Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:17]3=[N:18][CH:19]=2)[CH:9]=1)[C:5]([OH:7])=O)[CH3:3].[CH3:39][NH:40][CH3:41].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:3][N:2]([CH3:1])[CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:17]3=[N:18][CH:19]=2)[CH:9]=1)[C:5]([N:40]([CH3:41])[CH3:39])=[O:7]
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)O)N(C)C)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)N(C)C)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of dimethylamino-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (56 mg, 0.11 mmol), dimethylamine (2 N in THF, 0.08 mL, 0.16 mmol), and diisopropylethylamine (21 mg, 0.16 mmol) in THF (1.5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 560 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)c1cc(O)ccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-isopropylphenol (880.0 mg, 4.09 mmols) and imidazole (417.0 mg, 6.13 mmols) in 10 mL DMF was added chloro-triisopropylsilane (946.0 mg, 4.90 mmols). After stirring overnight at room temperature the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 1.30 g (92%), was isolated by column chromatography (1-2% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Yield: 92.8 %

Procedure:
To a solution of (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (300 mg, 1.019 mmol) in ethanol (15 mL) was added a suspension of 10% palladium-on-carbon (200 mg) in ethanol under nitrogen atmosphere. The mixture was hydrogenated using a hydrogen balloon for 2 h at room temperature then was filtered through a pad of Celite. The filtrate was concentrated to afford (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate (250 mg) which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C@@H:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(O)C.C(Cl)Cl>[CH2:1]([N:8]([CH2:12][C@H:13]1[CH2:14][CH2:15][C:16](=[O:18])[NH:17]1)[CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CC[C@H](CN(CCO)Cc2ccccc2)N1
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(Cc1ccccc1)C[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
To a solution of (R)-(−)-5-((benzyl(2-hydroxyethyl)amino)methyl)pyrrolidin-2-one (2.4 g, 9.67 mmol) in ethanol-free CHCl3 (80 ml), TEA (1.95 g, 19.34 mmol) and methansulfonyl chloride (2.21 g, 19.34 mmol) were added at 0° C. The mixture was allowed to warm to room temperature and left stirring for 6 hours, then it was diluted with DCM (80 ml) and washed with a saturated solution of NaHCO3. After drying (Na2SO4) and removal of the solvent, the crude was purified by flash chromatography (DCM/abs EtOH/Petroleum Ether/33% NH4OH/Et2O 300/180/900/9.9/360 respectively) to afford the title compound (2.3 g, 73% yield).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:34]>C(O)C>[ClH:34].[CH3:31][O:30][C:26]1[CH:25]=[C:24](/[C:16](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15]/[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2cccc(OC)c2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(/C(=C/OCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
E or Z-(R)-1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl) ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.50 g, 0.0012 mol) (prepared as described in Method D) was dissolved in ethanol (15 ml) and 12 N sodium hydroxide solution (0.2 ml) was introduced. After stirring the solution at room temperature for 6 h, ice (100 g) was added, and the pH of the reaction mixture was adjusted to ca. 7 with 37% hydrochloric acid solution Dichloromethane (200 ml) was added, and the pH was further adjusted to <2 with 37% hydrochloric acid solution. The dichloromethane phase was dried (Na2SO4) and evaporated to a solid (0.3 g, 60%), m.p. 188°-192°
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](OCC)=[O:6])(=O)[CH3:2].[F:16][C:17]1[C:23]([OH:24])=[C:22]([F:25])[CH:21]=[CH:20][C:18]=1[OH:19]>CS(O)(=O)=O>[F:25][C:22]1[CH:21]=[C:20]2[C:18](=[C:17]([F:16])[C:23]=1[OH:24])[O:19][C:5](=[O:6])[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:1]2[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Reactant: Oc1ccc(F)c(O)c1F
Agent: CS(=O)(=O)O
Product: CCOC(=O)Cc1c(C)c2cc(F)c(O)c(F)c2oc1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
Diethyl acetylsuccinate (2.4 g, 11.1 mmol) is added to a solution of Compound 4 (1.3 g, 8.9 mmol) in 20 mL methanesulfonic acid at 20° C. The reaction is stirred for 16 hours and poured into 200 mL ice water. The product is extracted with EtOAc (80 mL×2), washed with brine (40 mL), dried over anhydrous MgSO4, and concentrated in vacuo to yield a brown oil. The crude oil is purified by column chromatography on silica gel eluted with CHCl3 /MeOH (95:5 to 90:10) to yield 1.06 g (40%) of Compound 10 as an off-white solid. 1H-NMR (DMSO-d6) δ 7.56 (d, 1H), 4.08 (q, 2H), 3.67 (s, 2H), 2.34 (s, 3H), 1.19 (t, 3H). 19F-NMR (DMSO-d6) Φ 130.13 (t, 1F), 148.87 (d, 1F). Also isolated from the column is 0.50 g (20%) of 6,8-difluoro-7-hydroxy-4-methylcoumarin 3-acetic acid (Compound 11).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][NH:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CNCc4ccccc4)cc3)cc2)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-[4′-(3-Methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.100 g, 0.26 mmol) and benzylamine (0.034 mL, 0.31 mmol) were combined in NMP (5 mL) and the reaction was stirred overnight at 85° C. Additional benzylamine (0.05 mL, 0.46 mmol) was added and the reaction was stirred for two days at 85° C. Aqueous workup provided the title compound.
