Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=O)[CH2:10][C:11]([O:13]C)=[O:12].[N:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[N+:17]=[N-:18]>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[N:17]=[N:18][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COCCCCC(=O)CC(=O)OC
Reactant: Cc1ccccc1N=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCc1c(C(=O)O)nnn1-c1ccccc1C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A solution of sodium hydride (60% in oil, 280 mg) in DMF (10 ml) was cooled to 0° C.-5° C., methyl 7-methoxy-3-oxoheptanoate (1.32 g) was added, and the mixture was stirred at 0° C.-5° C. for 30 min. Then, 1-azido-2-methylbenzene (932 mg) was added, and the mixture was stirred at room temperature for 15 hr. The solvent was concentrated under reduced pressure, methanol (10 ml) was added to the residue, and 4N aqueous sodium hydroxide solution (5 ml) was added and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure and water (20 ml) was added to the residue. 6N Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate (20 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (930 mg) as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Br:43][C:44]1C=[CH:48][CH:47]=[CH:46][C:45]=1CBr>>[Br:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:15]=1[CH2:14][N:12]1[N:11]=[C:9]2[N:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:6]=[C:7]([N:16]3[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]3)[C:8]2=[N:13]1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: BrCc1ccccc1Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3Br)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-(bromomethyl)benzene and isolated as colorless gum (6.9 mg, 37%). MS (m/e): 451.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2C(OCC1C=CC=CC=1)=O)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[NH:12]1[C:13]2[C:9](=[C:8]([O:7][CH:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: [H][H]
Reactant: CCOC(=O)C(Oc1cccc2c1ccn2C(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Oc1cccc2[nH]ccc12)C(=O)OCC
Yield: 82 %

Procedure:
A solution of 12 (8.51 g, 20 mmol) in ethanol (250 mL) was mixed with 10% palladium on carbon (1.5 g) and hydrogenated at atmospheric pressure for 1 h until hydrogen uptake ceased. The catalyst was filtered off through a Celite bed and washed with ethanol, and the filtrate was evaporated to give a brown oil. Filtration through flash silica with ethyl acetate-hexanes (3:2) as eluent, followed by trituration with diethyl ether-hexanes at −20° C. gave 8 as white crystals (4.78 g, 82%), mp 52-53° C. (from diethyl ether-hexanes), identical to the material described above.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([O:34][CH:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])=[C:15]([CH2:18][O:19][C:20](=[O:31])[CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>CO>[NH2:10][CH:11]1[C:48](=[O:49])[N:13]2[C:14]([C:32]([O:34][CH:35]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])=[C:15]([CH2:18][O:19][C:20](=[O:31])[CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH2:16][S:17][C@H:12]12
Reactant: COc1ccc(OCC(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(OCC(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)cc1
Yield: 92.8 %

Procedure:
Benzhydryl 7-(2-phenylacetamido)-3-[2-(4-methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate (6.0 g.), phosphorus pentachloride (5.65 g.), pyridine (2.2 g.) and methanol (7.3 ml.) were reacted according to a similar manner to that of Preparation 30 (4) to give benzhydryl 7-amino-3-[2-(4-methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate (4.6 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](S(C3C=CC=CC=3)(=O)=O)[C@@H:16]([CH2:29][CH2:30][CH3:31])[CH2:15]2)[CH:3]=1.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:39](=[O:40])[CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:16]([CH2:29][CH2:30][CH3:31])[CH2:15]2)[CH:3]=1
Reactant: CCC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Product: CCC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccccc1

Procedure:
Prepared from the product from example 72 part (f) (0.70 g) and phenylacetyl chloride according to the procedure described in example 69 part (g) to give the title compound as a white solid (214 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([OH:11])[CH:10]=1.C(N(CC)CC)C.[Cl:27][C:28]1[C:29]([O:38][C:39]2[CH:50]=[CH:49][C:42]([O:43][CH:44]([CH3:48])[C:45](Cl)=[O:46])=[CH:41][CH:40]=2)=[N:30][CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>O1CCCC1>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([O:11][C:45](=[O:46])[CH:44]([O:43][C:42]2[CH:41]=[CH:40][C:39]([O:38][C:29]3[C:28]([Cl:27])=[CH:33][C:32]([C:34]([F:35])([F:36])[F:37])=[CH:31][N:30]=3)=[CH:50][CH:49]=2)[CH3:48])[CH:10]=1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Yield: 66.4 %

