Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[Br:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1Cc2cncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Br)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
20 g (93.8 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6 -one in 100 ml of dimethylformamide are treated with 17.5 g (98 mmol) of N-bromosuccinimide and stirred at room temperature for 35 minutes. The solution is poured into water and extracted twice with chloroform. The chloroform extracts are washed several times with water, dried over magnesium sulphate and evaporated. After recrystallization from ethyl acetate, the residue yields 3-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 196°-198°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH3:16])[C:10]([CH3:18])([CH3:17])[CH2:9]1.[C:19]([C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:39]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:40]4[CH:52]=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42](F)[CH:41]=4)[C:31]=3[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]>CS(C)=O.O>[C:19]([C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:39]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:40]4[CH:41]=[CH:42][C:43]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[C:51]([NH:7][CH:8]5[CH2:9][C:10]([CH3:18])([CH3:17])[N:11]([CH3:16])[C:12]([CH3:14])([CH3:15])[CH2:13]5)[CH:52]=4)[C:31]=3[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1C(C)(C)CC(Nc2cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc2C(=O)OC(C)(C)C)CC1(C)C
Temperature: 90 °C

Procedure:
0.95 g of potassium carbonate and 7.8 ml of 4-amino-1,2,2,6,6-pentamethylpiperidine are successively added to a solution of 1.06 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 2 hours and 15 minutes in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride and dried over magnesium sulphate. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (97/3 by volume), so as to give 0.8 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]benzoate in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1CCNC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(N3CCCC3)cc2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=547.2 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, pyrrolidine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: [Li+].[OH-].[N:3]1([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([CH:20]=2)[C:16]([O:18]C)=[O:17])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl>O.O1CCCC1>[N:3]1([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([CH:20]=2)[C:16]([OH:18])=[O:17])=[O:10])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of LiOH (420 mg, 10 mmol) in water (8 ml) was added to a stirred solution of methyl 5-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 56; 450 mg, 1.27 mmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was acidified with HCl (6 mol/l), extracted with ethyl acetate (3×40 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give crude title compound as a white solid. 400 mg.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]=[N:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12]C1C=C(C#CC=O)C=CC=1>>[Cl:12][C:3]1[CH:2]=[C:1]([C:7]#[C:8][CH:9]=[N:10][OH:11])[CH:6]=[CH:5][CH:4]=1
Reactant: O=CC#Cc1cccc(Cl)c1
Reactant: ON=CC#Cc1ccccc1
Product: ON=CC#Cc1cccc(Cl)c1
Yield: 96.4 %

Procedure:
The title compound was prepared following the method here described for Compound 1a, using Compound 31d instead of phenylpropiolaldehyde. The pale brown residue was used in the next step without further purification. Yield: 96.4%.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:13][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:21]([N:18]1[CH2:19][CH2:20][CH:15]([O:14][C:12]2[CH:11]=[CH:10][C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[CH:13]=2)[CH2:16][CH2:17]1)([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3sc(C(=O)O)cc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.3 %

Procedure:
The above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid methyl ester (0.222 g, 0.666 mmol) was dissolved in 1.3 mL of THF/ethanol=1/1 and treated with 0.333 mL of aq. NaOH (3M, 1.5 eq.). The mixture was stirred for 2 h at ambient temperature and was then neutralized by adding 0.50 mL of 2M HCl (1.5 eq.). Careful evaporation of all solvents, trituration in diethyl ether, and drying afforded then 0.256 g of the title compound as white solid, contaminated with innocouos inorganic salts.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:25])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH3:28]I.O>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=3[N:14]([CH3:28])[C:13]2=[O:25])[CH2:7][CH2:6]1)=[O:4]
Reactant: CI
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccc(C(F)(F)F)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](Cn2c(=O)n(C)c3ccc(C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
trans-4-(2-Oxo-6-trifluoromethyl-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarboxylic acid methyl ester (0.87 mg, 2.44 mmol) was dissolved in anhydrous DMF. NaH (1.95 g, 4.9 mmol, 60% in mineral oil) and MeI (0.30 ml, 4.9 mmol) were added and the mixture was stirred at room temperature for two days. H2O was added and the solvents were evaporated. The crude was dissolved in DCM (15 ml) and washed with H2O (10 ml). The organic layer was dried over Na2SO4, filtered and the solvent removed to give 0.93 g (yield quantitative) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[O:26])=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C[Si](C)(C)[C:29]([F:32])([F:31])[F:30].[F-].C([NH+](CCCC)CCCC)CCC>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([OH:26])[C:29]([F:32])([F:31])[F:30])=[CH:22][CH:23]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: CCCC[NH+](CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.4 %

