Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13](O)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:37])[NH:26][C:27]([CH3:36])=[CH:28][C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([NH:22][CH2:23][C:24]3[C:25](=[O:37])[NH:26][C:27]([CH3:36])=[CH:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3]
Reactant: Cc1cc(-c2ccccc2)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Product: Cc1cc(-c2ccccc2)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 11 from 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.531 mmol) and 3-(aminomethyl)-6-methyl-4-phenyl-2(1H)-pyridinone (133 mg, 0.531 mmol). The product was collected as a white solid, 0.041 g (15%). LCMS E-S (M+H)=479.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (d, J=6.82 Hz, 6 H) 2.23 (s, 3 H) 4.23-4.27 (m, 2 H) 5.33-5.42 (m, 1 H) 6.02-6.04 (m, 1 H) 7.35-7.42 (m, 1 H) 7.43 (s, 4 H) 8.23-8.26 (m, 1 H) 8.34-8.39 (m, 2 H) 8.41-8.42 (m, 1 H) 8.84-8.88 (m, 2 H) 8.91-8.96 (m, 1 H) 11.91 (s, 1 H).
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:31][C:23]1[CH:22]=[C:21]([CH2:20][C:19]([NH:18][C:14]2[C:13]([CH3:33])=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:34])=[O:32])[CH:26]=[CH:25][C:24]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (300.00 mg, 6.2704E-4 mol), potassium carbonate (260 mg, 0.0019 mol), methanol (20 mL, 0.4 mol) and 2 drops of water. The reaction was stirred at room temperature for 20 minutes. The solvent was removed and the reaction mixture was extracted with ethyl acetate and the solvent was removed to obtain the product as a light yellow solid. MS m/z=437.5 (M+H). 1H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.07 (d, J=8.45 Hz, 1H), 7.79 (t, J=7.85 Hz, 1H), 7.53 (d, J=12.68 Hz, 1H), 7.45 (d, J=7.85 Hz, 2H), 7.37 (d, J=8.45 Hz, 1H), 6.44 (d, J=7.66 Hz, 1H), 5.05-5.00 (m, 1H), 4.93 (t, J=5.66 Hz, 1H), 3.92 (s, 2H), 3.67-3.51 (m, 2H), 2.22 (s, 3H), 1.28 (d, J=7.51 Hz, 3H).
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[CH3:36][C:37]1([CH3:43])[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1>C(Cl)Cl.CO>[CH3:36][C:37]1([CH3:43])[NH:38][CH2:39][CH2:40][N:41]([C:9]2[N:10]([CH2:31][C:32]([F:34])([F:33])[F:35])[C:11]3[C:16]([N:17]=2)=[C:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:14]=[C:13]([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)[N:12]=3)[CH2:42]1
Reactant: CC1(C)CNCCN1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC1(C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Temperature: 120 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
An N-methyl-2-pyrrolidone suspension (5.0 ml) of 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (492.8 mg, 1.19 mmol) and 2,2-dimethylpiperazine (JMC, 1995, Vol. 38, No. 22, 4389) (571.3 mg, 4.75 mmol) was heated at 120° C. to dissolve and the resulting mixture was stirred at 100° C. for 12 hours. The resulting mixture was left standing to cool, poured into methylene chloride-methanol (10:1), and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=49:1 to 13:1) to give the title compound (554.4 mg, 95%) as a pale yellow solid.
Reaction SMILES: S(Cl)(Cl)(=O)=[O:2].[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14]([S:18]([Cl:21])(=[O:20])=[O:19])[CH2:15]2)=[CH:10][CH:9]=1>C(N(CC)CC)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:2][CH2:12][CH2:13][N:14]([S:18]([Cl:21])(=[O:20])=[O:19])[CH2:15][C:16]=2[CH:17]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CCO2

