Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CN(C)C=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>O>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ncc[nH]1)C12CC3CC(CC(C3)C1)C2

Procedure:
A solution of 5 g. of 1-adamantyl bromomethyl ketone in 10 ml. of dimethylformamide is added dropwise with stirring and ice-cooling to 7 g. imidazole in 10 ml. dimethylformamide. The resulting solution is stirred overnight at room temperature and then poured into 250 ml. water. The precipitate which forms is filtered off, washed with water and air dried. Thereafter the resulting residue is chromatographed on silica gel to effect purification. Elution with 10% acetone in dichloromethane yields 1-adamantyl 1-imidazolylmethyl ketone, M.P. 128.5°-129.5° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C@H:3]1[O:21][CH2:22][CH3:23].[CH2:24]([C:26]1[NH:30][C:29]([C:31](O)=[O:32])=[N:28][C:27]=1[C:34]([F:37])([F:36])[F:35])[CH3:25].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:24]([C:26]1[NH:30][C:29]([C:31]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=3)[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:4][C@H:3]2[O:21][CH2:22][CH3:23])=[O:32])=[N:28][C:27]=1[C:34]([F:36])([F:37])[F:35])[CH3:25]
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Reactant: CCO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c(CC)[nH]1
Yield: 83 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-3-(4-amino-3-ethoxypiperidin-1-yl)benzoate obtained in Example (48e) (about 0.22 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained by the method described in Example (39e) (40 mg, 0.19 mmol), WSC hydrochloride (120 mg, 0.63 mmol) and HOBT (40 mg, 0.30 mmol), to obtain 81.0 mg of the title compound (83%).
Reaction SMILES: [ClH:1].Cl.Cl.S1C(C2C=CN=C([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]3)N=2)=CC2C=CC=CC1=2.[CH:30]1([NH:33][C:34]([C:36]2[C:44]3[CH:43]=[C:42]([C:45]4[C:50]([Cl:51])=[CH:49][N:48]=[C:47](Cl)[N:46]=4)[S:41][C:40]=3[CH:39]=[CH:38][CH:37]=2)=[O:35])[CH2:32][CH2:31]1.C(OC(N1CCN(CCCN)CC1)=O)(C)(C)C>>[ClH:51].[ClH:1].[ClH:51].[CH:30]1([NH:33][C:34]([C:36]2[C:44]3[CH:43]=[C:42]([C:45]4[C:50]([Cl:51])=[CH:49][N:48]=[C:47]([NH:15][CH2:16][CH2:17][CH2:18][N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)[N:46]=4)[S:41][C:40]=3[CH:39]=[CH:38][CH:37]=2)=[O:35])[CH2:32][CH2:31]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Agent: Cl
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCN4CCNCC4)ncc3Cl)cc12

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid (43% yield). ES+(m/z) 471 (35Cl) and 473 (37Cl) [M+H].
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][C:31]1[S:32][C:33]([CH:37]=O)=[C:34]([CH3:36])[N:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:37][C:33]4[S:32][C:31]([CH3:30])=[N:35][C:34]=4[CH3:36])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)CC(C(=O)OC)=CC=N3)cc1
Reactant: Cc1nc(C)c(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2sc(C)nc2C)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 28.1 %

Procedure:
In 1,2-dichloroethane (21 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-benzazepine-4-carboxylate (0.70 g). To the solution were added 2,4-dimethyl-1,3-thiazole-5-carbaldehyde (0.62 g) and sodium triacetoxyborohydride (1.5 g), and the mixture was stirred at room temperature for 36 hours. After stirred at 60° C. for 12 hours, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=1/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2,4-dimethyl-1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.26 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]3[N:18]=[CH:17][C:16]([S:19][CH2:20][CH2:21]C(OC)=O)=[C:15]([O:26][C:27]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:28]=4[CH:29]=[CH:30][CH:31]=[N:32]5)[CH:14]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].BrCC1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]3[N:18]=[CH:17][C:16]([S:19][CH2:20][CH:21]4[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[CH2:47][CH2:46]4)=[C:15]([O:26][C:27]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:28]=4[CH:29]=[CH:30][CH:31]=[N:32]5)[CH:14]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: COC(=O)CCSc1cnc(Nc2nc(-c3ccccc3)cs2)cc1Oc1cccc2ncccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CSc2cnc(Nc3nc(-c4ccccc4)cs3)cc2Oc2cccc3ncccc23)CC1
Yield: 61.6 %

