Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][C:6]1[CH:11]=CC(C(C)(C)C)=CC=1)(=O)=[O:3].NC1C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=[O:32])=CC=1.C1C=CC(/C=C/[C:49](/[CH:51]=C/C2C=CC=CC=2)=[O:50])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:77].[Pd]>O>[CH3:11][C:6]([O-:5])=[O:32].[CH3:51][C:49]([O-:3])=[O:50].[Pd+2:77]
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)cc1
Reactant: [Pd]
Solvent: Nc1ccccc1
Solvent: O
Product: CC(=O)[O-]
Product: [Pd+2]
Yield: 99 %

Procedure:
Initial studies focused on the coupling of 4-t-butylphenyl methanesulfonate and aniline. Whereas catalyst systems based on the combination of Pd2(dba)3 and 1 failed to produce product (FIG. 8, Table 4, entry 1), precatalyst 10 provided a 98% yield in 3 h (FIG. 8, Table 4, entry 2). Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686. Similarly, utilization of water-mediated catalyst activation with 1 and Pd(OAc)2 gave the desired product in 99% yield (Entry 3). Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177; Amatore, C.; Carre, E.; Jutand, A.; M'Barki, M. A. Organometallics 1995, 14, 1818; Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008. ASAP. In contrast, the use of ligand 13 (XPhos), which has been shown to be efficient in couplings of other aryl sulfonates, but lacks the methoxy groups, provided only trace amounts of product when used either as precatalyst 11 or with the water-mediated activation protocol (FIG. 8, Table 4, entries 4 and 5). Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.NC1[N:20]=[CH:21][NH:22][C:23]=1[Br:24]>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:20]3[CH:21]=[N:22][C:23]([Br:24])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: Nc1nc[nH]c1Br
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccnc3c(Br)ncn23)c1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 0.01 mole of 4-amino-5-bromoimidazole and 50 ml. of glacial acetic acid is refluxed for 6 hours. The solvent is removed and the residue worked up as for Example 29 to give the product of the example.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[CH2:17][O:16]4)=[CH:11][CH:10]=2)O1.Br[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[O:38][C:39]([CH:42]3[CH2:45][CH2:44][CH2:43]3)=[N:40][N:41]=2)=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>O.CO>[CH:42]1([C:39]2[O:38][C:37]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([C:9]4[CH:14]=[CH:13][C:12]([C:15]56[CH2:20][CH2:19][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:21][CH2:22]5)[CH2:17][O:16]6)=[CH:11][CH:10]=4)=[CH:31][CH:32]=3)=[N:41][N:40]=2)[CH2:43][CH2:44][CH2:45]1
Reactant: Brc1ccc(Nc2nnc(C3CCC3)o2)cc1
Reactant: COC(=O)CC12CCC(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)(CC1)OC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cc4)cc3)(CC1)OC2
Temperature: 80 °C
Yield: 162.4 %

Procedure:
A vial was charged with methyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (20 mg, 0.052 mmol), N-(4-bromophenyl)-5-cyclobutyl-1,3,4-oxadiazol-2-amine (30.5 mg, 0.104 mmol), PdCl2(dppf)-CH2Cl2adduct (6.34 mg, 7.77 μmol), potassium phosphate (21.98 mg, 0.104 mmol), dimethoxyethane (0.6 ml), methanol (0.2 ml), and water (0.1 ml) at room temperature. The vial was sealed, flushed with nitrogen for three times and heated at 80° C. for 16 hours. The mixture was purified by flash chromatography (heptanes/acetone 1/1, washed with acetone/ethanol 1/1) to afford methyl 2-(1-(4′-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (40 mg, 40% purity, 65% yield) as white solid. LC/MS, ESI-MS(+1) m/z 474.19, RT 1.41 (Condition E).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C(=O)=O.[H][H].[ClH:27]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:27].[ClH:27].[CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: [H][H]
Reactant: CON(C)C(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CON(C)C(=O)C1CCN(c2ccc(N)cc2)CC1
Yield: 100 %

Procedure:
A solution of 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide (approximately 0.20 g, 0.8 mmol) in ethanol/ethyl acetate (1:1, 30 mL) and concentrated hydrochloric acid (1 mL) is degassed with dry ice. Palladium on carbon (10%, 35 mg) is added and the mixture is shaken for two hours under 40 psi of hydrogen. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 1-(4-amino-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide dihydrochloride (0.30 g, >100%).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:26][CH:25]=2)[C:20]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:19][C:14]=1[C:15](OC)=[O:16].O>CN(C=O)C>[Cl:12][C:13]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:28][CH:29]=2)[C:20]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:19][C:14]=1[C:15]([NH:4][C:3]([NH2:5])=[NH:2])=[O:16]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(CCN(C)C)cc2)cc1Cl
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCc1ccc(Oc2cc(Cl)c(C(=O)NC(=N)N)cc2S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
268 mg of guanidine hydrochloride were dissolved in 3 ml of DMF and a solution of 286 mg of potassium t-butoxide in 3 ml of DMF is added. The mixture was stirred at RT for 3 hours, then a solution of 210 mg of methyl 2-chloro-4-(4-(2-dimethylaminoethyl)phenoxy)-5-methylsulfonylbenzoate in 4 ml of DMF was added. The mixture was stirred at RT for 3 hours and allowed to stand at RT for 18 hours. The mixture was poured onto 150 ml of water and extracted 3 times using 100 ml of EA each time. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. 230 mg of a glassy solid were obtained.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NCC)C.[N+:22]([CH3:25])([O-:24])=[O:23].Cl.CC[OH:29]>>[OH:29][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:25][N+:22]([O-:24])=[O:23])=[CH:12][CH:13]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: CCO
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: CCNCC
Product: O=C(CC(C[N+](=O)[O-])c1ccccc1)c1ccc(O)cc1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A solution of 1-(4-hydroxyphenyl)-3-phenylpropenone 3 (9 mmol) in EtOH (15 mL) was treated with diethylamine (4.6 mL, 45 mmol) and nitromethane (4.8 mL, 90 mmol) and heated under reflux for 16 h. The solution was cooled and acidified with 4 M HCl, partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was stirred in cold Et2O (30 mL) for 10 min and filtered to give the product 4 as a colorless solid (1.84 g, 73%), m.p. 112-113° C. (MeOH). 1H NMR (300 MHz, CDCl3): δ 7.86 (d, J=8.5 Hz, 2H), 7.35-7.26 (m, 5H), 6.85 (d, J=8.5, 2H), 5.44 (s, 1H), 4.86-4.80 (m, 1H), 4.64-4.71 (m, 1H), 4.25-4.16 (m, 1H), 3.46-3.31 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 195.3, 160.3, 139.2, 130.6, 129.6, 129.0, 127.8, 127.4, 115.4, 79.6, 41.1, 39.4. IR (KBr disc): 3427, 1646 cm−1. ES-MS: m/z 284.1 [M−H]− HRMS [M+Na]+: 308.0887, C16H15NNaO4+ requires 308.0899.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH:11]=[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:24](O)=O.C=O>O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH:11]=[C:12]3[CH2:13][CH2:14][N:15]([CH3:24])[CH2:16][CH2:17]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=CO
Reactant: Clc1nc(N2CCOCC2)c2sc(C=C3CCNCC3)cc2n1
Agent: C=O
Solvent: O
Solvent: ClCCl
Product: CN1CCC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-chloro-4-morpholin-4-yl-6-piperidin-4-ylidenemethyl-thieno[3,2-d]pyrimidine (500 mg) and formic acid (2.5 mL) at room temperature was added formaldehyde (0.5 mL of a 37 wt % solution in water). The reaction mixture was stirred at 60° C. for 16 h. The mixture was then diluted with dichloromethane (2 mL) and washed with 2 M aqueous sodium hydroxide solution (20 mL) and brine (20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 2-chloro-6-(1-methyl-piperidin-4-ylidenemethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a yellow solid (0.15 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccccn2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of tert-butyl-3-iodobenzylcarbamate (166 mg, 0.50 mmol) in Dioxane (1.5 mL) was added Pd(PPh3)4 (58 mg, 0.05 mmol) and 2-(tributylstannyl)pyridine (275 mg, 0.75 mmol). After stirring at 100° C. for 2 h, it was concentrated and the residue was purified by column chromatography to give tert-butyl-3-(pyridin-2-yl)benzylcarbamate (111 mg).
