Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[S:5][CH:6]=1.OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[S:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: Clc1csc(-c2cccnc2)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1sc(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
4-Chloro-2-(pyridin-3-yl)thiazole (1.00 g, 5.09 mmol) was placed in a dry flask and concentrated H2SO4 (2.50 g, 25.4 mmol) was added. The contents were cooled to 0° C., and fuming HNO3 (641 mg, 10.17 mmol) was slowly added. The mixture was stirred at 40° C. for 3 h and cooled to room temperature. The contents were slowly added to an ice-cold saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate (2×50 mL) and the extracts were combined, rinsed with brine and concentrated in vacuo to give 4-chloro-5-nitro-2-(pyridin-3-yl)thiazole as a peach-colored solid (985 mg, 80% yield): mp 110-112° C.; 1H NMR (300 MHz, CDCl3) 9.18 (d, J=2.1 Hz, 1H), 8.81 (dd, J=5.1, 1.8 Hz, 1H)), 8.27 (ddd, J=7.3, 4.2, 2.4 Hz, 1H), 7.49 (dd, J=7.8, 5.1 Hz, 1H); EIMS m/z 241 ([M+H])+.
Reaction SMILES: NCC([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.C1C([NH:20][C:21]([C:23](O)=[O:24])=O)=CC=C([N+](O)=O)C=1.[NH2:29][C@H:30]([C:50]([OH:52])=[O:51])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[CH2:6]([O:5][NH:20][CH2:21][C:23]([NH:29][C@H:30]([C:50]([OH:52])=[O:51])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:24])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C(=O)Nc1ccc([N+](=O)O)cc1
Reactant: CC(C)(C)OC(=O)N(CCCC[C@H](N)C(=O)O)C(=O)OC(C)(C)C
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCC[C@H](NC(=O)CNOCc1ccccc1)C(=O)O)C(=O)OC(C)(C)C
Yield: 101.6 %

Procedure:
To a magnetically stirred solution of H-Gly-OBn.HCl (2.50 g, 12.4 mmol) in DMF (80 ml) was added TEA (4.4 ml, 31.0 mmol) followed by PNPO-Lys(Boc)2 (6.96 g, 14.9 mmol). The reaction and product isolation were carried out according to the method of Example 72.i to give BnO-GlyLys[Boc]2 as a pale yellow foam (6.42 g, 105%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C=O.F[C:11](F)(F)[C:12](O)=O.C=[C:18]1[C:28]2[CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[CH2:24][O:23][C:22]=2[CH:21]=[CH:20][CH:19]1[C:33]([O:35][CH3:36])=[O:34]>ClCC(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:11][CH:12]=[C:27]2[C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([C:33]([O:35][CH3:36])=[O:34])=[CH:18][C:28]2=3)[CH2:4][CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCNCC1
Reactant: C=C1C2=C(C=CC1C(=O)OC)OCc1ccccc1C2
Agent: C=O
Agent: ClCC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(=CCN1CCN(C)CC1)c1ccccc1CO2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-Methylpiperazine, 30 ml, and 74 g of paraformaldehyde were dissolved in 2 l of tetrachloroethane and 100 ml of trifluoroacetic acid was dropwise added to the solution. After stirring at 60° C. for 2 hours, a solution of 36 g of methyl 1-methylene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 600 ml of tetrachloroethane was dropwise added to the reaction mixture followed by stirring at 90° C. for further 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and 4 N hydrochloric acid aqueous solution was added to the residue to adjust pH to 1. Then, the mixture was washed with diethyl ether. Thereafter, 10 N sodium hydroxide aqueous solution was added to adjust pH to 13. Extraction was performed with 3 l of methylene chloride. After washing with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane: ethyl acetate: triethylamine=5:5:1) to give 44 g of colorles oily methyl 11-[2-(4-methyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[O:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[CH2:28][O:29][NH2:30]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[O:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[CH2:28][O:29]/[N:30]=[C:11]1\[NH:10][C@@H:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Br:20])[CH2:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:21])[C:5]\1=2
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: NOC[C@H]1COCCO1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/OC[C@H]1COCCO1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 319.3 %