Procedure:
Following the procedure of Example 201, methyl 3-(6-(4-phenylthiazol-2-ylamino)-4-(quinolin-5-yloxy)pyridin-3-ylthio)propanoate (0.200 g, 0.389 mmol) (prepared as in Example 137), THF (10 mL), potassium 2-methylpropan-2-olate (1.36 ml, 1.36 mmol), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.108 g, 0.389 mmol) were combined to give tert-butyl 4-((6-(4-phenylthiazol-2-ylamino)-4-(quinolin-5-yloxy)pyridin-3-ylthio)methyl)piperidine-1-carboxylate (0.15 g, 61% yield) as yellow solid. 1H NMR (CDCl3) δ 8.94 (dd, 1H), 8.36 (s, 1H), 8.17 (d, 1H), 7.98 (dd, 1H), 7.55 (t, 1H), 7.49 (s, H), 7.47 (s, 1H), 7.35 (dd, 1H), 7.12 (m, 3H), 6.94 (d, 1H), 6.84 (s, 1H), 6.02 (s, 1H), 2.18 (d, 2H), 2.61 (t, 2H), 1.81 (m, 2H), 1.60 (m, 1H), 1.40 (s, 9H), 1.22 (t, 2H), 1.12 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]#N)=[N:12][O:13][N:14]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:29]CC1>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:29])=[N:12][O:13][N:14]=1
Reactant: N#CCCNc1nonc1-c1nc2ccccc2[nH]1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCNc1nonc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.272 g, 0.947 mmol, Example 6a) in THF (5 ml) is added dropwise at 0° C. to an efficiently stirred suspension of LiAlH4 (0.054 g, 1.42 mmol) in THF (5 ml). After stirring for 16 hours at room temperature the mixture is quenched by careful addition of aqueous saturated solution of sodium sulphate. The suspension is filtered and the filtrate evaporated to dryness. Crystallization by addition of hexane yields the title compound in pure form. 1H-NMR (400 MHz, d6-DMSO): 13.6 (s, 1H); 7.66 (m, 2H); 7.31 (m, 2H); 6.92 (t, 1H); 4.61 (m, 1H); 3.51 (m, 2H); 3.39 (m, 2H); 1.81 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:25])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc2c(-c3ccc(OCc4ccccc4)cc3)n(Cc3ccccc3)nc12
Temperature: 60 °C

Procedure:
4-(2-Benzyl-7-trifluoromethyl-2H-indazole-3-yl)-phenol (10 mg, 1 eq) was treated with benzylbromide (10 μL, 3 eq) and potassium carbonate (19 mg, 5 eq) in acetone (1 mL). The reaction mixture was heated at 60° C. until completion of the reaction, as judged by TLC. Volatiles were removed in vacuo and the residue treated with a water/dichloromethane mixture followed by extraction with dichloromethane. Purification by flash chromatography (silica, ethyl acetate/n-heptane, 1:9) gave the title compound in 89% yleld.
Reaction SMILES: [CH:1]1([C:5]2[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH2:14][CH3:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[N:6][N:7]=1)=[O:12])[CH2:14][CH3:15]
Reactant: CCCNCC=O
Reactant: O=C=Nc1nnc(C2CCC2)s1
Solvent: c1ccccc1
Product: CCCN(CC=O)C(=O)Nc1nnc(C2CCC2)s1

Procedure:
A mixture of 5-cyclobutyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propyl-3-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)-ureido]acetaldehyde.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:9]1)C1C=CC=CC=1.[CH3:32][O:33][C:34](Cl)=[O:35]>C1COCC1>[CH3:32][O:33][C:34]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([CH2:18][N:19]2[CH2:20][CH2:21][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)[CH2:9]1)=[O:35]
Reactant: Fc1ccc(C2CCN(C[C@@H]3CN(Cc4ccccc4)C[C@H]3c3ccsc3)CC2)cc1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 4.35 g (10 mmol) of 1-benzyl-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(R)-(3-thienyl)pyrrolidine in 20 mL of THF at 0° C. was added 3.7 mL (26 mmol) of methylchloroformate and the reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone: hexanes, 1:3) to give 3.5 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH:10](=O)[CH3:11]>C(O)C>[C:6]([O:5][C:1]([NH:2][N:3]=[CH:10][CH3:11])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC=NNC(=O)OC(C)(C)C
Yield: 93.2 %