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=O.[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[NH:27][NH2:28].[C:29]([CH2:34][CH:35]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:30]>C(OCC)C.O>[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[N:27]1[C:29](=[O:30])[C:34]([CH3:35])=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[N:28]1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1c(C(F)(F)F)cnn(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5.3 g (53.3 mmol) of sodium acetate mixed with about 100 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoro-acetone, and the mixture was stirred at 70° C. for 20 minutes. The reaction mixture was cooled to room temperature, to which a solution of 5.8 g (21.5 mmol) of 2-fluoro-4-chloro-5-isopropoxyphenylhydrazine dissolved in about 20 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hour. The ether layer was separated and then concentrated. About 60 ml of tetrahydrofuran (hereinafter referred to as THF) was added to the residue, to which 8.3 g (23.0 mmol) of (carbethoxyethylidene)triphenylphosphorane was added, and the mixture was heated under reflux for 2 hours. The THF was distilled out under reduced pressure, and the residue was subjected to silica gel column chromatography, which afforded 3.8 g (10.5 mmol) of 2-[2-fluoro-4-chloro-5-isopropoxyphenyl]-4-methyl-5-trifluoromethyl-pyridazin-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1)=[O:4].[O:15]=[CH:16][C:17]([Cl:20])([Cl:19])[Cl:18]>COCCOCCOC>[OH:15][CH:16]([NH:12][C:10](=[O:11])[C:9]1[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=1)[NH2:14])[C:17]([Cl:20])([Cl:19])[Cl:18]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(C(N)=O)c1
Solvent: COCCOCCOC
Product: COC(=O)c1ccc(N)c(C(=O)NC(O)C(Cl)(Cl)Cl)c1

Procedure:
5-Methoxycarbonylanthranilamide (1.0 g.) anhydrous chloral (5 ml.) and bis(2-methoxyethyl) ether (20 ml.) were heated together on a steam bath for 20 minutes, then evaporated to dryness under reduced pressure. The residue solidified on stirring with diethyl ether, and it was filtered off and purified by chromatography on silica gel (250 g.). The column was eluted with a mixture of ethyl formate and toluene (7:3 by volume), and 50 ml. fractions were collected. Fractions 10 to 13 were combined and evaporated to dryness, and the residue solidified on stirring with petroleum ether (b.p. 60°-80° C.) to give the required starting material, N-(1-hydroxy-2,2,2-trichloroethyl)-5-methoxycarbonylanthranilamide, m.p. 93° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([C:6]([SH:9])([CH3:8])[CH3:7])[NH2:5].[CH2:11]([C:18](=[CH2:29])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:5][C@@H:4]([C:3]([O:2][CH3:1])=[O:10])[C:6]([S:9][CH2:29][CH:18]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])([CH3:8])[CH3:7]
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)C(C)(C)S
Product: COC(=O)[C@H](N)C(C)(C)SCC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
In an analogous manner to that described in Example 1, paragraph (d), by adding L-penicillamine methyl ester (J. Chem. Soc. Dalton Trans. 