Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][C@H:23]([C@@H:27]([OH:32])[C:28]([F:31])([F:30])[F:29])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][C@H:23]([C@@H:27]([OH:32])[C:28]([F:31])([F:29])[F:30])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F
Yield: 63.5 %

Procedure:
A solution of compound B (55 g) in ethanol (300 ml) was hydrogenated for 3 hours over 10% palladium on carbon catalyst (5.5 g), under a hydrogen pressure of 55 psi. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to give a viscous oil. The oil was triturated with diethyl ether (250 ml) for 16 hours and the resulting solid was collected by filtration to give (S)-1-[(S)-2-amino-3-methylbutyryl]-N-[(S)-2-methyl-1-((R)-2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide (C) (25.6 g) as a white solid; NMR (300 MHz, d6 -DMSO): 0.75-0.97 (m, 12H), 1.42 (s, 1H), 1.65-2.0 (m, 5H), 2.78, 3.20 (each d, total 1H), 3.45, 3.60 (each m, total 1H), 3.82 (m, 1H), 4.10 (m, 1H), 4.45, 4.57 (each m,total 1H), 6.45 (br d, 1H), 7.45, 7.60 (each d, total 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:14])=[CH:5][C:6]([Cl:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Cl:13][C:6]1[CH:5]=[C:4]([F:14])[C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1cc(CN)c(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(CNC(=O)C(C)(C)C)c(F)cc1Cl
Yield: 99.8 %

Procedure:
The title compound was prepared following the procedure described in step-2 of Intermediate-2 using methyl 5-(aminomethyl)-2-chloro-4-fluorobenzoate (180 mg, 0.83 mmol), DIPEA (321 mg, 2.49 mmol) and pivaloyl chloride (120 mg, 1.0 mmol) in CH2Cl2 (5 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.16 (t, 1H), 7.73 (d, J=6.9 Hz, 1H), 7.58-7.54 (d, J=10.2 Hz, 1H), 4.26-4.24 (d, J=5.7 Hz, 2H), 3.83 (s, 3H), 1.11 (s, 9H).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.S(O)(O)(=O)=O.[NH2:25][CH2:26][C:27]#[N:28].C([O-])(=O)C.[Na+]>COCCOC>[C:26]([CH2:27][N:28]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])#[N:25]
Reactant: N#CCN
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC#N

Procedure:
10.4 g (0.04 mol) of 6-phthalimido-2,5-hexanedione, 6.2 g (0.04 mol) of aminoacetonitrile sulphate and 6.8 g (0.08 mol) of sodium acetate are stirred in 200 ml of ethylene glycol dimethyl ether at 80° C. for 16 hours and the mixture is worked up as in Example 27.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl 2-[(aminooxy)methyl]piperidine-1-carboxylate 105 (0.312 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 106 (0.40 g, 91%) as a white foam.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:7])[N:15]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)[CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: COc1cc2ncnc(N3CCC(NCc4ccccn4)CC3)c2cc1OC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)N(Cc1ccccn1)C1CCN(c2ncnc3cc(OC)c(OC)cc23)CC1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
##STR23## n-Butyl isocyanate (1 g) was added slowly to a stirred solution of 4-[4 -(2-pyridylmethylamino)piperidino]-6,7-dimethoxyquinazoline, (1.4 g) prepared as in part A above, in dry chloroform, followed by standing at room temperature for 30 minutes. The solution was evaporated to dryness in vacuo to give a yellow oil which crystallized on trituration with ether. Recrystallization from ethyl acetate gave 4-[4-{3-n-butyl-1-(2-pyridylmethyl)ureido}piperidino]6,7-dimethoxyquinazoline (1.2 g) as pale yellow crystals, m.p. 162°-4° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH3:8][NH:9][C:10](=[S:13])[NH:11][NH2:12]>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH:5]1[N:9]([CH3:8])[C:10](=[S:13])[N:11]=[N:12]1)[CH3:2]
Reactant: CNC(=S)NN
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCC1N=NC(=S)N1C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
Ethoxyacetyl chloride (57 g.) was added slowly to a stirred solution of 4-methylthiosemicarbazide (53.5 g.) in dry pyridine (500 ml.) at 0°-5°. The mixture was allowed to attain room temperature and stirring was continued for 18 hours. Following concentration under reduced pressure the residue was treated with a solution of sodium (21.4 g.) in ethanol (500 ml.) and the mixture was heated under reflux for 24 hours. Following concentration and acidification with hydrochloric acid a solid was obtained. After partial concentration the solid was collected and recrystallised from ethyl acetate to give 3-ethoxymethyl-4-methyl-1,2,4-triazoline-5-thione (53 g.), m.p. 137°-138°. The thione (44 g.) was desulphurised by slow addition to a solution prepared from nitric acid (75 ml.) water (150 ml.) and sodium nitrite (1.5 g.) at 15°-20°. Following subsequent basification with sodium carbonate and concentration the residue was extracted with ethanol-ether 1:1 and distilled to afford 3-ethoxymethyl-4-methyl-1,2,4-triazole (30 g.) b.p. 154°-156°/0.05 mm. The above compound (15 g.) dissolved in 48% aqueous hydrobromic acid (150 ml.) was heated under reflux for 24 hours and concentrated to dryness to give 3-hydroxymethyl-4-methyl-1,2,4-triazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:33])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:30](O)[CH3:31])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:13][CH:12]=1)=[O:10].C([SiH](CC)CC)C.B(F)(F)F>ClCCl>[Cl:33][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:30][CH3:31])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:13][CH:12]=1)=[O:10]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(C)O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Product: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
A stirred solution of N-(3,5-dichloro-pyridin-4-yl)-3-(1-hydroxyethyl)-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide [0.06 g, Example 16(a)] in dichloromethane (2 ml), under nitrogen and at 0° C., was treated with triethylsilane (0.028 g,) and boron trifluoride dietherate (0.015 ml). The mixture was allowed to warm to room temperature and then stirred at this temperature for 3 hours. The solution was partitioned between ethyl acetate (15 ml) and saturated sodium bicarbonate solution (15 ml). The organic layer was dried over sodium sulphate then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (gradient elution, 1:3 to 2:1, v/v) to give the title compound (22 mg) as a white solid, m.p. 147-149° C. [Elemental analysis:— C, 56.69; H, 4.04; N, 8.15%. Calculated for C23H19Cl2N3O3S:— C, 56.56; H, 3.92; N, 8.60%].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:16]([O:18]C)=[O:17])[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=[N:3]1.[OH-].[K+]>C1COCC1.O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[S:10][C:11]=2[C:12]([F:13])([F:14])[F:15])=[CH:5][CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C(F)(F)F)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1-c1cc(C(=O)O)sc1C(F)(F)F
Temperature: 50 °C
Yield: 110.5 %

