Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1.[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:32]=1)[C:26](N(OC)C)=[O:27].CC(O)C>CCOCC>[Br:20][C:21]1[CH:32]=[C:25]([C:26]([C:7]2[C:15]3[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=2)=[O:27])[CH:24]=[N:23][CH:22]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
n-BuLi (15.3 mL, 2.5 M in Hexane, 38.2 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 36.4 mmol) in Et2O (300 mL) at −78° C. and stirred for 1 h. 5-Bromo-N-methoxy-N-methyl-nicotinamide (8.9 g, 36.4 mmol) was added to the reaction mixture slowly and stirred for 3 h, warmed to room temperature, and stirred for an additional I h. The reaction mixture was quenched with saturated aqueous NH4Cl (200 mL) and stirred for 20 min. The aqueous layer was extracted with EtOAc (3×300 mL) and the combined organic layers were washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated in vacuo to provide a crude brown solid. Trituration with 2-propanol provided the title compound as a pure off-white solid (7.0 g, 51%). MS: 380.7 (MH+); HPLC Rf: 5.5 min. (HPLC method 4).
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([NH:13][NH2:14])([CH3:12])([CH3:11])[CH3:10].[CH3:15][O:16][C:17](=[O:28])[C:18]([C:23]([CH:25]1[CH2:27][CH2:26]1)=O)=[CH:19]N(C)C>C(O)C>[CH3:15][O:16][C:17]([C:18]1[CH:19]=[N:14][N:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:23]=1[CH:25]1[CH2:27][CH2:26]1)=[O:28]
Reactant: COC(=O)C(=CN(C)C)C(=O)C1CC1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cnn(C(C)(C)C)c1C1CC1
Yield: 36.3 %

Procedure:
Triethylamine (4.8 mL, 34.2 mmol) and tert-butyl hydrazine hydrochloride (1.4 g, 11.4 mmol) were added sequentially to a solution of crude 2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester (2.4 g, 11.4 mmol) in ethanol (24 mL). The resulting suspension was mixed well and divided equally into two 25 mL Personal Chemistry Microwave Process Tubes (Biotage AB, Sweden). The tubes were sealed with a septum and submitted to 150 W microwave irradiation using a Personal Chemistry Microwave Synthesis System (Biotage AB, Sweden) at 160° C. for 30 minutes. The reaction mixtures in the two tubes were combined and ethanol was evaporated under reduced pressure. The remaining mixture was partitioned between dichloromethane and water, and the water phase was extracted three times with dichloromethane. The organic phases were combined, concentrated in vacuo, and purified by silica chromatography eluting with a gradient of 10-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (921 mg, 36%). LRMS m/z calcd for C12H18N2O2 (M+H) 223.1, found 223.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[C:17]1([NH2:24])[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>C(O)(C)C>[CH3:16][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:23][C:20]2[CH:21]=[CH:22][C:17]([NH2:24])=[CH:18][CH:19]=2)[CH:8]=1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: Nc1ccc(N)cc1
Solvent: CC(C)O
Product: Cn1ccnc1-c1cc2nccc(Nc3ccc(N)cc3)c2s1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A mixture of 214 (500 mg, 2.0 mmol, scheme 46) and benzene-1,4-diamine (500 mg, 4.62 mmol) in iso-PrOH (15 mL) was refluxed overnight, cooled to room temperature and filtered. The solid was collected, washed with iso-PrOH/H2O mixture, to afford the title compound 301 (300 mg, 44% yield) as a yellowish solid. MS (m/z): 322.1(M+H) (found).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([N:34]3[C@@H:38]([CH2:39][CH3:40])[CH2:37][O:36][C:35]3=[O:41])[S:32][CH:33]=2)=[CH:25][CH:24]=1>C(#N)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([N:34]3[C@@H:38]([CH2:39][CH3:40])[CH2:37][O:36][C:35]3=[O:41])[S:32][C:33]=2[F:21])=[CH:25][CH:24]=1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: CC[C@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC[C@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)c(F)s1