Procedure:
This compound was prepared from 1.4 g of 7-methoxy-2,3,4,5-tetrahydro-benzo[f]l[1,4]oxazepine, 0.91 mL of sulfuryl chloride and 4.7 mL of triethylamine using the procedure described for 63f. Yield: 0.23 g (oil), EI-MS: 277 (M+).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[I-].[K+].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN3CCCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-(trifluoromethyl)-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and pyrrolidine in tetrahydrofuran are reacted to give 8-(trifluoromethyl)-1-(pyrrolidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:4].[Br-].[CH3:28][C:29]1[CH:54]=[CH:53][C:32]([CH2:33][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:31][CH:30]=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:6]1[C:5]([CH2:3][OH:4])=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([CH2:18][CH2:19][CH2:28][C:29]2[CH:54]=[CH:53][C:32]([CH3:33])=[CH:31][CH:30]=2)=[C:8]([CH:21]([CH3:22])[CH3:23])[N:7]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(CCCc2c(C(C)C)nc(C(C)C)c(CO)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 4-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1H NMR (300 MHz, CDCl3): δ 7.08 (m, 4 H), 7.01 (d, J=8 Hz, 2 H), 6.85 (d, J=8 Hz, 2 H), 4.30 (s, 2 H), 3.39 (sept, J=6.6 Hz, 1 H), 3.13 (sept, J=6.6 Hz, 1 H), 2.41 (t, J=7 Hz, 2 H), 2.31 (s, 3 H), 2.27 (m, 2 H), 1.58 (m, 2 H), 1.31 (d, J=6.6 Hz, 6 H), 1.26 (d, J=6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.33; H, 8.28; N, 3.22. mp 79-80° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[CH2:5]CN.C(=O)([O-])[O-].[Na+].[Na+].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].[CH3:30][N:31](C)C=O>>[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:31]([CH2:5][C:4]2[CH:8]=[C:9]([Br:11])[CH:10]=[C:2]([Br:1])[CH:3]=2)[CH3:30])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: NCCc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
N-(3,5-dibromobenzyl)methylamine (4.38 g; 15.7 mmol) and sodium carbonate (2.37 g; 22.4 mmol) were added to N,N-dimethylformamide (40 ml). While the mixture was stirred at room temperature, p-tert-butylbenzyl bromide (3.40 g; 14.9 mmol) in N,N-dimethylformamide (20 ml) was added dropwise. After completion of the addition, the mixture was stirred for 100 minutes at 50° C., and left to cool to room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution, and extracted with 2N hydrochloric acid twice (100 ml each). Crystals that precipitated were collected, and combined with the aqueous layer. The mixture was alkalinized with aqueous sodium hydroxide solution, and extracted with chloroform (100 ml). The organic layer was washed with water and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=40:1), to thereby yield 4.21 g of the target compound as pale white oily matter (yield: 66.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:9]=1
Reactant: CCOC(=O)/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2cc(/C=C/C(=O)O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
A mixture of ethyl (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol5-yl)-2-propenoate (300 mg), 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (5 mL) and ethanol (3 mL) was stirred at 60° C. for 5 hrs. 1N Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol5-yl)-2-propenoic acid (270 mg, yield 95%). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 194-195° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[CH3:15][CH:16]([CH3:22])[C:17](=O)[CH2:18][CH:19]=O>>[CH2:8]([S:7][C:5]1([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:2]2[N:1]=[C:17]([CH:16]([CH3:22])[CH3:15])[CH:18]=[CH:19][N:3]2[NH:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(C)C(=O)CC=O
Product: CC(C)C1=NC2=NC(SCc3ccccc3)(SCc3ccccc3)NN2C=C1
Yield: 96 %

Procedure:
This material was prepared in 96% yield from 3-amino-5-benzylthio-1,2,4-triazole and 4-methyl-3-oxopentanal following the general procedure described in Example 7. The desired product was isolated as a solid, m.p. 65°-66° C. IR and 1H NMR were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:23][CH3:24])[C:11]=1[O:12][CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16])[C:6]([OH:8])=O.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>>[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:23][CH3:24])[C:11]([O:12][CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:33]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC/C=C(\C)CCC=C(C)C
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OC/C=C(\C)CCC=C(C)C)c(OC)c1
Yield: 95.9 %