Procedure:
To a solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxylate (250 mg, 0.77 mmol), in THF/H2O (3 mL/0.3 mL), was added KOH (217 mg, 3.88 mmol). The reaction mixture was heated to 50° C. for 4 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (5 mL×3). The collected organic layers were concentrated under vacuum to give crude acid (235 mg, 80% pure) which was used directly in the next step without further purification: LC-MS (ES) 277 (M+H)+.
Reaction SMILES: [CH2:1]([Si:4]([CH2:14][CH:15]=[CH2:16])([CH2:11][CH:12]=[CH2:13])[CH2:5][CH2:6][CH2:7][O:8]C=O)[CH:2]=[CH2:3].CO.C(=O)([O-])O.[K+]>O>[CH2:14]([Si:4]([CH2:1][CH:2]=[CH2:3])([CH2:11][CH:12]=[CH2:13])[CH2:5][CH2:6][CH2:7][OH:8])[CH:15]=[CH2:16]
Reactant: C=CC[Si](CC=C)(CC=C)CCCOC=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=CC[Si](CC=C)(CC=C)CCCO
Temperature: 50 °C
Reaction time: 5 h

Procedure:
The triallyl formyloxypropyl silane intermediate was converted to the hydroxylpropyl product by charging 5.0 grams of the intermediate, together with 50 ml of methanol (commercially available from Burdick and Jackson of Muskeegon, Mich.) and 10 ml of deionized water, in a 250 ml flask with stir bar. 1.0 gram (10 millimoles) of potassium hydrogen carbonate (commercially available from Aldrich Chemical Co.) was added to the solution, which was then stirred at 50° C. for five hours. The solution was filtered and was concentrated in vacuo. The sample was then taken up in cyclohexane and was washed with saturated aqueous sodium chloride before drying over anhydrous sodium sulfate (commercially available from Aldrich Chemical Co.). The sample was then purified using flash chromatography on silica with 99/1 cyclohexane/acetone eluent initially, followed by 80/20 cyclohexane/acetone. The recovered fractions were concentrated in vacuo to yield triallyl 3-hydroxypropyl silane, as shown by capillary GC/FID analysis using a 30 meter DB-5 column. Spectroscopic analysis using mass spectrometry, FTIR and NMR was consistent with triallyl-3-hydroxypropyl silane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O.[Cu]I>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([N:25]4[CH:29]=[N:28][CH:27]=[N:26]4)=[CH:24][C:6]2=3)=[CH:18][CH:19]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nnc2n1-c1ccc(-n3cncn3)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Temperature: 150 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
A mixture of (R)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (40.2 mg, 0.1 mmol), 1H-1,2,4-triazole (13.8 mg, 0.2 mmol), copper(I) iodide (3.8 mg, 0.02 mmol), and cesium carbonate (59 mg, 0.18 mmol) in N-methyl-2-pyrrolidone (3 mL) was stirred at 150° C. for 16 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (3*20 mL). The combined organic layer was washed with water (3*20 mL) and brine (3*20 mL) in turns, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silica-gel, dichloromethane/methanol=15:1) to give (R)-6-(4-chlorophenyl)-1,4-dimethyl-8-(1H-1,2,4-triazol-1-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as a white solid (10 mg, 25.7%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[O:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:7][CH2:6]1.N1C=CC=CC=1>C(Cl)Cl>[O:16]=[C:12]1[N:11]([CH:8]2[CH2:9][CH2:10][O:5][CH2:6][CH2:7]2)[CH2:15][CH2:14][N:13]1[C:1]([Cl:4])=[O:2]