Procedure:
Thiolactam (31I (Example 31), 0.087 g, 0.0272 mmol), (R)—O-((1,4-dioxan-2-yl)methyl)hydroxylamine (2M (Example 2-E), 0.145 g, 1.09 mmol), and mercury (II) acetate (0.173 g, 0.045 mmol) were dissolved in 3.5 mL of dry toluene and heated in 100° C. oil bath for 1 h. The reaction was done as judged by LC/MS. The crude mixture was filtered through Celite, rinsed with methanol and then concentrated and purified on preparatory LC/MS (25-55% CH3CN in H2O) to afford (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—((R)-1,4-dioxan-2-yl)methyl oxime (39A, 0.0405 g, 36.7% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.90 (s, 3H) 3.04 (dd, J=17.05, 8.97 Hz, 2H) 3.28 (dd, J=17.56, 4.17 Hz, 1H) 3.43 (dd, J=11.62, 9.85 Hz, 1H) 3.58-3.68 (m, 1H) 3.70-3.76 (m, 2H) 3.77-3.88 (m, 2H) 3.93-4.00 (m, 1H) 4.01-4.08 (m, 1H) 4.09-4.18 (m, 1H) 5.01 (d, J=5.05 Hz, 1H) 5.78 (s, 1H) 7.11 (td, J=8.21, 2.53 Hz, 1H) 7.37 (dd, J=7.96, 2.65 Hz, 1H) 7.41 (dd, J=8.84, 5.81 Hz, 1H). ESI-MS: m/z 468.1 (M+H)+.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20].N(OC(C)(C)C)=O.ClCCl.C(Br)(Br)[Br:37]>>[Br:37][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20]
Reactant: Nc1c(S(=O)(=O)C(F)(F)F)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: O=S(=O)(c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 43 %

Procedure:
A suspension of 28 g (0.065 mole) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylsulphonyl-pyrazole in 70 ml of bromoform are added to a solution of 15.5 ml (0.13 mole) of t-butyl nitrite in 30 ml of bromoform at 20° C. to 25° C. The temperature rises to 40° C. The mixture is then stirred for 15 hours at room temperature, 200 ml of dichloromethane are added, the mixture is washed in sequence with aqueous sodium hydrogen carbonate, sodium thiosulphate and sodium chloride solution, the organic phase is dried over magnesium sulphate and the solvent is removed in vacuo. The oil remaining is purified by chromatography (silica gel, eluent: dichloromethane). 13.8 g (43% of theory) of 5-bromo-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylsulphonylpyrazole of melting point 90° C. to 91° C. are obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].COC1N=C(OC)N=C([O:17][C:18](=O)[C:19]2[CH:24]=[C:23]([CH3:25])[C:22](/[CH:26]=[CH:27]/[S:28]([N:31]3[CH2:47][CH2:46][C:34]4([N:38]=[C:37]([CH:39]5[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]5)[NH:36][C:35]4=[O:45])[CH2:33][CH2:32]3)(=[O:30])=[O:29])=[C:21]([CH3:48])[CH:20]=2)N=1.C(N(CC)CC)C.O>C(#N)C>[CH:39]1([C:37]2[NH:36][C:35](=[O:45])[C:34]3([CH2:33][CH2:32][N:31]([S:28](/[CH:27]=[CH:26]/[C:22]4[C:23]([CH3:25])=[CH:24][C:19]([C:18]([N:3]5[CH2:4][CH2:5][O:1][C:2]5=[O:6])=[O:17])=[CH:20][C:21]=4[CH3:48])(=[O:30])=[O:29])[CH2:47][CH2:46]3)[N:38]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: COc1nc(OC)nc(OC(=O)c2cc(C)c(/C=C/S(=O)(=O)N3CCC4(CC3)N=C(C3CCCCC3)NC4=O)c(C)c2)n1
Reactant: O=C1NCCO1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCOC2=O)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Temperature: 80 °C
Reaction time: 15 h
Yield: 33.6 %

