Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N([Al:8]([N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[N:9]([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])C(C)C)(C)C.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[CH:23]([O:26][Al:8]([N:9]([CH:10]([CH3:11])[CH3:12])[CH:13]([CH3:14])[CH3:15])[N:16]([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])([CH3:25])[CH3:24].[CH:23]([O:26][Al:8]([O:26][CH:23]([CH3:25])[CH3:24])[N:16]([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])([CH3:25])[CH3:24]
Reactant: CC(C)O
Reactant: CC(C)N(C(C)C)[Al](N(C(C)C)C(C)C)N(C(C)C)C(C)C
Product: CC(C)O[Al](N(C(C)C)C(C)C)N(C(C)C)C(C)C
Product: CC(C)O[Al](OC(C)C)N(C(C)C)C(C)C

Procedure:
and (d) were prepared by the method of J K Ruff (J. Amer. Chem. Soc. 1961, 83 2835); (a) was then further reacted with 1 and 2 equivalents of isopropanol to give (c) and (b) respectively.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([O:20]C)[CH:11]=1>C(O)(=O)C.Br>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:11]=[C:12]([OH:20])[C:13]([OH:19])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: COc1cc(-c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1O
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3[nH]2)cc(O)c1O

Procedure:
A suspension of 860.1 mg of 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol in 10 ml of glacial acetic acid and 10 ml of 48 percent hydrobromic acid is heated to boiling under reflux for 72 hours. The mixture is then evaporated and the residue is treated four times with 50 ml of toluene each time, which is again distilled each time. There is obtained 5-(2-benzimidazolyl)-3-nitropyrocatechol of m.p.>300° (from acetone/water).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[NH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16](Cl)[N:15]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[NH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([O:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[Cl:1])[N:15]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 76.5 %

Procedure:
12.5 g of 2-chloro-4-trifluoromethylphenol, 10.0 g of 2-amino-3-nitro-6-chloropyridine, 10.5 g of potassium carbonate, and 200 ml of dimethyl sulfoxide were charged in a flask, and the mixture was allowed to react at 30° C. for twenty-four hours while stirring. After completion of the reaction, the reaction product was poured into water, followed by extracting with methylene chloride. The extracted phase was washed with water and dried, and the methylene chloride was distilled off under reduced pressure to obtain 14.7 g of a titled compound having a melting point of 80° to 84° C.
Reaction SMILES: Br[C:2]1[C:7]([SiH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([CH3:21])=[CH:4][N:3]=1.[Br-].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Zn+].N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[CH3:21][C:5]1[CH:6]=[C:7]([SiH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[N:3][CH:4]=1
Reactant: [Zn+]c1ccccn1
Reactant: Cc1cnc(Br)c([SiH](c2ccccc2)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccccn2)c([SiH](c2ccccc2)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a reaction container equipped with a cooling apparatus, 2.28 g of tetrakis(triphenylphosphine)palladium, 7 g of 2-bromo-5-methyldiphenylsilylpyridine obtained in the above-mentioned Example 5-2 and 125 mL of tetrahydrofuran were added. To the obtained mixture, 39.51 mL of 2-pyridyl zinc bromide (0.5 M/tetrahydrofuran solution) was added with stirring at room temperature. The obtained mixture was stirred at 50° C. for 7 hours and 25 minutes to effect reaction. The reaction mixture was cooled until room temperature and then, 170 mL of 28% aqueous ammonia solution was added thereto. The obtained mixture was extracted three times with 200 mL of chloroform. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography followed by further recrystallization with hexane to obtain 2.56 g of 5-methyldiphenylsilyl-2,2′-bipyridine.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:12])OCC)[CH:3]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:8]([C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)=[NH:12]
Reactant: COC(CN)OC
Reactant: CCOC(=N)c1cccnc1
Agent: Cl
Product: COC(CNC(=N)c1cccnc1)OC

Procedure:
Ethyl 3-pyridinecarboximidate hydrochloride and aminoacetaldehyde dimethyl acetal were subjected to a procedure similar to that described in Example 8.b. to provide pure N-(2,2-dimethoxyethyl)-3-pyridinecarboxamidine as an oil; MS: m/z=210(M+1).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:32]=[CH:31][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][S:28][CH2:29][CH3:30])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:33])[CH:9]=1>O.CO>[Br:7][C:8]1[CH:32]=[CH:31][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][S:28]([CH2:29][CH3:30])=[O:1])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:33])[CH:9]=1
Reactant: O=S([O-])OO
Reactant: CCSCCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCS(=O)CCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
A solution of OXONE, (trade mark of E.I. duPont de Nemours & Co., Inc), (150 mg) in water (2 ml) was added to a solution of 4-(4-bromo-2-fluoroanilino)-7-(2-ethylthioethoxy)-6-methoxyquinazoline (125 mg, 0.28 mmol), (prepared as described in Example 24), in methanol (10 ml). The reaction mixture was stirred for 16 hours at ambient temperature, the methanol was removed by evaporation, the aqueous residue was basified with sodium hydrogen carbonate solution and then extracted with ethyl acetate (3×30 ml). The extracts were combined, washed with water (×2), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate and then with methylene chloridetmethanol (9/1) to give 4-(4-bromo-2-fluoroanilino)-7-(2-ethylsulphinylethoxy)-6-methoxyquinazoline (32 mg, 31%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.O1CCCC1>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH2:16])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(COc2ccccc2)cn1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1ccc(COc2ccccc2)cn1
Yield: 51 %