Procedure:
To a solution of 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetaldehyde (0.114 g, 0.31 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (0.053 g, 0.38 mmol). The mixture stirred at 0° C. for 1 h after which tributylammonium fluoride (1.0 M, 0.078 mL, 0.078 mmol) was added. The mixture stirred at rt for 16 h. After this time, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.010 g, 7%) as a light yellow solid. MW=433.85. 1H NMR (DMSO-d6, 500 MHz) δ 8.82 (s, 1H), 8.30-8.22 (m, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.56-7.49 (m, 2H), 7.31 (d, J=8.5 Hz, 2H), 6.20 (d, J=11.5 Hz, 1H), 4.23-4.12 (m, 1H), 2.95-2.85 (m, 4H), 2.76-2.68 (m, 1H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 434 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[S:8][CH:9]=1)=[O:4].CO.[OH-].[Na+]>O>[F:25][C:22]([F:23])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]([NH:11][CH2:10][C:7]2[S:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=2)=[O:26])=[CH:16][CH:17]=1
Reactant: COC(=O)c1csc(CNC(=O)COc2ccc(OC(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(COc1ccc(OC(F)(F)F)cc1)NCc1nc(C(=O)O)cs1
Reaction time: 12 h
Yield: 85.8 %

Procedure:
2-{[2-(4-Trifluoromethoxy-phenoxy)-acetylamino]-methyl}-thiazole-4-carboxylic acid methyl ester (8.6 g, 22 mmol) was mixed with methanol (110 mL). NaOH (1.3 g, 33 mmol) was dissolved in water (110 mL) and added to the methanol solution. The reaction mixture was stirred for 12 hours. The mixture became homogenous after three hours. The methanol was removed in vacuo and the resulting slurry was acidified with 1 N HCl. The resulting slurry was extracted with EtOAc ×3. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was recrystallized from methanol to afford the title compound (7.1 g, 86%). 1H NMR (400 MHz, d6-DMSO): 9.08 (t, 1H), 8.33 (s, 1H), 7.31 (d, 2H), 7.06 (d, 2H), 4.63 (s, 2H), 4.61 (d, 2H); MS (ESI-LCMS) for C14H12F3N2O5S: 377 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28](Br)[C:27](=[O:32])[N:26]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:51]([O:53][CH2:54][CH3:55])=[CH2:52])CCC>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28]([C:51]([O:53][CH2:54][CH3:55])=[CH2:52])[C:27](=[O:32])[N:26]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 104.6 %

Procedure:
A 6-dram vial was charged with {1-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (379 mg, 0.65 mmol) and tetrakis(triphenylphosphine) palladium(0) (75 mg, 0.065 mmol) and the atmosphere replaced with argon. Toluene (5 ml) was added followed by tributyl-(1-ethoxy-vinyl)-stannane (352 mg, 0.97 mmol). The vial was heated to 110° C. and stirred for 12 h. The reaction mixture was diluted with chloroform (25 ml) and adsorbed onto silica gel. Chromatographic purification on silica gel (chloroform/2-propanol+1% TEA gradient) gave (1-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester as a yellow solid (394 mg, 0.68 mmol). MS: (APCI +) 576 (M+1, 100), 548.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:9]([CH2:23][OH:24])=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:12]=1.[H-].[Na+].I[CH3:33]>O1CCCC1.O>[CH3:33][O:24][CH2:23][C:9]1[C:8]([O:7][C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([O:3][C:2]([F:1])([F:28])[F:29])[CH:5]=2)=[N:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[N:10]=1
Reactant: CI
Reactant: OCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-[3-(trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole-4-methanol (i.e. the product of Example 5, Step I, 0.075 g, 0.18 mmol) in anhydrous tetrahydrofuran (2 mL) was added sodium hydride (0.011 g, 0.28 mmol, 60% dispersion in oil). After 15 min., iodomethane (0.017 mL, 0.27 mmol) was added. The mixture was stirred at 23° C. for 1.75 h. The reaction mixture was diluted with water (20 mL), extracted with diethyl ether (3×15 mL), and washed with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product which was purified by chromatography on silica gel eluting with 0 to 10% ethyl acetate in hexanes to obtain the title compound (0.045 g.) as a clear, colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[F:20][C:21]([F:28])([F:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[F:20][C:21]([F:28])([F:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: FC(F)(F)[C@@H]1CCCN1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@H]3C(F)(F)F)n2)c1