Procedure:
5-(2,4-Dichlorophenoxy)-2-nitrophenol (0.8 g) and triethylamine (0.6 ml) were dissolved in dry tetrahydrofuran (10 ml), and the solution was stirred at room temperature for 2 hours, with an addition of a solution of 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride (0.8 g), in dry tetrahydrofuran (10 ml). After completing the reaction, the solvent was distilled off under a reduced pressure and the residue was dissolved in methylene chloride (20 ml), followed by washing with 1 N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, water, and a saturated aqueous sodium chloride solution. The resultant reaction mixture was dried over anhydrous magnesium sulfate, ether was evaporated under a reduced pressure, and the resultant residue was subjected to silica gel medium pressure column chromatography for purification. Thus, the title compound (0.9 g) was obtained in the form of a colorless oily product.
Reaction SMILES: N.[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1C[N:21]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15](=[O:17])[NH2:21])=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O
Reaction time: 5 h
Yield: 90.4 %

Procedure:
Anhydrous ammonia gas was bubbled through a solution of (S)-(−)-1-(tert-butoxycarbonyl)-2-piperidine carboxylic acid (500 mg, 2.18 mmol) in DMF (50 ml) for 15 minutes. PyBop (1.25 g, 2.40 mmol) was added. After 5 hours, solvent was evaporated under reduced pressure. A solution of the resultant residue in ethyl acetate was washed with 5% citric acid (50 ml×3), 1 N NaOH (50 ml×3), dried with MgSO4, filtered, and concentrated to give 450 mg of (S)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester as a clear oil in 95% yield, which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[O:7])[CH2:5][CH2:4]1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>CN(C=O)C>[CH:3]1([C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)=[O:7])[CH2:4][CH2:5]1
Reactant: O=C(c1n[nH]c2ncccc12)C1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)C3CC3)c3cccnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
NaH (0.030 g, 0.75 mmol) was added to cyclopropyl(1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (100 mg, 0.534 mmol) in DMF (2 mL) at 0° C. After 10 minutes, tosyl chloride (0.13 g, 0.69 mmol) was added, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 hours and then quenched with ice and water. The mixture was extracted with EtOAc (3×10 mL) and dried over sodium sulfate. Column chromatography afforded cyclopropyl(1-tosyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (127 mg, 70%) as an oil, which crystallized upon standing.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[F:5][C:6]([F:21])([S:17](F)(=[O:19])=[O:18])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]>C(OCC)(=O)C>[CH2:1]([NH:4][S:17]([C:6]([F:5])([F:21])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:11])[F:10])(=[O:19])=[O:18])[CH2:2][CH3:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCN
Solvent: CCOC(C)=O
Product: CCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
n-Propylamine (26.60 g) and ethyl acetate (120 mL) were placed in a glass flask equipped with a stirrer, a condenser and a thermometer, and perfluorobutansulfonyl fluoride (available from Azumax Company) (45.31 g) was added dropwise over 1 hour using a dropping funnel to the flask in an ice bath. After completion of the dropping, the mixture in the flask was heated at 40□ with an oil bath and the mixture was stirred for 5 hours. Then the mixture was cooled to the room temperature and was washed twice with 75 ml of 9% aq. hydrochloric acid solution. Ethyl acetate layer was dried with magnesium sulfate and then was filtered off. Ethyl acetate was evaporated under vacuum to obtain N-propylperfluorobutanesulfonamide (46.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](C([O-])=O)[C:2]=1[C:10]([O-:12])=[O:11].[OH-].[K+:14]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([O-:12])=[O:11].[K+:14]
Reactant: O=C([O-])c1cccnc1C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccccn1