Temperature: 25 °C
Reaction time: 21.5 h

Procedure:
The Selectfluor® reagent (2.2125 g, 6.25 mmol) in 250 mL of acetonitrile was added under nitrogen dropwise over 1.5 h to a solution of (4S)-3-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-4-ethyl-1,3-oxazolidin-2-one (2.0015 g, 5.67 mmol), prepared in step 2 of Example 7, in 250 mL of acetonitrile at room temperature. After the addition, the reaction was stirred at room temperature for 21.5 h. The reaction was concentrated under reduced pressure to remove the acetonitrile. The residue was partitioned between methylene chloride and 2 N HCl. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give 2.11 g of a tan foam. Purification of the foam on 800 g of silica gel (230-400 mesh) using 50% methylene chloride-hexane to 100% methylene chloride as the eluents gave the title compound (914.8 mg, 44%) as a white solid, mp 105-107° C.; MS (ES) m/z 370.9 [M+H]+; Anal. Calcd for C14H12BrFN2O2S: C, 45.30; H, 3.26; N, 7.55. Found: C, 45.53; H, 3.09; N, 7.37.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].C1C=CC=CC=1>O>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][CH2:9][CH:7]([OH:8])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: O=CC(=O)c1ccccc1
Reactant: COC(=O)c1ccc(CCN)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(CCNCC(O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
Phenyl glyoxal (0.8 g) and 2-(4-carbomethoxyphenyl)ethanamine (1.1 g) were heated in refluxing benzene (100 ml) under a Dean and stark head until the theoretical amount of water had been collected. The solvent was replaced with methanol and sodium borohydride (2.0 g) was added portionwise with ice cooling. The mixture was stirred for 2 hours, the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The dried organic extract was evaporated and crystallised from benzene/hexane, mp 105°-106°. (CDCl3) 6.80-7.60 (8H, m), 6.18 (3H, s), 5.34 (1H, m), 2.94 (2H, d, J=8 Hz), 2.77 (5H, m), 2.09 (2H, d, J=8 Hz).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[C:15]2[C:19]([CH:20]=[CH:21][CH:22]=1)=[N:18][N:17]([CH3:23])[C:16]=2[S:24]([NH2:27])(=[O:26])=[O:25].[Cl:28][CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:28][CH2:29][CH2:30][O:13][C:14]1[C:15]2[C:19]([CH:20]=[CH:21][CH:22]=1)=[N:18][N:17]([CH3:23])[C:16]=2[S:24]([NH2:27])(=[O:26])=[O:25]
Reactant: OCCCl
Reactant: Cn1nc2cccc(O)c2c1S(N)(=O)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc2cccc(OCCCl)c2c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
3.8 g (22 mmol) of diethylazo dicarboxylate was added to a solution containing 5 g (22 mmol) of 4-hydroxy-2-methyl-2H-indazole-3-sulfonamide, 1.8 g (22 mmol) of 2-chloroethanol and 5.8 g (22 mmol) of triphenylphosphine in 50 ml of THF, and the mixture was stirred at room temperature for 20 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, then concentrated and purified by column chromatography (hexane/ethyl acetate=2/1) to obtain 1.66 g (yield: 26%) of the desired product. Melting point: 177°-179° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([NH2:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1.S(Cl)(Cl)(=O)=O>CC(C)=O>[O:19]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:14][NH:20][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NCc1ccco1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Solvent: O=S(=O)(Cl)Cl
Product: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