Procedure:
B16 was prepared following the general procedure reported for B10 using A1 and (S)-2-(trifluoromethyl)pyrrolidine. The title compound (B16) was purified by reverse phase RP-HPLC (column: C18), using H2O (0.1% TFA) and MeOH (0.1% TFA) as eluents. Yield: 58.7 mg (15%), colorless amorphous solid. MS (ES) C15H17F3N6O2S requires: 402. found: 403 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl>[CH2:19]1[C:20](=[O:21])[N:16]([O:13][C:12]([CH2:11][CH2:10][CH2:9][S:8][S:7][C:2]2[N:1]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:14])[C:17](=[O:22])[CH2:18]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCCSSc1ccccn1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CCCSSc1ccccn1)ON1C(=O)CCC1=O
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Compound 11a (1.10 g, 4.8 mmol) and N-hydroxysuccinimide (0.64 g, 5.5 mmol) were dissolved in dichloromethane (50 mL). The solution was magnetically stirred as 1-[3-(dimethylamino)propyl]-3 ethylcarbodiimide (1.05 g, 5.5 mmol) was added. After 2 h, ethyl acetate (150 mL) was added and the solution was transferred to a separatory funnel and washed consecutively with 0.5 M HCl (30 mL) and saturated sodium chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under vacuum. The residue was taken up in a minimum volume of ethyl acetate and was purified by silica chromatography using a mobile phase of hexanes:ethyl acetate:acetic acid (2.5:1:0.02, v/v/v). Fractions containing pure product were combined and solvent was removed to give N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB, 3a) (1.2 g, 76% yield). 1H NMR (CDCl3): δ 2.12-2.19 (2H, m), 2.78-2.87 (6H, m), 2.91 (2H, t, J=7.0), 7.06-7.12 (1H, m), 7.62-7.71 (2H, m), 8.48 (1H, d, 4.4 Hz). MS (M+Na+) Found: 348.8 Calculated: 349.4.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[H-].[Na+].Br.Br[CH2:21][C:22]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)=[O:23]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:21][C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: Cc1ccc(C(=O)CBr)cn1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CN2c3nc(Cl)cc(=O)n3CC[C@H]2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g (3.94 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one is added to a suspension of 394.27 mg (9.86 mmol) of sodium hydride in 40 mL of DMF. The reaction mixture is placed under magnetic stirring at room temperature for 15 minutes. A solution of 1.16 g (3.94 mmol) of 2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide in 10 mL of DMF is added dropwise to the reaction medium at 0° C. The reaction is stirred at room temperature overnight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40 min 60% B), 480 mg of (8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])=[O:2].[O-:26][Mn](=O)(=O)=O.[K+]>C1COCC1.O>[C:18]([C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:24]([CH3:25])=[C:3]([CH:4]=3)[C:1]([OH:26])=[O:2])=[O:7])[CH2:9][CH2:10]2)=[CH:21][CH:20]=1)#[N:19]
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a stirred mixture of 4-(1-(3-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 39.2, 600 mg, 1.81 mmol, 1.00 equiv) in THF (5 mL) was added dropwise a solution of KMnO4 (1 g) in water (10 mL). The resulting mixture was stirred overnight at 60° C. in an oil bath. After cooling to ambient temperature, the solids were removed by filtration and the pH of the filtrate was adjusted to ≧10 with sodium hydroxide (aqueous, 1 M). The resulting mixture was washed with 20 mL of ethyl acetate. Aqueous 1 M HCl was then employed to adjust the pH of the aqueous layer to ˜4. The resulting aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 500 mg (80%) of the title compound as light yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:16])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19].C[O-].[Na+]>COCCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:7][C:6](=[O:16])[C:5]=1[C:3]([NH:17][C@@H:18]([CH3:19])[C:20]([OH:22])=[O:21])=[O:4]
Reactant: COC(=O)c1c(O)c2ccccc2sc1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2ccccc2sc1=O)C(=O)O