Procedure:
The pyridinedicarboxylate 30 (19.5 g, 0.1 mol) was treated with solid KOH (6.51 g, 0.1 mol) in 300 mL of methanol at room temperature for 2 h, giving rise to a thick pale white suspension, which was filtered and dried to provide the mono-potassium pyridinecarboxylate 3 in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[C:12](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(F)cc1C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
4-Fluoro-2-methylbenzoic acid (1.6 g, 10.3 mmol) was dissolved in CH2Cl2 (20 mL) and DMF (1 drop) and stirred as oxalyl chloride (10.3 mL, 20.8 mmol) was added. The reaction stirred for 15 minutes before the solvent was removed under reduced pressure. The product was dissolved in anhydrous CH2Cl2 and MeOH (5 mL) and stirred for a further 15 minutes. The solvent was removed under reduced pressure and purified by column chromatography on silica (2% EtOAc/Hexanes) to afford a colourless oil (1.33 g). 1H NMR (300 MHz, CDCl3): δ 7.95 (d, 1H), 6.96 (d, 1H), 6.75-6.77 (m, 1H), 3.86 (d, 3H), 2.62 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[C:4]([NH:10][CH3:11])[CH:3]=1.C[O:13][C:14](=O)[CH2:15][C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:22][C:20]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([C:15]2[C:14](=[O:13])[N:10]([CH3:11])[C:4]3[C:5]([CH:8]=2)=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=3)[CH:21]=1
Reactant: CNc1cc(Cl)ncc1C=O
Reactant: COC(=O)Cc1cc(N)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
6-Chloro-4-methylamino-pyridine-3-carbaldehyde 6 (19.8 g, 116 mmol) is mixed with 2-(5-amino-2-methyl-phenyl)acetic acid methyl ester 7 (27 g, 151 mmol) and potassium carbonate (48.1 g, 348 mmol) in DMF (1 L). The mixture is heated to 100° C. for 16 h. After cooling to rt and removing solvent in vacuo, the crude product is purified using flash chromatography (ethyl acetate:petroleum ether=1:1). The title compound 8 is obtained as a pale solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.63 (s, 1H), 7.27 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.74 (dd, J=2.4, 8.1 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 3.71 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.O>C1COCC1>[CH3:1][S:2]([NH:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCCOc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCCOc2ccccc21
Reaction time: 8 h
Yield: 74.7 %

Procedure:
1.54 g (13.4 mmol) of methanesulfonyl chloride were added dropwise with ice cooling to a solution of 2.0 g (12.2 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine (Example 6b) and 3.7 g (36.6 mmol triethylamine in 40 ml of THF. The mixture was allowed to come to RT and was stirred overnight and treated with 50 ml of water, and the THF was distilled off in vacuo. The residue was diluted with a further 50 ml of water and stirred for 3 h, and the deposited product was filtered off with suction. After drying in vacuo, 2.2 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine were obtained, m.p. 105-106° C. b) A solution of 1.1 g (6.2 mmol) of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF was added dropwise to a suspension of 0.23 g (6.2 mmol) of 80 percent sodium hydride in 10 ml of THF. After 2 h at RT, 0.94 g (6.7 mmol) of iodomethane were added and the mixture was stirred overnight at RT. After distilling off the solvent in vacuo, the residue was taken up in EA, and the solution was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated. Subsequent recrystallization of the product from isopropanol yielded 0.5 g of 5-(N-methyl-N-methylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine, m.p. 143-145° C.
Reaction SMILES: COCCOC.C([O-])([O-])=O.[Na+].[Na+].Br[C:14]1[N:19]=[C:18]2[N:20]([CH2:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[CH:29][CH:28]=[CH:27]4)[N:21]=[N:22][C:17]2=[N:16][CH:15]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:14]1[N:19]=[C:18]2[N:20]([CH2:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[CH:29][CH:28]=[CH:27]4)[N:21]=[N:22][C:17]2=[N:16][CH:15]=1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1ccccc1-c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 80 °C
Yield: 74.5 %