Procedure:
A solution of tert-butyl carbazate (50.0 g, 0.38 mole) and acetaldehyde (17.5 g, 0.4 mole) in ethanol (250 mL) was refluxed for 72 h. The solution was concentrated in vacuo and dissolved in ethyl acetate. The solution was washed with water, dried (anhydrous sodium sulfate) and concentrated to afford N′-ethylidene-hydrazinecarboxylic acid tert-butyl ester (56 g) as a light yellow oil that solidified on standing. MS (ESI+) for C7H14N2O2 m/z 159.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=[O:19])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[N:21]1([C:6]([NH2:8])=[O:5])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=[O:19])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Agent: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)N1CCOCC1

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-carboxyindan (1.01 g, 3.6 mmol), morpholine (0.48 ml, 5.5 mmol), triethylamine (3.6 ml, 26 mmol), propanephosphonic acid anhydride (5.3 ml), dimethylaninopyridine (a catalytic amount) and methylene chloride (27 ml), a similar procedure to a) in Production Example 218 was carried out. The product obtained was purified by silica gel chromatography (methylene chloride:methanol=95:5) to obtain 2-(tert-butoxycarbonylamino)indan-5-carboxylic acid morpholinamide (1.0 g, 2.9 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][S:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=3[N:3]12.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]2[S:10][CH2:9][C:4]3=[N:5][NH:6][C:7](=[O:8])[CH:2]([CH3:1])[N:3]3[C:12]=2[CH:13]=1
Reactant: CC1C(=O)NN=C2CSc3ccc([N+](=O)[O-])cc3N21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CC1C(=O)NN=C2CSc3ccc(N)cc3N21
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 1-methyl-9-nitro-3,5-dihydrobenzo[5,6][1,4]thiazino[3,4-c][1,2,4]triazin-2(1H)-one (0.308 g, 1.11 mmol) in MeOH (25 mL) and THF (25 mL) was added powdered zinc (0.724 g, 11.1 mmol) and NH4Cl (0.592 g, 11.1 mmol) and the mixture was heated at reflux for 16 h. After cooling to ambient temperature, the mixture was filtered to give crude 9-amino-1-methyl-3,5-dihydrobenzo[5,6][1,4]thiazino[3,4-c][1,2,4]triazin-2(1H)-one (100%), which was used in the next step directly without further purification. TLC (eluting with 50% EtOAc/PE) Rf=0.3.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[C@H:3]([OH:8])[CH2:4][N:5]=[N+:6]=[N-:7].[CH2:18]([N:21]([CH2:35][CH2:36][CH3:37])[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([CH2:33]C)[CH:32]=1)[C:27](O)=[O:28])=[O:23])[CH2:19][CH3:20].C(O)(C)(C)C.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>ClCCl.C(OCC)(=O)C.CCCCCC.CO.ClCCl>[N:5]([CH2:4][C@@H:3]([OH:8])[C@@H:2]([NH:1][C:27](=[O:28])[C:26]1[CH:30]=[C:31]([CH3:33])[CH:32]=[C:24]([C:22]([N:21]([CH2:18][CH2:19][CH3:20])[CH2:35][CH2:36][CH3:37])=[O:23])[CH:25]=1)[CH2:9][C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1)=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCCCCC
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN=[N+]=[N-])c1
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
To (2R, 3S)-3-amino-1-azido-4-(3,5-difluorophenyl)-2-buta (XIV, EXAMPLE 166, 0.34 g, 1.4 mmole) in dichloromethane (20 ml) is added N,N-dipropylamidoisophthalic acid (IX, 0.53 g, 2 mmole), t-butyl alcohol (0.27 g, 2 mmole) and triethylamine (0.84 ml, 6 mmole) and ethyl-1-(3-dimethylaminopropyl)carbodiimide (0.58 g, 3 mmole). The mixture is stirred at 20-25 degrees C. for 16 hours. The reaction is monitored by TLC (methanol/dichloromethane, 20/80 +ethyl acetate/hexane, 50/50; Rf=0.76). When the reaction is complete as measured by TLC, the reaction mixture is partitioned between dichloromethane and water, washed with hydrochloric acid (0.5 N), bicarbonate, saline, dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure with heat to produce a concentrate. The concentrate is column chouromatographed on silica gel to give the title compound; MS (MH+)=488.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22]C(C#N)=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]([OH:42])(=[O:41])[CH3:40]>Cl.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:27][CH2:28][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:30][CH2:31]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]4[CH:23]=[CH:22][C:40]([C:39]([OH:42])=[O:41])=[CH:18][CH:17]=4)=[CH:24][CH:25]=3)[C:3]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C#N)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C(=O)O)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (0.200 g, 0.000394 mol) was dissolved in a mxture of acetic acid (15 mL) and 6N solution of hydrochloric acid in water (15 mL) and the solution was heated at reflux for 12 hours. It was cooled to ambient temperature and concentrated under reduced pressure and the residue recrystallized from N,N-dimethylformamide to yield cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzoic acid (0.100 g, 0.00019 mol) as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[CH:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:22]([CH3:24])[CH3:23])[CH:17]=2)(O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]([CH3:25])[CH:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:22]([CH3:24])[CH3:23])[CH:17]=2)=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1cc(C2(O)CCC(N(C)Cc3ccccc3)CC2)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1cc(C2=CCC(N(C)Cc3ccccc3)CC2)ccn1
Yield: 57 %