1984, 1333) to benzyl 2-benzylacrylate there was obtained benzyl (RS)-α-[[[(S)-2-amino-2-(methoxycarbonyl)1,1-dimethylethyl]thio]methyl]hydrocinnamate, MS: 416 (M+H)+, as an oil, the amino group of which was protected according to a general procedure known from the literature by reaction with di-tert-butyl dicarbonate. Subsequent oxidation with 3-chloroperbenzoic acid in methylene chloride gave benzyl (RS)-α-[[[(S)-2-(1-tert-butoxyformamido)-2-(methoxycarbonyl)-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 448 (M-Boc+H)+. p1 (1) Catalytic hydrogenation of benzyl (RS)-α-[[[(S)-2-(1-tert-butoxy- formamido)-2-(methoxycarbonyl)-1,1-dimethylethyl]sulfonyl]-methyl]hydrocinnamate analogously to Example 1, paragraph (g), yielded (RS)-α-[[[(S)-2-(1-tert-butoxyformamido)-2-(methoxycarbonyl)-l,1dimethylethyl]sulfonyl]methyl]hydrocinnamic acid as a colourless solid, MS: 401 (M-C4H8)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:22][C:5]2[C:6]([C:19]([OH:21])=[O:20])=[N:7][N:8]([S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[C:4]=2[CH2:3]1.O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C(Cl)CCl>C(Cl)Cl>[O:30]=[C:25]1[CH2:26][CH2:27][C:28](=[O:29])[N:24]1[O:20][C:19]([C:6]1[C:5]2[CH2:22][C:2](=[O:1])[CH2:3][C:4]=2[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1)=[O:21]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C(=O)O)c3c2CC(=O)C3)cc1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)ON3C(=O)CCC3=O)c3c2CC(=O)C3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step C above, (320 mg, 1.0 mmol) in CH2Cl2(20 mL) was added N-hydroxy succinimide (230 mg, 2.0 mmol) followed by EDC (384 mg, 2.0 mmol). After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL), washed with saturated NaHCO3, solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A yellow solid was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1C=[CH:9][C:8]([CH2:11][CH2:12][CH2:13]O)=[CH:7][CH:6]=1.Cl[CH:16]([Cl:18])Cl>>[Cl:3][CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][N:5]=[C:16]([Cl:18])[CH:9]=1
Reactant: OCCCc1ccncc1
Reactant: ClC(Cl)Cl
Reactant: O=S(Cl)Cl
Product: ClCCCc1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (1.6 ml) was added to a solution of 4-pyridine propanol (2 g, 14.5mmol) in trichloromethane (20 ml) cooled at 0° C. After stirring for 1 hour at ambient temperature followed by 1 hour at 60° C., the solvent was evaporated and the residue was triturated with ether to give 4-(3-chloropropyl)pyridyl hydrochloride as a white solid.
Reaction SMILES: [C:1]([CH:8](N)[CH2:9][NH:10][CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=C.[CH2:22]([N:24](CC)CC)C>C(O)C>[C:4]([O:3][C:1](=[O:2])[CH2:8][CH2:9][N:10]([CH2:11][CH2:22][NH2:24])[CH2:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:7])([CH3:6])[CH3:5]
Reactant: CNCC(N)C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)CCN(CCN)CC(=O)OC(C)(C)C

Procedure:
1-Boc-amino-2-methylamino-ethane (1 g, 4.75 mmol) and tert-butyl acrylate (0.61 g, 4.75 mmol) were dissolved in ethanol (10 mL) with triethylamine (1.32 mL, 9.5 mmol) and refluxed overnight. The solvent was evaporated in vacuo, and 3-(Boc-aminoethyl-methyl-amino)-propionic acid tert-butyl ester was isolated by addition of ethyl acetate (300 ml) and washing with 2×5% sodium carbonate, water and brine followed by drying over magnesium sulphate and evaporation in vacuo to leave an oil (630 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]([N:14]1[CH2:15][C@@H:16]([CH3:19])[CH2:17][CH2:18][C@H:13]1[C:11]1[NH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][N:10]=1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)NC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)CC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of 2S,5S)-2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine (400 mg, 1.25 mmol) and (S)-2-methoxycarbonylamino-3-methyl-butyric acid (219 mg, 1.25 mmol), HATU (475 mg, 1.25 mmol), and DIPEA (485 mg, 3.75 mmol) in DCM (20 mL) was stirred at RT overnight. The reaction mixture was concentrated and purified by thin layer chromatography (1:1 petroleum ether:EtOAc) to provide the title intermediate (550 mg, 92% yield). (m/z): [M+H]+ calcd for C22H28BrN4O3 476.13, 478.13, found 478.7.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1CC(CC[Si](OC)(OC)OC)[CH2:5][CH2:6]2.COC([SiH3])(OC)OC.C1([Si](OC)(OC)OC)C=CC=CC=1.[C:38](O)(=O)[C:39]([OH:41])=[O:40]>CO.O>[C:39]([O:41][CH:6]([CH3:5])[CH2:7][O:1][CH3:2])(=[O:40])[CH3:38]
