])=[O:31])[C:12]1=[O:45])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[Si:1]([O:8][CH2:9][CH2:10][CH:11]1[NH:16][CH2:15][CH2:14][N:13]([CH:29]([CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[C:30]([NH:32][CH3:33])=[O:31])[C:12]1=[O:45])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CCO[Si](C)(C)C(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCNC(CCO[Si](C)(C)C(C)(C)C)C1=O

Procedure:
2-[3-[2-(tert-butyldimethylsilanyloxy)ethyl]-4-(2-nitrobenzene-sulfonyl)-2-oxo-piperazin-1-yl]-N-methyl-3-naphthalen-2-yl propionamide, 57, (6.5 g, 10 mmol), trifluoroacetic acid (5 mL), and dichloromethane (50 mL) is stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product is dissolved in dichloromethane and the organic layer washed with saturated sodium bicarbonate, dried, and concentrated in vacuo to afford the desired product.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>C(Cl)(Cl)Cl>[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)=[O:34])=[CH:8][CH:7]=1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N(CCCl)CCCl)cc1)Nc1cccc([N+](=O)[O-])c1
Reaction time: 0.71 h

Procedure:
To a stirred mixture of N-mustard amine 18 (7.66 g, 25 mmol) and triethylamine (TEA, (4 mL, 27.5 mmol) in CHCl3 (100 mL) was added a solution of 3-nitrophenyl isocyanate 44a (4.1 g, 25 mmol) in CHCl3 (50 mL) dropwise at room temperature. After being stirred additional 40-45 minutes, the solvent was removed by evaporation under reduced pressure and the solid residue was triturated with saturated aqueous solution of NaHCO3 and then collected by filtration. The solid was washed with water, hexane, and dried. The solid was recrystallized from ethyl acetate to give 1-(4-(bis(2-chloroethyl)amino)phenyl)-3-(3-nitrophenyl)urea (45a), 9.1 g (92%); mp 246-247° C. 1H NMR (DMSO-d6) δ: 3.69-3.71 (8H, m, CH2), 6.71-6.74 (2H, d, J=9.0 Hz, Ar—H), 7.29-7.31 (2H, d, J=8.9 Hz, Ar—H), 7.52-7.56 (1H, t, J=8.1 and 8.2 Hz, Ar—H), 7.69-7.71 (1H, d, J=8.0 Hz, Ar—H), 7.78-7.80 (1H, q, J=8.2 and 1.8 Hz, Ar—H), 8.52 (1H, brs, NH), 8.54-8.55 (1H, d, J=2 Hz, Ar—H), 9.11 (1H, brs, NH).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>O1CCOCC1.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>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cn1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C
Yield: 34.6 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (2.2 g, 4.58 mmol) and 5-bromo-1-methylpyridin-2(1H)-one (1.37 g, 7.33 mmol) in dry 1,4-dioxane (4 mL) was added aqueous CsCO3 solution (10 mL, 10 mmol) and Pd(PPh3)2Cl2 (967 mg, 1.38 mmol). After addition, the mixture was heated at 110° C. for 30 min in a microwave. After TLC showed the stating material had disappeared, the solid was filtered off. Water (20 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by preparative HPLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (730 mg, 35%). 1H NMR (CDCl3): 1.09 (s, 3H), 1.16 (s, 3H), 1.51 (m, 3H), 2.05-2.20 (4H), 2.40 (m, 1H), 2.84 (m, 1H), 3.59 (s, 3H), 5.64 (m, 1H), 6.62 (m, 1H), 6.96 (m, 2H), 7.14 (m, 2H), 7.28-7.39 (m, 5H), 7.48 (m, 1H), 7.50 (m, 1H). The compound was recrystallized by two methods.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])=[CH:16][N:15]=2)[CH2:7][CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])=[CH:16][N:15]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](CC#Cc2ccc([C@@H]3CCCN3C)cn2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CCCc2ccc([C@@H]3CCCN3C)cn2)CC1