Procedure:
Oxazolidin-2-one (47 mg, 0.53 mmol) was added to a solution of 4-[(E)-2-(2-cyclohexyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-vinyl]-3,5-dimethyl-benzoic acid 4,6-dimethoxy-[1,3,5]triazin-2-yl ester (109 mg, 0.17 mmol) and triethylamine (0.12 ml, 0.88 mmol) in anhydrous acetonitrile (1 ml), and the mixture was heated with stirring at 80° C. for 15 hours. The mixture was cooled and water was then added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 2-cyclohexyl-8-{(E)-2-[2,6-dimethyl-4-(2-oxo-oxazolidine-3-carbonyl)-phenyl]-ethenesulfonyl}-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (31 mg, 32%).
Reaction SMILES: ClC(Cl)(Cl)C(O[C:6]1[CH:11]=C[C:9](C#N)=[CH:8][C:7]=1CC=C)=O.[Cl-:19].N1C=CC=CC=1CN1C=C[N+]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=C1>ClCCCl.Cl[Cu]>[Cl:19][C:6]1[CH:11]=[CH:32][CH:33]=[C:38]2[C:7]=1[CH:8]=[CH:9][C:36]([C:35]#[N:34])=[CH:37]2
Reactant: c1ccc(Cn2cc[n+](Cc3ccccn3)c2)nc1
Reactant: C=CCc1cc(C#N)ccc1OC(=O)C(Cl)(Cl)Cl
Reactant: [Cl-]
Agent: Cl[Cu]
Solvent: ClCCCl
Product: N#Cc1ccc2c(Cl)cccc2c1

Procedure:
A solution of INT 26 (1.01 g, 3.6 mmol) in degassed 1,2-dichloroethane (20 mL) containing CuCl (14.3 mg, 0.144 mmol) and 1,3-bis(pyridin-2-ylmethyl)-1H-imidazol-3-ium chloride (41.3 mg, 0.144 mmol, prepared according to: Journal of Organometallic Chemistry (2001), Vol. 617-618, 546-560.) was irradiated in the microwave for 2 hours at 200° C. and concentrated. The residue was purified by flash chromatography on silica gel (cyclohexane/EtOAc) to give INT 27.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].OO.[OH-].[Na+].O>O1CCCC1.C(OCC)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(OC(F)(F)F)cc1CO
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
The 2-amino-5-trifluoromethoxybenzoic acid (2.0 g, 9.0 mmol) in tetrahydrofuran (20 mL) was added dropwise to borane methyl sulfide complex (1.5 mL, 15.0 mmol) in tetrahydrofuran (5 mL). The reaction was refluxed overnight and allowed to cool. A solution of 30% aqueous hydrogen peroxide (0.5 mL), 2.5 N sodium hydroxide (0.5 mL) and water (10 mL) was added drop-wise and the reaction stirred 0.5 hours. After diluting with diethyl ether (50 mL), the organic layer was washed with 0.1 M aqueous sodium meta-bisulfite (2×10 mL) and 2.5 N aqueous sodium hydroxide (2×10 mL). The organic layer was diluted further with hexanes (50 mL) and washed with brine (2×20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo leaving an amber oil (1.9 g) which solidified. The solid was recrystallized from ethyl acetate-hexanes to afford the 2-amino-5-trifluoromethoxybenzyl alcohol as a light amber solid (1.44 g, 77%): mp 75.9–77.6° C. 1H NMR (CDCl3, 300 MHz) 7.00 (m, 2H), 6.65 (d, 1H, J=8.0 Hz), 4.05 (s, 2H), 3.25 (brs, 3H). ESHRMS m/z 208.0592 (M+H+, Calc'd 208.0585). Anal. Calc'd for CH8NO2F3: C, 46.39; H, 3.89; N, 6.76. Found: C, 46.61; H, 3.79; N, 6.71.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:25])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]([CH3:24])[CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:25])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:34](=[O:35])[CH2:33][Cl:32])[CH:19]([CH3:24])[CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: CC1Cc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1Cc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc2N1C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
4-Phenyl-1-(2-methylindoline-5-sulfonyl)-2-imidazolone (300 mg, 0.85 mmol) prepared in Preparation 3 was dissolved in 10 ml of dichloromethane. Pyridine (75 μl, 0.93 mmol) and chloroacetylchloride (74 μl, 0.93 mmol) were added thereto one after another, and then the reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. After stirring, the reaction mixture was diluted with 50 ml of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1, v/v) to afford 342 mg of the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>O1CCOCC1.CCOCC>[ClH:29].[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[N:20]=3)[NH:16][N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cccc(C(F)(F)F)n3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)(F)c1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Temperature: 25 °C