Procedure:
A mixture of 4-(benzyl(methyl)amino)-1-(2-(dimethylamino)pyridin-4-yl)cyclohexanol (300 mg, 0.88 mmol, 1.0 eq.) and PTSA (1.1 g, 5.31 mmol, 6.0 eq.) in toluene (10 ml) was refluxed for 16 hours. After monitoring by TLC, the mixture was concentrated and the residue was taken up in DCM and washed with sat. NaHCO3 solution (3×30 ml), water (30 ml) and sat. NaCl solution (30 ml). The org. phase was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 3% MeOH in DCM). Yield: 57% (160 mg, 0.50 mmol)
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1)=[O:5].Cl.Cl[CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH2:16][N:9]1[CH:10]=[CH:11][C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:13])=[O:5])=[CH:7][C:8]1=[O:12]
Reactant: CN(C)CCCCl
Reactant: CON(C)C(=O)c1cc[nH]c(=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CON(C)C(=O)c1ccn(CCCN(C)C)c(=O)c1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A stirred mixture of N-methoxy-N-methyl-2-oxo-1,2-dihydropyridine-4-carbox-amide (200 mg, 1.0 eq), 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (350 mg, 2.0 eq) and K2CO3 (455 mg, 3.0 eq) in 20 mL acetone was heated under reflux overnight. After cooling to rt, water was added, and the mixture was extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (255 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=7.2 Hz, 1H), 6.75 (d, J=1.2 Hz, 1H), 6.30 (dd, J=6.8 Hz, 2.0 Hz, 1H), 4.02 (t, J=7.2 Hz, 2H), 3.62 (s, 3H), 3.33 (s, 3H), 2.30 (t, J=6.8 Hz, 2H), 2.23 (s, 6H), 1.93 (t, J=7.2 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])=[CH:9][N:10]=2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([C:30]3[N:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[N:27]=[CH:28][CH:29]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)c(F)c1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Product: Fc1ccc(-n2nccc2-c2ccc3ncc(-c4ccc(F)cc4F)n3c2)cc1

Procedure:
The title compound, white solid (56 mg, 44%), MS (ISP) m/z=391.5 [(M+H)+], mp 168° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(2,4-difluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate K) (0.1 g, 0.324 mmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.38 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].O>C(Cl)Cl>[C:25]([NH:29][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][N:10]=3)[N:13]=2)[CH2:19][CH2:20]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (80 mg, 0.23 mmol) and t-Butylamine (17.2 mg, 0.23 mmol) in CH2Cl2 (1.2 mL) was added dropwise Ti(Oi-Pr)4 (0.27 mL, 0.92 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was poured into water (150 mL) and extracted with EtOAc (100 mL*3). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep. HPLC to give EX. 8-78 (15 mg, 16.5%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1O[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[N:8][N:7]=1.[NH2:23][C:24]1[C:25]([CH3:33])=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[O:28].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(Cl)(Cl)Cl>CN1CCN(C)C1=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:23]([C:24]2[C:25]([CH3:33])=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:9]([C:11]2[CH:16]=[N:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:8][N:7]=1
Reactant: COCCCc1nnc(-c2ccc(-c3ccccc3)nc2)o1
Reactant: Cc1c(N)cccc1C(N)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CN1CCN(C)C1=O
Solvent: ClC(Cl)Cl
Product: COCCCc1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc(C(N)=O)c1C
Temperature: 200 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
5-[5-(3-Methoxypropyl)-1,3,4-oxadiazol-2-yl]-2-phenylpyridine (1.0 g) prepared in the Reference Example 7 was dissolved in 1,3-dimethyl-2-imidazolidinone (10 ml), followed by addition of 3-amino-2-methylbenzamide (1.53 g) prepared in the Reference Example 6 and D-10-camphorsulfonic acid (290 mg), and stirred at 200° C. for 16 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, which was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1), to afford the entitled compound (812 mg, 56%). The physico-chemical values are as follows.