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:6].[N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N+:14]=[N-:15].O>CCO>[CH2:11]([O:10][C:8]([C:7]1[N:15]=[N:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[NH2:6])=[O:9])[CH3:12]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2ccccc2)c1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
To a freshly prepared NaOEt (1.18 mmol) solution in EtOH (0.75 mL) is added ethyl cyanoacetate (100 mg, 0.88 mmol) at 0° C. After stirring at 0° C. for 10 min., azido-benzene (100 mg, 0.84 mmol, prepared according to the method reported by M. Kurumi et al. Heterocycles. 2000, 53, 2809) is added. After the addition, the mixture is allowed to slowly warm up to room temperature and stirred for 14 h. The mixture is then treated with water (3 mL) and extracted with EtOAc (3×3 mL). The combined extracts is concentrated and purified by flash column chromatography (silica gel, 0%-70% EtOAc/hexane) to provide 5-amino-1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester as a white solid (100 mg, 51%). HPLC-MS calculated C11H12N4O2 (M+1+): 233.1. Found: 233.1.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH3:28])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[CH3:29]NC>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CNC
Reactant: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Product: CN(C)C(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
Compound 18 was prepared in a manner similar to that of compound 16 using dimethylamine instead of methylamine, MS 405.12 (M+1).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-].[Na+].[C:27](#[N:30])[CH:28]=[CH2:29]>O>[C:1]([CH2:4][N:5]1[CH2:16][CH2:15][N:14]([CH2:29][CH2:28][C:27]#[N:30])[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50 ml round bottom flask was placed 5.22 g (0.0151 mol) of 1,4,7,-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (DO3A) and dissolved in 21 ml of water. The pH of the solution was raised to 8.28 with 6N NaOH. Then 1.35 ml (1.09 g, 0.0205 mol) of acrylonitrile was added and the reaction allowed to stir overnight at room temperature. The reaction is then concentrate in vacuo, and then re-dissolved in methanol and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH2:6][O:7][CH3:8].[I-].[CH3:21][N:22]1[C:30]2[C:25](=[C:26]([CH3:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:32][N+](C)(C)C)=[CH:23]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:32][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[N:22]([CH3:21])[CH:23]=2)[C:10]1=[O:18])[CH2:6][O:7][CH3:8]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: COCC(CC(=O)OC)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(CC(=O)OC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 100 °C
Yield: 60.8 %

Procedure:
To a solution of 4-Methoxy-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyric acid methyl ester (205 mg, 0.78 mmol) in DMF (10 mL) are added (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (470 mg, 1.4 mmol) and K2CO3 (210 mg, 1.6 mmol) at room temperature. The solution is heated to 100° C. for 5.5 hours. The solution is cooled down and 30 mL of water is added. The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, washed with water (3×100 mL), dried with MgSO4 and concentrated to give crude product. Purification by flash column chromatography affords 200 mg (61%) of 3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-butyric acid methyl ester.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[OH:8].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:9][C:4]1([OH:8])[CH2:5][CH2:6][CH2:7][CH:3]1[CH2:2][O:1][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: CC1(O)CCCC1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 7a (1.78 g, crude), pyridine (5.5 mL, 68.0 mmol) and 4-dimethylaminopyridine (0.17 g, 1.37 mmol) in CH2Cl2 (40 mL) was added p-toluenesulfonyl chloride (3.13 g, 16.4 mmol) in one portion, and the mixture was left to stand at 4° C. overnight. The mixture was stirred at ambient temperature for 100 min. To the mixture was added ice and the mixture was stirred at ambient temperature and the organic layer was separated. The aqueous layer was extracted with EtOAc and ,he combined organic layers were washed with water, CuSO4 solution, water, NaHCO3 solution and NaCl solution, and dried over Na2SO4. Filtration and concentration gave 3.86 g of 8a, which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncccc2C(F)(F)F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncccc2C(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