Procedure:
A mixture of 4-[5-(6-trifluoromethyl-pyridine-2-yl)-1H-[1,2,4]triazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (3.26 g) and 4M HCl in dioxane (47 mL) was stirred at rt until the reaction was complete. The reaction was diluted with Et2O and stirred for 30 minutes. The solid was filtered, taken up in ACN and stirred for 15 minutes. The solid was filtered, dissolved in warm MeOH, cooled to 0° C. and triturated with Et2O. The resulting solid was filtered and dried to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12][C:13](=[O:16])[CH2:14]Cl)=[O:4].[NH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[O:16]=[C:13]1[CH2:14][NH:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][OH:23])[CH2:2][C:3](=[O:4])[NH:5][CH:6]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[NH:12]1
Reactant: O=C(CCl)N[C@@H]1CCCC[C@H]1NC(=O)CCl
Reactant: NCCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1CNCCN(CCO)CC(=O)NC2CCCCC2N1
Temperature: 82 °C

Procedure:
Into a 5 l. erlenmeyer flask containing 5 l. of anhydrous acetonitrile was placed 17.4 g. (65 mmol.) of N,N'-bis(chloroacetyl)-trans-1,2-diaminocyclohexane (see Example 2), 6.8 g. (65 mmol.) of 2-(2-aminoethylamino)ethanol and 130 g. (1.23 mmol.) of sodium carbonate. The reaction mixture was heated at 82° C. under nitrogen for 50 hours. After eliminating sodium carbonate by filtration, acetonitrile was eliminated under vacuum until the volume was reduced to 500 ml. A precipitate formed immediately and the reaction mixture was stirred for several hours at room temperature. The precipitate was filtered off and was washed with a few ml. of acetonitrile and dried under vacuum. 8.2 g. of compound (A) was obtained as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.Cl.[CH3:29][O:30][NH2:31].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:29][O:30][NH:31][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: CON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CONC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), O-methyl-hydroxylamine hydrochloride (15 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 21.6 mg (67%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.23 (1H, s), 8.71 (1H, d, J=2.2), 8.05 (4H, m), 7.51 (5H, m), 7.25 (1H, s), 7.10 (1H, d, J=7.7 Hz), 6.91 (1H, m), 5.98 (1H, m), 4.31 (1H, d, J=14.3), 7.20 (1H, d, J=7.3),4.42 (2H, d, J=3.2). ESIMS (M+H+): 412.1.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].CCN(C(C)C)C(C)C.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5])(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(N)CCO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCO)NS(=O)(=O)c1ccccc1Br
Reaction time: 12.5 h