Procedure:
A solution of 5 (0.13 g, 0.4 mmol) in MeOH (40 mL) was hydrogenated at room temperature and atmospheric pressure over 10% Pd/C (0.06 g). After 40 min the catalyst was filtered off and washed with MeOH. The volatiles was evaporated under reduced pressure and the residue was chromatographed [SiO2, acetone/iso-hexane (1:2)] to afford 0.13 g (93%) of 6.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-(trifluoromethyl)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:28]1([C:34]2[O:38][CH:37]=[N:36][C:35]=2[C:39]([OH:41])=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:39]([C:35]3[N:36]=[CH:37][O:38][C:34]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:41])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ncoc3-c3ccccc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 5-phenyl-1,3-oxazole-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:37][C:38](=[O:40])[CH3:39])[S:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:16][CH:15]=1.CNN>CN(C)C=O>[NH2:3][O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:37][C:38](=[O:40])[CH3:39])[S:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CON3C(=O)c4ccccc4C3=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: CNN
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCc2ccc(CON)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 4 h
Yield: 9.3 %

Procedure:
To a solution of N-{4-[2-(4-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}phenyl)ethyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (116.8 mg) in N,N-dimethylformamide (1.1 ml) was added methylhydrazine (11.9 μl) under N2 atmosphere, and the mixture was stirred at 20° C. for 4 hrs. The reaction mixture was concentrated in vacuo. Ethyl acetate was added to the residue, and the precipitate was filtered off. The filtrate was concentrated in vacuo to give a crude yellow solid (105.1 mg). The crude material was purified by preparative thin-layer chromatography over silica gel with chloroform/methanol (30:1) as an eluent to give a pale yellow powder. The obtained powder was washed with acetonitrile, and the precipitate was collected by filtration to give N-(4-(2-{4-[(aminooxy)methyl]phenyl}ethyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl)acetamide (8.4 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1C=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([OH:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O>[CH2:3]([OH:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:3]([O:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:2])[CH3:4]
Reactant: COC(=O)c1ccccc1
Solvent: CCCCCCO
Solvent: O
Product: CCCCCCOC(C)=O

Procedure:
The data in Table 2 was obtained in the following manner. The charge was brought to boiling and after a half hour of operation in the 4.5 theoretical plate column to establish equilibrium throughout, methylbenzoate at 95° C. and 10-16 ml/min. was pumped in. The rectification was continued for 11/4 hours with sampling of the overhead and bottoms after 75 minutes. The analysis is shown in Table 2 and was 97.3% n-hexyl alcohol in the overhead and 81% n-hexyl alcohol in the bottoms, both on a water-free basis, which gives a relative volatility of 1.605 of n-hexyl alcohol to n-hexyl acetate. This indicates that the ternary azeotrope has been negated and the separation accomplished. The n-hexyl alcohol comes off in the form of its binary azeotrope with water which on condensation, immediately forms two layers. The solubility of n-hexyl alcohol in liquid water is only 0.6%.
Reaction SMILES: [CH2:1]([C:5]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])[CH:2]([CH3:4])[CH3:3].O.OS(O)(=O)=O>C(O)(=O)C>[CH3:3][CH:2]([CH3:4])[CH2:1][CH:5]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([C:25]([F:26])([F:27])[F:28])[CH:17]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CC(C(=O)O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 75.7 %

Procedure:
To a solution of diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 184 mmol) in acetic acid (500 mL) were added water (157 mL) and concentrated H2SO4 (55 mL) carefully. The reaction mixture was refluxed for three days and then concentrated under reduced pressure. The residue was diluted with water (400 mL) and extracted with ethyl acetate (6×100 mL). The combined organic extracts were washed with water (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a brown oil. The residue was purified by silica-gel flash chromatography eluting with heptane/EtOAc (5:1 and then 2:1) to give 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.5 g, 76%) as a yellowish oil: 1H NMR (300 MHz, CDCl3): δ 11.51 (s, 1 H, br), 7.87 (d, 1 H, J=8.4 Hz), 7.78 (s, 1 H), 7.71 (d, 1 H, J=8.4 Hz), 3.84 (t, 1 H, J=7.8 Hz), 2.06 (m, 1 H), 1.72 (m, 1 H), 1.49 (m, 1 H), 0.95 (d, 3 H, J=6.6. Hz), 0.94 (d, 3 H, J=6.3 Hz); 13C NMR (75 MHz, CDCl3): δ 178.76, 147.09, 143.94, 132.66, 127.70 (q, J=5 Hz), 125.40, 123.95 (q, J=34 Hz), 121.74 (q, J=271 Hz), 42.16, 25.96, 22.44, 22.09.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[C:18]([CH3:24])[N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:7]=1[CH2:35][C:36]([OH:38])=[O:37])=[O:5])C.[OH-:39].[Na+]>CCO>[NH2:23][C:22]([C:21]1[C:16]([O:15][C:12]2[CH:11]=[C:10]3[C:9](=[CH:14][CH:13]=2)[N:8]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=2)[C:7]([CH2:6][C:4]([OH:3])=[O:5])=[C:35]3[C:36]([OH:38])=[O:37])=[N:17][C:18]([CH3:24])=[CH:19][CH:20]=1)=[O:39]
Reactant: [OH-]
Reactant: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3nc(C)ccc3C#N)cc12
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(N)=O)c(Oc2ccc3c(c2)c(C(=O)O)c(CC(=O)O)n3-c2ccc(OC(C)C)cc2)n1
Temperature: 80 °C