Reactant: O=C1NCCN1C1CCOCC1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 0.267 mL, 0.506 mmol) in DCM (5 mL) was treated slowly drop-wise with a solution of Example B1 (0.086 g, 0.505 mmol) and pyridine (0.082 mL, 1.011 mmol) in DCM (3 mL). The mixture was warmed to RT, stirred for 1 hour, then concentrated to dryness to afford 2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carbonyl chloride as an off-white solid. The material was carried on to the next step assuming 100% yield (118 mg). MS (ESI) m/z: 304.1 (M+H+) (for material quenched into benzylamine).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20](Br)([CH3:22])[CH3:21].O>CN(C=O)C>[CH:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1)([CH3:22])[CH3:21]
Reactant: O=C1CCCCc2ccc(O)cc21
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)C(=O)CCCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a suspension of 2-hydroxy-6,7,8,9-Tetrahydro-5H-benzocyclohepten-9-one (9.69 g, 56.3 mmol) and potassium carbonate (23.3 g, 0.17 mol) in DMF (60 ml) was added dropwise, under ice-cooling, isopropyl bromide (34.6 g, 0.28 mol). The reaction mixture was stirred for one hour at 100° C., which was poured into water, followed by extraction of the organic substance with ethyl acetate. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=9:1) to give the above-titled compound (11.4 g, yield 93%, oil).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:38][CH2:37][O:36][CH:35]([CH2:39][NH2:40])[CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][CH:35]4[O:36][CH2:37][CH2:38][N:33]([CH3:32])[CH2:34]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CN1CCOC(CN)C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CN(C)CCO3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (4-methylmorpholin-2-yl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3 H) 2.78-2.94 (m, 4 H) 2.98-3.15 (m, 1 H) 3.31-3.58 (m, 4 H) 3.68 (t, J=11.75 Hz, 1 H) 3.78-3.95 (m, 1 H) 4.08 (dd, J=12.88, 3.03 Hz, 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.21 (d, J=6.32 Hz, 1 H) 8.44 (d, J=7.07 Hz, 2 H) 8.85-9.06 (m, 2 H) 9.93 (br. s., 1 H) 12.57-13.73 (m, 1 H). MS m/z [M+H]+ 433.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12]>>[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1cccc2ccccc12
Temperature: 150 °C
Reaction time: 4 h

Procedure:
128 g naphthalene (1.0 m) and 160 g sulfuric acid 98% (1.6 m) were charged to a reactor and mixed. This mixture was heated rapidly to 150° C. and agitated at 150° C. for 4 hours to obtain a naphthalenesulfonic acid having an acid value of 408.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[C:17]([F:26])[CH:16]=1.N>C(O)C>[F:21][C:19]1[CH:20]=[C:15]([NH:14][C:2]2[N:7]3[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]3[N:5]=[C:4]([CH3:13])[CH:3]=2)[CH:16]=[C:17]([F:26])[C:18]=1[C:22]([F:24])([F:25])[F:23]
Reactant: Nc1cc(F)c(C(F)(F)F)c(F)c1
Reactant: CSc1nc2nc(C)cc(Cl)n2n1
Agent: N
Solvent: CCO
Product: CSc1nc2nc(C)cc(Nc3cc(F)c(C(F)(F)F)c(F)c3)n2n1
Temperature: 25 °C