0.69 g of 5-(4-chlorophenyl)-6-methyl-4-(3-trifluoromethyl-2-pyridyl)-2H-pyridazin-3-one and 6.3 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.50 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.11 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(3-trifluoromethyl-2-pyridyl)pyridazine (hereinafter, described as compound (7) of the present invention.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([O:14][CH3:15])[C:10]([OH:24])([CH3:23])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2([O:14][CH3:15])[CH2:12][CH2:13][NH:8][CH2:9][C:10]2([CH3:23])[OH:24])=[CH:17][CH:18]=1
Reactant: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(c2ccc(Cl)cc2)CCNCC1(C)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-(4-Chloro-phenyl)-3-hydroxy-4-methoxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.74 mmol) was dissolved in methylene chloride (5 mL) and the resulting solution was cooled to 0° C. Trifluoroacetic acid (1 mL) was added and the mixture was stirred 2 h. Solvents were then removed under reduced pressure and the residue dissolved in ethyl acetate. Water and 6 N aqueous sodium hydroxide were added until the pH=10. The organic phase was washed with brine and dried over magnesium sulfate, filtered and concentrated to afford 4-(4-chloro-phenyl)-4-methoxy-3-methyl-piperidin-3-ol.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile in an analogous manner to example 730. Product was isolated as a tan solid (0.044 g, 31%). Mp 80-83° C.; LCMS (m/e) 478 (M+1); 1H-NMR (DMSO, 400 MHz) δ 9.17 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.99-7.97 (d, 1H, J=8.36 Hz), 7.28-7.22 (m, 2H), 7.16-7.07 (q, 2H, J=8.31 Hz), 7.05 (s, 1H), 6.95-6.87 (d, 1H, J=7.56 Hz), 5.21 (s, 2H), 3.76-3.57 (br, 1H), 3.09-2.97 (q, 2H, J=7.08 Hz), 2.93-2.85 (m, 2H), 2.83-2.70 (m, 2H), 2.48-2.35 (br, 2H), 1.15-1.08 (t, 3H, J=7.08 Hz), 1.07-0.99 (t, 3H, J=6.82 Hz).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:11][CH2:12][CH2:13][CH2:14]Br>>[Br:11][CH2:12][CH2:13][CH2:14][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(CC)CC
Product: CCOC(=O)C(CC)(CC)CCCBr

Procedure:
Using ethyl 2-ethylbutyrate and 1,3-dibromopropane, the title compound was produced in the same manner as in Reference Example 6.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1>O1CCOCC1.CO>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
173 mg (0.15 mmol) of tetrakistriphenylphosphine palladium and 4.4 mL (8.8 mmol) of a 2M sodium carbonate solution is added at ambient temperature to a solution of 1.124 g (4.04 mmol) of ethyl (E)-3-(4-bromophenyl)acrylate in 50 mL of dioxane. 0.689 g (4.404 mmol) of 4-chlorophenylboric acid dissolved in 10 mL of methanol is added to this reaction mixture and refluxed for 5 hours. The reaction mixture is evaporated down, the residue is taken up in dichloromethane, and extracted with water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether/ethyl acetate (9:1)). Yield: 0.94 g (74.4% of theory); C17H15ClO2 (M=286.76); calc.: molecular ion peak (M+H)+: 287/289; found: molecular ion peak (M+H)+: 287/289; Rf value: 0.44 (silica gel, petroleum ether/ethyl acetate (40:10)).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O>C(OCC)C>[OH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCC2OC2C1
Reactant: C1CCNC1
Solvent: CCOCC
Solvent: O
Product: OC1CCCCC1N1CCCC1
Yield: 88.6 %

Procedure:
Cyclohexene oxide (982 mg, 10 mmol), pyrolidine (2.134 g, 30 mmol), and 1.8 mL of water were heated at 90° C. for 18 hours. The reaction was then cooled and diluted with 75 mL of diethyl ether. The mixture was then washed with aqueous sodium bicarbonate (15 mL), brine (2×15 mL), dried over magnesium sulfate, filtered, and evaporated to give 1.499 g (89%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[O:26])[CH:19]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25]([NH:24][C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([CH3:27])[CH:19]=4)=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)c1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and m-tolyl isocyanate (32 μL, 0.25 mmol) in CH2Cl2 (5 mL) are reacted according to method C yielding the title product as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4](C2CC3N(C(OC(C)(C)C)=O)C(CC3)C2)[C:3]=1[S:38]([CH3:41])(=[O:40])=[O:39].[ClH:42].O1[CH2:48][CH2:47]OCC1>CO>[CH:48]12[NH:13][CH:14]([CH2:17][CH2:47]1)[CH2:15][CH:16]([C:9]1[C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)=[C:6]3[N:5]=[CH:4][C:3]([S:38]([CH3:41])(=[O:40])=[O:39])=[C:2]([NH2:1])[N:7]3[N:8]=1)[CH2:11]2.[ClH:42]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c1S(C)(=O)=O)C2
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)c1cnc2c(-c3ccc(-c4ccccc4)nc3)c(C3CC4CCC(C3)N4)nn2c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the crude tert-butyl 3-(7-amino-6-(methylsulfonyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate in MeOH (5 mL) was added 4M HCl in 1,4-dioxane at r.t. It was stirred further at room temperature for 2 h, at which time LC/MS analysis confirmed full consumption of the starting material. The solvent was removed in vacuo to afford the desired product as an HCl salt.