Reactant: O=C(O)C(=O)O
Reactant: CO[Si](CCC1CCC2OC2C1)(OC)OC
Agent: COC([SiH3])(OC)OC
Agent: CO[Si](OC)(OC)c1ccccc1
Solvent: O
Solvent: CO
Product: COCC(C)OC(C)=O
Temperature: 40 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
In a 1000 ml glass flask, to a mixture of 150 g of methanol, 22 g of 2-(3,4-epoxycyclohexyl) ethyl trimethoxy silane, 77 g of trimethoxymethyl silane, 14 g of phenyl trimethoxy silane, and 1.5 g of oxalic acid was added dropwise a mixed solution of 40 g of deionized water and 20 g of methanol at a liquid temperature of 40 degrees C. After that, this solution was stirred for 12 hours at 40 degrees C. After the reaction finished, the solvent was removed under a reduced pressure. Thus-obtained residue was dissolved in 1000 ml of ethyl acetate, and washed with deionized water for washing. After the water layer was separated, the organic layer was washed twice with deionized water. To this organic layer was added 600 g of propylene glycol monomethyl ether acetate (PGMEA), and the contents were heated up to a liquid temperature of 40 degrees C. under a reduced pressure to remove ethyl acetate and to give a PGMEA solution of a polymer.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[C:17]1([CH3:24])[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:17]1([CH3:24])[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=1[O:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 63.7 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added o-cresol (20 mg, 0.185 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-(4-o-tolyloxymethyl-phenyl)-isoxazole-5-carboxylic acid amide (21 mg, 64%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.92 (d, J=8.1 Hz, 2H), 7.53-7.67 (m, 3H), 7.05-7.20 (m, 2H), 6.99 (d, J=7.7 Hz, 1H), 6.74-6.90 (m, 1H), 5.19 (s, 2H), 2.21 (s, 3H).
Reaction SMILES: CN(C)/C=C(\[F:16])/C(C1N(C(C)C)C(C)=NC=1)=O.S([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:50]=[CH:49][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]([CH3:46])[CH3:45])[C:42]([CH3:47])=[N:41][CH:40]=4)[C:36](Cl)=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)(C)(=O)=O.C[O:52][CH2:53][CH2:54]O>>[C:53]([N:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:50]=[CH:49][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]([CH3:46])[CH3:45])[C:42]([CH3:47])=[N:41][CH:40]=4)[C:36]([F:16])=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1)(=[O:52])[CH3:54]
Reactant: COCCO
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)ncc2Cl)n1C(C)C
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(-c4cnc(C)n4C(C)C)n3)cc2)CC1

Procedure:
A solution of (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 6.0 g, 25 mmol) and N-[4-(4-acetylpiperazin-1-yl)phenyl]guanidine bicarbonate salt (Method 2; 12.12 g, 37.5 mmol) in 2-methoxyethanol (90 ml) was heated under reflux for 18 hrs. The reaction mixture was evaporated under reduced pressure and the title compound was isolated by MPLC on silica gel (3% MeOH/DCM). It was obtained as a crisp foam on evaporation. Yield=8.9 g (81%). NMR: 1.36 (d, 6H), 2.03 (s, 3H), [2.5 (s, 3H) under DMSO signal], 2.98 (m, 2H), 3.08 (m, 2H), 3.57 (m, 4H), 5.44 (septuplet, 1H), 6.90 (d, 2H), 7.34 (d, 1H), 7.42 (d, 2H), 8.44 (d, 1H), 9.24 (s, 1H); m/z 438.