4-(Chlorosulfonyl)benzoic acid (5.0 g, 22.7 mmol) was added in three portions over a 10 minute period to a stirring solution of furfuryl amine (6.6 g, 68 mmol) in acetone (200 mL) cooled to 0° C. via an ice water bath. After addition of the sulfonyl chloride was complete the ice bath was removed and the solution was stirred for 1 hour at ambient temperature. The mixture was concentrated and subjected to silica gel chromatography (90% ethyl acetate, 8% hexanes and 2% acetic acid) to afford 4.4 of 4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (4.4 g, 68%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 4.04 (d, 2H, J=6 Hz), 6.13 (d, 1H, J=3.2 Hz), 6.25 (m, 1H), 7.43 (m, 1H), 7.83 (d, 2H, J=8.4 Hz), 8.05 (d, 2H, J=8.4 Hz), 8.36 (t, 1H, J=6 Hz), 13.4 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH2:27][C:28]1[S:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:27][C:28]1[S:29][C:30]([C:33]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:34])=[CH:31][N:32]=1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Reactant: Nc1ncc(C(=O)O)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(N)s1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (250 mg, 0.70 mol) was dissolved in DMF (4 mL), and 2-amino-1,3-thiazole-5-carboxylic acid (110 mg, 0.76 mmol) was added. PYBOP (543 mg, 1.04 mmol) and diisopropylethylamine (0.61 mL, 3.50 mmol) were subsequently added, and the mixture was stirred at room temperature overnight. The desired product was isolated via HPLC to give the title compound (80.0 mg, 24%): HPLC MS RT=1.03 min, MH+=486.3; 1H NMR (MeOH-d4+2 drops TFA-d) δ: 7.90 (1H, d), 7.79 (1H, d), 7.50-7.60 (2H, m), 3.70 (2H, m), 3.30 (2H, d), 3.20 (2H, q), 2.10 (2H, s), 1.35 (10H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:6]=2[CH:34]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:6]=2[CH:34]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2F)=NC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2F)=NC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.3 %

Procedure:
A mixture of [9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-nitro-phenyl)-amine (I-212, 500 mg, 1.05 mmol), stannous chloride dihydrate (1.42 g, 6.3 mmol) and ethyl acetate (15 mL) was refluxed for 28 hours, then cooled to room temperature and allowed to sit overnight. The mustard-yellow reaction mixture was poured onto ˜50 g cracked ice with stirring, and sat. NaHCO3 solution was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (3×100 mL). The extracts were combined, dried (Na2SO4), filtered and evaporated in vacuo to provide N-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-benzene-1,4-diamine as an orange/yellow solid (500 mg, 100%) MS m/z=448 (M+H). A solution of this product (50 mg, 0.1 mmol), 4-methylpiperazine-1-carbonylchloride (89 mg, 0.6 mmol), diisopropylethylamine (142 mg, 1.1 mmol), in dioxane (0.5 nit) was submitted to microwave irradiation (300 W) for 60 minutes at 160° C. The reaction solution was cooled to room temperature and slowly poured into a stirring saline solution (10 mL). The resulting precipitate was collected by filtration, washed with water and purified by RP-HPLC (C18, 0 to 100% CH3CN in 0.1% aqueous HCO2H) to yield I-280 as a pale yellow solid (6 mg, 10%) MS m/z=574 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[NH:11][C:10]3[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=3[N:8]=2)[CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N:1]2[CH2:6][CH2:5][O:4][CH:3]([C:7]3[NH:8][C:9]4[CH2:15][CH2:14][CH2:13][CH2:12][C:10]=4[N:11]=3)[CH2:2]2)[N:20]=[C:19]([NH2:24])[N:18]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C1CCc2[nH]c(C3CNCCO3)nc2C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4c([nH]3)CCCC4)C2)n1
Yield: 15.5 %

Procedure:
A solution of 2-(2-morpholinyl)-4,5,6,7-tetrahydro-1H-benzimidazole (0.8 g, 3.86 mmol), 4,6-dichloro-2-pyrimidinamine (0.633 g, 3.86 mmol) and Hunig's base (1.681 mL, 9.65 mmol) in ethanol (19.3 mL) was heated at 85° C. overnight. The mixture was concentrated and chromatographed (eluent EtOAc+NH4OH) to afford the title compound (200 mg). LC-MS (ES) m/z=335 [M+H]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19](=[O:20])[C:18]2=[CH:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=[C:17]2[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:15]1.[C:35](=[O:37])=[O:36]>O1CCCC1>[CH3:13][N:14]1[C:19](=[O:20])[C:18]2=[CH:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23]([C:35]([OH:37])=[O:36])=[C:17]2[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:15]1
Reactant: O=C=O
Reactant: CC(C)Cc1nn(C)c(=O)c2cn(Cc3ccccc3)cc12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Cc1nn(C)c(=O)c2cn(Cc3ccccc3)c(C(=O)O)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (2.5M in hexanes, 2.35 m) was added dropwise to a stirred solution of diisopropylamine (0.85 ml) in dry tetrahydrofuran (10 ml) at 0° C., under nitrogen. The reaction was stirred at 0° C. for 30 minutes, then cooled to −78° C. To this was added a solution of 2,6-dihydro-2-methyl-4-(2-methylpropyl)-6-(1-phenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (1.5 g, prepared as in Example 14 step b) in dry tetrahydrofuran (10 ml), and stirring was continued for 30 minutes. This anion was then added to an excess of solid carbon dioxide. The reaction was allowed to warm to room temperature overnight, and was then quenched by the addition of water. The mixture was extracted into ethyl acetate, washed with brine, dried and evaporated to give a yellow oil, which was chromatographed, eluting with ethyl acetate:isohexane(3:7), to give the sub-title compound as a yellow solid (0.91 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:20][N:21]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[N:22]4)[C:16](=[O:30])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:20][N:21]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[N:22]4)[C:16](=[O:30])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)ncn1Cn1ccc(C(F)(F)F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1nc(N2CC=C(c3ccc(Cl)cc3)CC2)ncn1Cn1ccc(C(F)(F)F)n1
Yield: 56.5 %

Procedure:
To a dichloromethane solution (1.0 mL) of 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,5-triazin-2(1H)-one (14 mg, 0.03 mmol) synthesized in Reference Synthesis Example 91a, trifluoroacetic acid (0.5 mL) was added and the resultant mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and to the resultant concentrate, water and saturated sodium hydrogen carbonate aqueous solution were added. A deposited solid was washed with water and was dried under reduced pressure to obtain the title compound (7.4 mg, yield: 55%).
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: CN(C)C
Reactant: CCC(C)C(NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)NCCCCN
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.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])([O-:3])=[O:2].O[CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][N:13]([CH2:20][CH2:21][NH2:22])[N:14]=2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=[N+]([O-])c1ccc(-c2ccn[nH]2)cc1C(F)(F)F
Product: NCCn1ccc(-c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n1
Yield: 62.9 %

Procedure:
The title compound was prepared from 5-(4-nitro-3-(trifluoromethyl)phenyl)-1H-pyrazole (1.69 g, 6.57 mmol) and tert-butyl 2-hydroxyethylcarbamate (1.059 g, 6.57 mmol) using the method of Example 34(c) to afford 1.24 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.33 (m, 2H), 4.53 (t, 2H), 7.13 (d, 1H), 8.00 (d, 1H), 8.38 (m, 1H), 13.45 (m, 1H).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C@H:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH3:8])[C:3]1=[O:16].[F:17][C:18]1([F:31])[CH:23]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][NH:20][CH2:19]1.C(N(CC)CC)C>>[F:31][C:18]1([F:17])[CH:23]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]([CH:2]2[CH2:6][CH2:5][N:4]([C@H:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH3:8])[C:3]2=[O:16])[CH2:19]1