Procedure:
The title compound was prepared in accordance with step (b) Example 24 from (2-carboxymethyl-5-(3-cyano-6-methyl-2-pyridinyloxy)-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (184 mg, 0.36 mmol, see step (b) Example 28), NaOH (aq, 2 M, 0.9 mL) and EtOH (1.5 mL). The mixture was heated at 80° C. for 4 h and the title compound was isolated as described before. Yield 40 mg (22%), mp 196° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:19][O:20][CH3:21])[C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:8]=2[CH:7]=1>ClCCl.CO.[Pd]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:19][O:20][CH3:21])[C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][NH:16][C:17]=3[C:8]=2[CH:7]=1
Reactant: COCn1c(=O)c2cccnc2c2cc(CCCN(C)C)ccc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COCn1c(=O)c2c(c3cc(CCCN(C)C)ccc31)NCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
The compound (110 mg, 0.67 mmol) prepared in step 8 was dissolved in dichloromethane/methanol (10 ml), added with 10%-palladium (11 mg). The resulting mixture was stirred for one day at room temperature under hydrogen gas. Once the reaction was completed, the solution was celite-filtered and the filtrate was concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (112 mg, yield: 99%, white solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:30]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)/C=C/c2ccc(Cl)cc2F)ccc1=O
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: O
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Product: Cn1cc(C(=O)CC(c2cccc(S(C)(=O)=O)c2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 203, step 1, (E)-5-(3-(4-chloro-2-fluorophenyl)acryloyl)-1-methylpyridin-2(1H)-one (example 314, step 2) was reacted with 3-(methylsulfonyl)phenyl-boronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a yellow solid, MS (ESI+): m/z=448.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:18]2[O:17][C:16]3[C:19]([CH:25]=O)=[C:20]([OH:24])[CH:21]=[C:22]([CH3:23])[C:15]=3[C:14](=[O:27])[O:13][C:12]=2[C:11]([CH3:28])=[C:10]([O:29][CH3:30])[CH:9]=1)=[O:7])[CH2:2][CH2:3]C.[N:31]1([CH2:37][CH2:38][NH2:39])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH2:1]([O:5][C:6]([C:8]1[C:18]2[O:17][C:16]3[C:19]([CH2:25][NH:39][CH2:38][CH2:37][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[C:20]([OH:24])[CH:21]=[C:22]([CH3:23])[C:15]=3[C:14](=[O:27])[O:13][C:12]=2[C:11]([CH3:28])=[C:10]([O:29][CH3:30])[CH:9]=1)=[O:7])[CH2:2][CH3:3]
Reactant: NCCN1CCOCC1
Reactant: CCCCOC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Product: CCCOC(=O)c1cc(OC)c(C)c2c1Oc1c(CNCCN3CCOCC3)c(O)cc(C)c1C(=O)O2

Procedure:
This compound was prepared from the compound from Example 8 by means of a procedure similar to that used for Example 18 except replacing ethanolamine with 2-morpholin-4-yl-ethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:11]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)=[N:12][C:13]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:14][C:15]=3[O:16]C)=[N:7][C:6]=2[CH:38]=1.Cl.O>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:15](=[O:16])[NH:14][C:13]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:12][C:11]=3[NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)=[N:7][C:6]=2[CH:38]=1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(Br)ccc2s1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: O=c1[nH]c(N2CCOCC2)nc(N[C@@H]2CCCNC2)c1-c1nc2cc(Br)ccc2s1
Reaction time: 0.08 h