Procedure:
A mixture of 4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester compound 3(c) (103 mg, 0.44 mmol), L-alanine (583 mg, 6.55 mmol) and NaOMe (285 mg, 5.28 mmol) in 2-methoxyethanol (14 mL) was refluxed for 6 h and concentrated. Residue was dissolved in water (100 mL) and acidified by 1 N HCl solution to pH=3-4. Precipitate was collected and rinsed with water. It was dried in vacuo and then triturated in MeOH (10 mL). Solid was collected and dried in vacuo to provide the title compound (57 mg). MS ESI(−) m/e: 291.12 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:8]2[O:12][CH2:11][CH2:10]O2)[CH:5]=[CH:6][CH:7]=1.Br[C:14]1[CH:19]=[CH:18]C=[CH:16][C:15]=1COCOC>>[Cl:1][C:2]1[CH:3]=[C:4]([B:8]2[C:16]3[CH:15]=[CH:14][CH:19]=[CH:18][C:10]=3[CH2:11][O:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(B2OCCO2)c1
Reactant: COCOCc1ccccc1Br
Product: Clc1cccc(B2OCc3ccccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-chlorophenyl)-[1,3,2]-dioxaborolane and 1-bromo-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: O=S(Cl)[Cl:3].[CH2:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[N:11]=[N:10][C:9]=1[CH2:17]O)[CH3:6]>C(Cl)Cl>[Cl:3][CH2:17][C:9]1[N:10]=[N:11][C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=1[O:7][CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCOc1cc(OCC)c(CO)nn1
Solvent: ClCCl
Product: CCOc1cc(OCC)c(CCl)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Excess SOCl2 is added to a stirred solution of (4,6-diethoxy-pyridazin-3-yl)-methanol (174 mg, 0.88 mmol) in CH2Cl2 (4 mL). The reaction mixture is stirred at room temperature for 4 hours. The solvent is then removed in vacuo and toluene (4 mL) is added and evaporated to dryness. Flash column chromatography purification (eluted with 3:1 Hexane, EtOAc) of the residue provides the title product as a clear oil. H1 NMR δ (CDCl3) 6.28(s, 1H), 4.78 (s, 2H), 4.54 (q, 2H, J=7.2 Hz), 4.11 (q, 2H, J=7.2 Hz), 1.48 (t, 3H, J=7.2 Hz), 1.41 (t,3H, J=7.2 Hz,) LC-MS (M+1) 217.1.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH2:4][CH:5]([CH:7](NC([C@H]1O[C@@H]1C(O)=O)=O)[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14]N)=O)[CH3:6].C[N:26]([CH3:28])C>O>[CH2:13]1[C:12]2[C:11](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:10]([CH2:8][CH2:7][C:5]2[CH:4]=[CH:3][N:26]=[CH:28][CH:6]=2)[CH2:14]1
Reactant: CCC(C)C(NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)NCCCCN
Reactant: CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)CCN2CCc1ccncc1
Reaction time: 0.5 h

Procedure:
Another core-shell polymer, according to the present invention, was prepared by combining 300 g of SP-1 with 500 g of demineralized water and adjusting the pH to 10 with sodium hydroxide. The mixture was combined with 200 g of CPI-2 and stirred for 30 minutes. 44.28 g of trimethylamine (25% aq.) were added and allowed to stir for one hour. After one hour, the pH was raised to 12 and the mixture was vacuum distilled for 3 hours to remove residual trimethylamine.