Reactant: C[C@@H](c1ccc(F)cc1)N1CCC(Br)C1=O
Reactant: Oc1ccc(C2CCNCC2(F)F)cc1
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(F)cc1)N1CCC(N2CCC(c3ccc(O)cc3)C(F)(F)C2)C1=O
Temperature: 120 °C

Procedure:
To a mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (0.134 g, 0.47 mmol, from Example 50, step B) and 4-(3,3-difluoropiperidin-4-yl)phenol (0.05 g, 0.23 mmol, E-1a from Example 56, step D) was added triethylamine (0.16 mL, 1.2 mmol) and the resulting mixture was heated at 120° C. for 1 h. After cooling, the reaction was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with water and brine, then dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified via preparative HPLC (method B) to yield the homochiral Examples 56 P-3 and P-4 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one diastereomers. The relative and absolute configurations of Examples 56 P-3 and P-4 were not determined and are arbitrarily named P-3 and P-4 based on the order of elution during the HPLC purification. Data for P-3: 11.5 mg pale yellow solid, LCMS (method O) RT 1.23 min (99.8% AP), m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.55 (d, J=7.2, 3H), 1.83 (m, 1H), 1.91-1.99 (m, 1H), 2.10-2.30 (m, 2H), 2.57-2.64 (q, 1H), 2.82-3.95 (m, 3H), 3.07-3.20, (m, 1H), 3.33-3.42 (m, 2H), 3.67 (t, J=9, 1H), 5.40 (d, J=7.2, 1H), 6.75 (m, 2H), 7.09-7.15 (m, 4H), 7.37-7.41 (m, 2H); 19F NMR δ ppm-102.515, -103.158, -114.576, -115.216, -117.070. Data for P-4: 13.7 mg pale yellow solid; LCMS (method O) RT 1.215 min (100% AP), m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.59 (d, J=6.4, 3H), 1.80-1.90 (m, 1H), 2.01-2.29 (m, 3H), 2.53 (t, 1H), 2.81-2.97 (m, 3H), 3.01-3.25 (m, 3H), 3.34-3.43 (m, 1H), 3.64 (t, J=8.8, 1H), 5.42 (d, J=7.2, 1H), 6.74-6.77 (m, 2H), 7.09-7.16 (m, 4H), 7.35-7.38 (m, 2H); 19F NMR δ ppm-102.632, -103.271, -115.162, -115.801, -116.989.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1>C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: Fc1ccc(F)c(Cc2ccncc2)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Fc1ccc(F)c(CC2CCNCC2)c1
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A mixture of platinum oxide (0.5 g) and 4-(2,5-difiuorobenzyl)pyridine from above in acetic acid (100 ml) was hydrogenated for 3 hr. The catalyst was removed and the solution concentrated in vacuo. The residue was dissolved in water and the solution basified with sodium hydroxide. The basic mixture was extracted with ether and the extracts concentrated in vacuo. The crude oil was vacuum distilled to give the product (5.1 g, 72.9%, bp: 110° C.). A sample of the hydrochloride was prepared in ether (mp: 182°-183° C.).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]([C:28]#[N:29])[C:14](=[O:27])[NH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CO>CN(C=O)C>[O:27]=[C:14]1[C:13]([C:28]#[N:29])=[CH:12][C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:10]=2)=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[NH:15]1
Reactant: CS(=O)(=O)c1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccnc(Nc3ccccc3)n2)c(-c2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
To 5-(2-methylsulfonylpyrimidin-4-yl)-2-oxo-6-(3-trifluoromethylphenyl)-1,2-dihydropyridine-3-carbonitrile (160 mg, 0.35 mmol) in DMF, under argon, was added a prepared mixture of aniline (129 μL, 1.30 mmole) and potassium bis(trimethylsilyl)amide (0.5M in toluene) (2.6 mL, 1.30 mmole) under argon. The reaction was stirred for 15 minutes and then quenched into ethyl acetate and water. The pH was adjusted to 5.4 with aqueous potassium hydrogen sulfate solution and the ethyl acetate layer removed and concentrated to give a solid. Trituration of the solid from methanol (4 mL) gave 80 mg of a solid.