Procedure:
Following the same procedure as in step 4 of Example 337 using tert-butyl (3R)-3-[[5-(5-bromo-1,3-benzothiazol-2-yl)-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (60.0 mg, 0.10 mmol, 1.00 equiv) and cone, hydrochloric acid (4.0 mL). The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm,; mobile phase, water with 50 mmol NH4HCO3 and CH3CN (38.0% CH3CN up to 53.0% in 7 min, up to 100.0% in 5 min, down to 38.0% in 1 min); Detector, Waters 2489 254&220 nm to afford the title compound as a white solid. 1H-NMR(400 MHz, DMSO-d6) δ ppm 1.54-1.72(m, 3H), 1.92-1.93(m, 1H), 2.65-2.75(m, 2H), 2.86(m, 1H), 3.10-3.13(m, 1H), 3.62-3.69(m, 8H), 4.17(m, 1H), 7.37-7.39(d, J=8.4 Hz, 1H), 7.89-7.94(m, 2H), 10.74-10.75(m, 1H); MS m/z [M+H]+ (ESI): 492. IRAK4 IC50=19 nM
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:6]=2[CH:23]=1.FC(F)(F)C(O)=O>ClCCl>[NH:13]1[CH2:12][CH2:11][CH:10]([N:7]2[C:6]3[CH:23]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3ccc(N)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2ncn(C3CCNCC3)c2c1
Yield: 82.1 %

Procedure:
tert-Butyl 4-(6-amino-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (5.69 mmol, 1.799 g) was stirred in dichloromethane (5 mL)/trifluoroacetic acid (5 mL) for 1 hour at room temperature. The reaction was concentrated at reduced pressure and passed down an SCX column to afford the title compound (1.01 g). MS (ESI) m/z 217.1 [M+H]+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C(C)(C)C)[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.Cl>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:15]=[C:9]([C:9]([CH3:15])([CH3:10])[CH3:8])[C:8]2[O:12][C:11](=[O:13])[C:10](=[C:10]3[C:7]4[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:15]=[C:9]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:8]=4[O:12][C:11]3=[O:13])[C:7]=2[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2=C1C(=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Temperature: 25 °C

Procedure:
78.7 g of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (prepared as in Ex. 2b) are placed in 150 ml of toluene, and 3 drops of dimethylformamide (DMF) and 45 ml of thionyl chloride are added thereto. The solution is then slowly heated to 373 K at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. It is then stirred at that temperature for a further hour. Approximately 150 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 480 ml of toluene and, at room temperature, 42 ml of triethylamine are added dropwise. The thick, red reaction mixture is then heated under reflux for 15 min. After cooling to room temperature, the triethylamine hydrochloride which has precipitated is filtered off, and the filtrate is washed with water and concentrated NaCl solution and concentrated to an oily consistency using a rotary evaporator. The isoxindigo is crystallised out by adding 225 ml of acetonitrile, is filtered off, washed with acetonitrile and dried, yielding 57.7 g (78.7% of the theoretical yield) of 5,7,5′,7′-tetra-tert-butyl-[3,3′]bibenzofuranylidene-2,2′-dione of formula (LIa).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[N:19]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:20]([C:18]2[N:19]=[C:15]([N:12]3[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]3)[S:16][CH:17]=2)=[O:21])=[CH:25][CH:26]=1)([O-:32])=[O:31]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)c1csc(N2CCC(O)CC2)n1
Yield: 53.9 %

Procedure:
To a solution of 4-t-butyldimethylsilyloxy-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)piperidine (300 mg, 0.628 mmol) (obtained as described in Reference Example 14(3)) in anhydrous tetrahydrofuran (15 ml) were added acetic acid (0.22 ml, 0.628 mmol) and a solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (3.76 ml, 3.76 mmol) in an ice bath, and the mixture was then stirred at room temperature for 21 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (123 mg, yield 54%) as a pale yellow solid.