Procedure:
To a 20 mL vial were added a stirbar, 3-amino-3-methylbutan-1-ol (428 mg, 4.15 mmol), ACN (5 mL), and DIPEA (2.0 mL, 12 mmol). The mixture was then treated with 2-bromobenzene-1-sulfonyl chloride (994 mg, 3.89 mmol) and stirred for 12.5 hours before concentrating to dryness and subjecting the residue to FCC to give the title compound. (676 mg, 54%). MS (ESI): mass calcd. for C11H16BrNO3S 321.00, m/z found 344.0 [M+Na]+; 1H NMR (600 MHz, CDCl3) δ 8.15 (dd, J=7.9, 1.7, 1H), 7.70 (dd, J=7.8, 1.2, 1H), 7.46-7.39 (m, 1H), 7.39-7.31 (m, 1H), 6.15 (s, 1H), 3.93-3.81 (m, 2H), 1.76 (t, J=6.0, 2H), 1.20 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.[Cl-].[Na+].O>[S:30]([O:1][CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:27]1[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1 g) in dichloromethane (50 mL) was added triethylamine (1.604 mL) and 4-methylbenzene-1-sulfonyl chloride (1.097 g). The mixture was stirred at ambient temperature under nitrogen for 72 hours. The reaction was diluted with methylene chloride (50 mL) and brine (100 mL). The brine layer was extracted with methylene chloride (75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified on a silica gel column eluting with a 15-65% ethyl acetate in hexane gradient to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)[CH3:9].[CH:34]([S:37](Cl)(=[O:39])=[O:38])([CH3:36])[CH3:35].O>ClCCl>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][S:37]([CH:34]([CH3:36])[CH3:35])(=[O:39])=[O:38])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)[CH3:9]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(=O)(=O)C(C)C)cc2)cc1)OCC
Temperature: 25 °C
Yield: 90.1 %

Procedure:
Triethylamine (0.64 g; 6.28 mmole) was slowly added to a solution of 2-ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (1.5 g; 4.18 mmole) in dry dichloromethane (20 ml). After cooling to 0° C. isopropylsulfonyl chloride (0.9 g; 6.28 mmole) was added slowly. The reaction mixture was stirred over night at room temperature, water was added and the mixture was extracted with dichloromethane. The organic phase was washed with hydrochloric acid (1M) and sodium bicarbonate solution, dried (magnesium sulfate) and evaporated in vacuo to give 1.75 g (yield 90%) of 2-ethoxy-3-(4-{2-[4-(2-propanesulfonyloxy)phenyl]ethoxy}phenyl)propanoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][C:43]1=[O:48]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:45]4[CH2:46][CH2:47][NH:42][C:43](=[O:48])[CH2:44]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][C:36](=[O:41])[NH:37][S:38]3(=[O:40])=[O:39])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Reactant: O=C1CNCCN1
Product: O=C1CN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CCN1

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (134 mg, 0.2 mmol) was treated as described in general procedure R using excess piperazin-2-one (200 mg, 2 mmol) to give 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperazin-2-one.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]2=[N:7][C:6]=1[CH3:18])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:3].[S:19]([O:24]C)([O:22][CH3:23])(=[O:21])=[O:20].[CH2:26](OCC)C>O1CCCC1>[CH3:23][O:22][S:19]([O-:24])(=[O:21])=[O:20].[CH3:18][C:6]1[N:7]=[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]2[C:5]=1[CH2:4][N+:2]([CH3:26])([CH3:1])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CCOCC
Reactant: Cc1nc2c3ccccc3ccn2c1CN(C)C
Solvent: C1CCOC1
Product: COS(=O)(=O)[O-]
Product: Cc1nc2c3ccccc3ccn2c1C[N+](C)(C)C

Procedure:
A solution of 3-dimethylaminomethyl-2-methylimidazo[2,1-a]isoquinoline (7.7 g) in tetrahydrofuran (20 ml) was added dropwise to a solution of dimethyl sulfate (15 ml) in tetrahydrofuran (40 ml) with ice-cooling and stirring, and the mixture was stirred for 2 hours under the same conditions. To the reaction mixture was added diethyl ether (60 ml) and stirred with ice-cooling for 1 hour. The resulting precipitates were collected by filtration, washed with diethyl ether and recrystallized from ethanol to give 2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline methylsulfate (10 g).