Procedure:
To a suspension of 7-chloro-5-methyl-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 8 (0.286 g, 1.332 mmol)) in ethanol (5 mL), 4-amino-2,6-difluorobenzotrifluoride (FLUOROCHEM, 0.263 g, 1.332 mmol) was added and the mixture was stirred at room temperature until reaching completion. Anhydrous ammonia (0.190 mL, 1.332 mmol) was added and solvent was removed in vacuo. The residue was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 95:5 to 40:60%). Upon collection of the appropriate fractions, the title compound was obtained as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:39])[C@H:7]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:8][N:9]([C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:14][CH:13]=1)[NH2:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[NH:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([N:9]([NH2:10])[CH2:8][C@H:7]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:6]([OH:39])=[O:5])=[O:28])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)[C@@H](CN(N)C(=O)c1ccc(OCCNc2ncccn2)cc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NN(C[C@@H](C(=O)O)C(=O)OCc1ccccc1)C(=O)c1ccc(OCCNc2ncccn2)cc1
Reaction time: 4 h

Procedure:
A solution of 25-1 (840 mg, 1.6 mmol) and CH2Cl2 (10 ml) at ambient temperature was treated with TFA (10 ml). After stirring for 4.0 h, the reaction mixture was concentrated and the residual TFA removed azeotropically with toluene. Trituration of the resulting waxy solid with ether provided 25-2 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][C:13]1[C:21]([CH3:22])=[CH:20][C:16]2[N:17]=[CH:18][NH:19][C:15]=2[CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:17]2[C:16]3[CH:20]=[C:21]([CH3:22])[C:13]([CH3:12])=[CH:14][C:15]=3[N:19]=[CH:18]2)[N:3]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: Cc1cc2ncn(-c3nc(Cl)nc4[nH]cnc34)c2cc1C
Reaction time: 17 h
Yield: 43.4 %

Procedure:
283 mg of 2,6-dichloropurine, 5 ml of butanol and 219 mg of 5,6-dimethylbenzimidazole are mixed and brought to a temperature of 100° C. for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with isopropanol and drying under vacuum at 50° C. are carried out, and 194 mg of expected product are obtained, in the form of cream-colored crystals.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:16]=[C:9]2[N:10]=[CH:11][C:12]([Br:15])=[C:13]([CH3:14])[C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Br:15][C:12]1[CH:11]=[N:10][C:9]2=[CH:16][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=3)([C:3]#[N:4])[CH3:17])[N:7]=[C:8]2[C:13]=1[CH3:14]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: Cc1c(Br)cnc2cn(CC(C)(N)C#N)nc12
Product: Cc1c(Br)cnc2cn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure adapted from that described in Example 1, using 2-amino-3-(6-bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (56.7 mg, described in Example 150) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (26 mg, 27%). MS (ES): M/Z [M+H]=498. 1H NMR: (400 MHz, CHLOROFORM-d): 1.97 (s, 3H), 2.67 (s, 3H), 4.82 (d, 1H), 4.97 (d, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.92 (d, J=8.3 Hz, 2H), 8.38 (s, 1H), 8.54 (s, 1H) and 8.61 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:30])[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]=1[N+:27]([O-:29])=[O:28])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH3:31]I.O>CN(C)C=O>[CH2:11]([O:10][C:8](=[O:9])[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]=1[N+:27]([O-:29])=[O:28])([CH3:31])[C:6]([O:5][CH2:3][CH3:4])=[O:30])[CH3:12]
Reactant: CI
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(C(=O)c2ccccc2)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C(=O)OCC)c1cccc(C(=O)c2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
A slurry of 0.6 g (0.012 mole) of 50% sodium hydride/oil (washed, petroleum ether) in a 10 ml dimethylformamide was treated dropwise with a solution of 3.6 g (0.009 mole) of 2-(3-benzoyl-2-nitrophenyl)propanedioic acid diethyl ester in 20 ml of dimethylformamide. The mixtue was stirred for 5 min and the 4 ml (9.1 g, 0.065 mole) of methyliodide was added and the solution stirred at ambient temperature overnight. The solution was poured into 500 ml of cold water and let stand overnight. The aqueous layer was decanted and the gummy residue was dissolved in diethylether. The ether solution was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to give 3.5 g (95%) of a gray solid, m.p. 102°-104° C. (recrystallized from 2-propanol).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.[N+:15]([CH3:18])([O-:17])=[O:16]>CO>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:18][N+:15]([O-:17])=[O:16])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (1 N, 2.3 mL) was added dropwise to 4-formyl-benzoic acid methyl ester (0.33 g) and nitromethane (0.11 ml) in 5 mL methanol at 0° C. The solution was acidified after 0.5 h and a precipitate was formed. The precipitate was isolated by filtration to give 228 mg of 4-(2-nitro-vinyl)-benzoic acid methyl ester.