Procedure:
In a manner identical to Example 15, 3,5-dimethoxy-4-geranyloxy benzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.31 g), thereby yielding 1.02 g(95%) of the aimed compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[C:21]([C:2]2[N:6]3[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: FC(F)(F)c1ccc2ncc(Br)n2c1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc2ncc(-c3cccnc3Cl)n2c1
Temperature: 95 °C

Procedure:
To a solution of 3-Bromo-6-trifluoromethyl-imidazo[1,2-a]pyridine (1 eq, 2.9 mmol, 0.77 g), 2-chloropyrid-4-yl boronic acid (1.05 eq, 3.05 mmol, 0.478 g), Na2CO3 (2 eq, 5.81 mmol, 0.616 g) in dioxane (45 ml) and water (13.5 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.03 mmol, 200 mg). The reaction mixture is heated at 95° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+=297/299.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:20]1([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:13]=3)[CH:19]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cc(-c2ccccc2)ccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cc(-c3ccccc3)ccn2)sc2ccccc12
Yield: 53 %

Procedure:
A mixture of methyl thiosalicylate (1.00 g, 5.9 mmol), 2-cyano-4-phenylpyridine (1.10 g, 5.9 mmol), triethylamine (1.30 ml, 9.0 mmol) and toluene (2.5 ml) was refluxed for 20 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.99 g, 53%).
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].[PH2:9](=[O:11])[OH:10].[NH3:12]>CO>[NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].[NH4+:12].[PH2:9](=[O:10])[O-:11]
Reactant: O=[PH2]O
Reactant: N
Agent: CCCC(N)C(=O)O
Solvent: CO
Product: O=[PH2][O-]
Product: [NH4+]
Temperature: 65 °C

Procedure:
181 g (1 mole) of (3-amino-3-carboxy-propyl)-methane-phosphinic acid are reacted at room temperature with 17 g (1.0 mole) of ammonia (previously dissolved at 0° C. in methanol). The mixture warms up spontaneously to 35° C. and is then refluxed at 65° C. for 30 minutes, cooled, filtered and the crystals are dried to give 193 g of (3-amino-3-carboxy-propyl)-methane-phosphinic acid ammonium salt, which is non-hygroscopic, readily soluble in water, melting at 207°-209° C., containing 90% of (3-amino-3-carboxy-propyl)-methane-phosphinic acid. Yield: 97.5%
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:25][CH2:24]1.Cl>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])=[N:7][C:2]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)[CH:30]=2)=[N:3][CH:4]=1
Reactant: O=C(NCCO)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: Cl
Solvent: CC(C)O
Product: CN1CCN(c2cccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCO)n3)c2)CC1
Temperature: 95 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
2-[(2,5-Dichloro-4-pyrimidinyl)amino]-N-(2-hydroxyethyl)benzamide (150 mg, 0.45 mmol) and 3-(4-methyl-1-piperazinyl)aniline (87 mg, 0.45 mmol) were combined in a vessel with 8 mL isopropanol and 12N HCl (38 μL, 0.45 mmol). The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction was cooled to room temperature and the solid was filtered off and washed with ether to give 184 mg (76%) of an off-white solid as the HCl salt. Mass (M+H)+=482, 484.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:12][C@@H](C)CSC)[O:5][C:6]2=[O:11].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CC1[N:29]=C(C)C(N)=CC=1>C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:6]([NH2:29])(=[O:11])[C:7]1[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=1)[C:4]([NH2:12])=[O:5]
Reactant: CSC[C@H](C)N=C1OC(=O)c2cccc(Cl)c21
Reactant: Cc1nc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccccc1C(N)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 194.4 %