Procedure:
A mixture of DME (3.0 mL) and 1 M aqueous Na2CO3 (0.88 mL) was degassed by bubbling in Argon for 10 minutes. The mixture was transferred via syringe to a vial containing 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (100 mg, 0.29 mmol), 2-fluorophenylboronic acid (45 mg, 0.32 mmol) and Pd(dppf)2Cl2.CH2Cl2 (6.2 mg, 0.01 mmol). The vial was capped and heated to 80° C. for 3.5 hours. The crude reaction mixture was diluted with dichloromethane then washed with water. The dichloromethane was dried over Na2SO4, filtered and concentrated by rotary evaporation. The residue was purified by column chromatography using gradient elution with ethyl acetate and dichloromethane to afford 6-((6-(2-fluorophenyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (77 mg, 74%).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][CH:21]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:29]2[CH:28]([C:27](=[O:32])[N:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:34])[F:33])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CCCN1c1ccc(OC(F)(F)F)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CN(Cc3ccccc3)CC2CCN1c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To N-benzyl(methoxy)-N-((trimethylsilyl)methyl)methanamine (1.7 g, 7.0 mmol) and 1-(4-trifluoromethoxy-phenyl)-5,6-dihydro-1H-pyridin-2-one (0.6 g, 2.3 mmol) in DCM (30 mL) was added a solution of trifluoroacetic acid (0.026 g, 0.23 mmol) in DCM (10 mL) at 4° C. After the mixture was stirred at 50° C. for 3 h, the solution was washed with saturated sodium bicarbonate and brine, then dried over anhydrous Na2SO4. After removal of the DCM, the residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate P (10:1 to 5:1) to yield the title compound (0.19 g, 21%). 1H NMR (300 MHz, CDCl3): δ 7.34-7.20 (m, 9H), 3.77-3.55 (m, 4H), 3.18-3.01 (m, 2H), 2.93-3.83 (m, 3H), 2.43-2.41 (m, 1H), 2.07-2.05 (m, 1H), 1.80-1.75 (m, 1H); LC-MS: [M+1]+ 391.1.
Reaction SMILES: [N:1]([CH:4]([CH3:6])[CH3:5])=[C:2]=[O:3].[NH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH:11]=[CH:10][N:9]=1.C(N(C(C)C)CC)(C)C>ClCCCl>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[C:15]([NH:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:2]([NH:1][CH:4]([CH3:6])[CH3:5])=[O:3])[CH:13]=1)=[O:24]
Reactant: CC(C)N=C=O
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of 2-isocyanatopropane (0.050 g, 0.59 mmol), N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (0.047 g, 0.17 mmol) and diisopropylethylamine (50 mg, 0.39 mmol) in 1,2-dichloroethane (3.0 mL) was stirred at 60° C. for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified via prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product as a white solid (0.025 g, yield: 41%). 1H NMR (DMSO-d6, 500 MHz): δ 8.02 (d, J=5.5 Hz, 1H). 7.51 (s, 1H), 7.40-7.34 (m, 3H), 7.05 (m, 1H), 3.87 (m, 1H), 1.14 (t, J=6.5 Hz, 6H). LCMS (ESI) m/z: 367.1 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[NH2:21][C:19]1[C:18]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[O:31])=[CH:17][N:16]=[C:15]([NH:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[N:20]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C(=O)c1cnc(NC2CCCNC2)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (76 mg, Example 52) was dissolved in dichloromethane (4 mL), cooled to 0° C. and treated with trifluoroacetic acid (1 mL). After stirred 30 minutes at 0° C., the reaction mixture was concentrated in vacuo to give [4-amino-2-(piperidin-3-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone as a trifluoroacetic acid salt. A portion of this material was partitioned between ethyl acetate and aqueous sodium carbonate to give the free base. (129.5 mg). MS (M+H)+, 328.
Reaction SMILES: [CH3:1][N:2]1[C:7]([SH:8])=[N:6][C:5](=[O:9])[C:4]([OH:10])=[N:3]1.Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+].Cl>O>[CH3:1][N:2]1[C:7]([S:8][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:6][C:5](=[O:9])[C:4]([OH:10])=[N:3]1
Reactant: ClCc1ccncc1
Reactant: Cn1nc(O)c(=O)nc1S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nc(O)c(=O)nc1SCc1ccncc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of 2-methyl-3-mercapto-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (15.91 g), 4-chloromethylpyridine hydrochloride (19.68 g) and sodium bicarbonate (33.6 g) in water (500 ml) was stirred for 2 hours at 45° C. The mixture was cooled to 10° C. and adjusted to pH 6.2 with 6N hydrochloric acid. The resulting precipitates were collected by filtration, washed with water and acetone, and dried to give 2-methyl-3-(4-pyridylmethylthio)-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine (17.2 g), mp. 219° to 222° C. (dec.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([F:24])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl>FC(F)(F)C(O)=O.ClCCl>[F:24][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[C:20]([F:22])([F:21])[F:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(N2CCNCC2)ccc1C(F)(F)F
Yield: 77.8 %

Procedure:
4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (853 mg, 2.45 mmol) was stirred in a mixture of trifluoroacetic acid/dichloromethane (5 mL, 25% v/v) for 20 min at room temperature. The reaction mixture was combined with 25 mL of CH2Cl2 and was washed with sat'd NaHCO3 (2×10 mL) and brine. The resulting CH2Cl2 layer was dried over anhydrous Na2SO4 and was concentrated to yield crude amine. The product was further purified by silica gel chromatography (gradient eluent 0-10% MeOH in dichloromethane) to provide 4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine (473 mg, 78%). The product was used directly in step 3.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[O:11]1[CH2:12][CH2:13][N:8]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: C1COCCN1
Reactant: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: C1=C(N2CCOCC2)CCCC1
Yield: 94 %

Procedure:
Illustratively, cyclohexanone may be reacted with morpholine by refluxing these reactants in toluene for a period of about three hours at a temperature of about 110° Centigrade (°C) to yield the preferred enamine reactant, 1-morpholino-1-cyclohexene, in a yield of about 94 percent together with water which is readily removed therefrom.