Procedure:
4-Chloro-3-[(S)-1-methyl-2-methylthioethylimino]-3-H-isobenzofuran-1-one (0.2 g) and 6-(3,5-bis-trifluoromethyl-benzyl)-2-methyl-pyridin-3-ylamine (0.22 g) were dissolved in acetonitrile (10 ml), to which p-toluenesulfonic acid hydrate (0.01 g) was added, and stirred at 60° C. for 20 hours. After the reaction, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain N1-[6-3,5-bis-trifluoromethyl-benzyl)-2-methyl-pyridin-3-yl]-3-chloro-N2-(S)-1-methyl-2-methylhioethyl)phthalamide (0.21 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:38][CH2:37][C:36]([CH3:41])([CH3:40])[CH3:35])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: CC(C)(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCC(C)(C)C)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.042 g, 0.090 mmol), 3,3-dimethylbutan-1-ol (0.046 g, 0.448 mmol) and Ph3P (0.071 g, 0.269 mmol) in THF (5 mL) was added DEAD (0.043 ml, 0.269 mmol) at 0° C. After 1 h, cold bath was removed and stirred overnight (15 h) at rt. Then, reaction mixture was concentrated and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(5-(4-(3,3-dimethylbutoxyl)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0205 g, 0.037 mmol, 41.4% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.14-7.17 (m, 1H), 7.05-7.09 (m, 1H), 6.95-6.99 (m, 2H), 6.09 (s, 1H), 4.27 (qd, J=7.1, 10.8 Hz, 1H), 4.17 (qd, J=7.1, 10.7 Hz, 1H), 4.08-4.13 (m, 2H), 3.19 (d, J=11.8 Hz, 1H), 2.88 (t, J=12.1 Hz, 1H), 2.61 (s, 3H), 2.28 (d, J=11.8 Hz, 1H), 2.21 (s, 3H), 2.07 (t, J=11.8 Hz, 1H), 1.79 (t, J=7.3 Hz, 2H), 1.56 (td, J=3.7, 12.4 Hz, 1H), 1.34-1.42 (td, J=3.5, 12.5 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.17-1.20 (m, 1H), 1.08 (d, J=12.9 Hz, 1H), 1.04 (s, 9H), 0.90 (s, 3H), 0.66 (s, 3H). LCMS (M+H)=553.4.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1>>[Cl:12][C:8]1[C:9]([CH3:11])=[CH:10][C:4]2[N:3]=[C:2]([N:24]3[CH2:25][CH2:26][N:21]([C:16]4[C:15]([C:14]([F:28])([F:13])[F:27])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:22][CH2:23]3)[NH:6][C:5]=2[CH:7]=1
Reactant: Cc1cc2[nH]c(Cl)nc2cc1Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: Cc1cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2cc1Cl

Procedure:
The benzoimidazole from step (b) above (201 mg, 1.0 mmol) reacted with 1-(3trifluoromethylpyridin-2-yl)piperazine (231 mg, 1.0 mmol, Oakwood) under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 396.1 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1>ClC(Cl)Cl>[ClH:3].[Cl:3][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOc1cccnc1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCOc1cccnc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
Thionyl chloride (0.89 ml, 12 mmol) was added slowly to a solution of 3-(2-hydroxyethoxy)pyridine (1.13 g, 8 mmol) in trichloromethane (20 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then at ambient temperature for 2 hours. The volatiles were removed by evaporation, the residue azeotroped with toluene and dried under vacuum to give 3-(2-chloroethoxy)pyridine hydrochloride (300 mg, 19%) as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].[BrH:20]>C(O)(=O)C>[BrH:20].[CH2:18]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:7]=[CH:6][N:5]=1)[CH3:19]
Reactant: CCN(CC)c1cc(-c2ccc(OC)cc2)ncn1
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC)c1cc(-c2ccc(O)cc2)ncn1

Procedure:
A solution of 18.6 g. (0.1 mole) of 4-diethylamino-6-(p-methoxyphenyl)pyrimidine in 30 ml. of 48% hydrobromic acid and 30 ml. of glacial acetic acid is heated to the reflux temperature and gaseous hydrogen bromide slowly introduced below the surface during the first two hours of refluxing. Heating is continued until thin layer chromatography indicates the reaction is complete. The reaction is cooled and the excess acetic acid and hydrobromic acid are removed under reduced pressure. The residual product is triturated with acetone, filtered and recrystallized from ethanol/hexane.