Procedure:
2-(5-Phenoxymethyl-pyridin-2-ylmethyl)-isoindol-1,3-dione described in Preparation Example 188 (383 mg, 1.11 mmol) was dissolved in ethanol (3 mL) and tetrahydrofuran (3 mL). Hydrazine monohydrate (538 μL, 11.1 mmol) was added to this solution at room temperature, and the solution was stirred under reflux for 1 hour. The reaction solution was partitioned in water and ethyl acetate. The organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=10/1), and the title compound (122 mg, 51%) was obtained as a colorless oil.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.C(ON=O)CC(C)C.[I:28]CI>>[I:28][C:2]1[N:3]=[CH:4][C:5]([CH3:19])=[C:6]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:7]=1
Reactant: Cc1cnc(N)nc1Oc1cc(C(F)(F)F)nn1C
Reactant: ICI
Agent: CC(C)CCON=O
Product: Cc1cnc(I)nc1Oc1cc(C(F)(F)F)nn1C
Temperature: 90 °C

Procedure:
To a suspension of 2-amino-4-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-5-methylpyrimidine (5 g) in diiodomethane (25 ml) is added isopentylnitrite (48 ml) and the mixture is heated to 90° C. for 30 min. After cooling, the brownish reaction mixture is evaporated in vacuo and the residue is purified by silica-gel flash chromatography. One obtains the title compound as crystals of mp. 94° C.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1([CH3:20])[CH3:19])=O)(C)(C)C.I[CH2:22][CH3:23].[H-].[Na+].C(O)(C(F)(F)F)=O.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:22]([CH:10]1[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][C:9]1([CH3:19])[CH3:20])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC1C(=O)c2ccccc2NC1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (EXAMPLE 325) (0.10 g, 0.36 mmol) and iodoethane (0.50 mL, 6.3 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 40 mg, 1.0 mmol) and the resulting mixture was stirred at rt for 15 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded a mixture of products, which was treated with TFA (0.50 mL) in methylene chloride (1.0 mL) for 3 h. The reaction was neutralized to pH 10 by 5% NaOH and was extracted with EtOAc (2×20 mL). Chromatography (silica gel, EtOAc/hexane, 3/7) afforded 30 mg (41%) of R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (30 mg, 0.15 mmol as a colorless oil. The quinolinone (30 mg, 0.15 mmol) was treated with Et3SiH (1.0 mL) and BF3 -OEt2 (0.05 mL, 0.4 mmol) in CH2Cl2 (1.0 mL) at 100° C. for 15 h in a sealed tube. Purification of the crude product by chromatography (silica gel, EtOAc/hexane, 1/9) afforded 20 mg (71%) of (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline. Data for (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 6.98 (d, J=7.5, 1H), 6.96 (t, J=7.5, 1H), 6.61 (t, J=7.5, 1H), 6.44 (d, J=7.5, 1H), 3.60 (s, 1H), 2.90 (dd, J=16.7, 5.2, 1H), 2.41 (dd, J=16.7, 10.7, 1H), 1.68 (m, 1H), 1.52 (m, 1H), 1.23 (m, 1H), 1.22 (s, 3H), 1.05 (s, 3H).
Reaction SMILES: C([Li])CCC.[Si:6]([O:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([F:31])[CH:30]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:32][C:33]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:34]=1[CH:35]=[O:36].C(=O)(O)[O-].[Na+]>CCCCCC.O.C(OCC)C>[Si:6]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([CH:35]([C:34]2[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:33]=2[F:32])[OH:36])=[N:27][CH:26]=1)([C:19]([CH3:21])([CH3:22])[CH3:20])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](OCc1cncc(F)c1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)ccc1F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](OCc1cnc(C(O)c2cc(F)ccc2F)c(F)c1)(c1ccccc1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
At −78° C., a hexane solution (30.0 ml, 46.8 mmol) of n-butyl lithium and N,N,N′N′-tetramethylethylenediamine (7.06 ml, 46.8 mmol) were added sequentially to diethyl ether (250 ml). After stirring at −20° C. for 30 minutes, the reaction mixture was cooled to −78° C., and a diethyl ether (50 ml) solution of 3-(t-butyldiphenylsilyloxymethyl)-5-fluoropyridine (15.5 g, 42.5 mmol) was added thereto. The resulting mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 2,5-difluorobenzaldehyde (6.04 g, 42.5 mmol). The resulting mixture was stirred for 2 hours. Water and then, a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture. The resulting mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then, filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=9:1 eluate was concentrated under reduced pressure to give the title compound (17.0 g, 33.5 mmol, 79%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[Cl:65])[CH2:54][CH2:53]1>CN(C=O)C.O>[Cl:65][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[NH:58][CH:55]1[CH2:56][CH2:57][N:52]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[O:13])[CH2:53][CH2:54]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2)on1
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (0.075 g, 0.00027 mol) in DMF (2 mL) was added DIPEA (0.171 g, 0.00132 mol), HOBt (0.0448 g, 0.00033 mol) and EDCI.HCl (0.064 g, 0.00033 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-chloro-phenyl)-amine dihydrochloride (0.066 g, 0.00027 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using basic aluminium oxide (25% ethyl acetate in hexane) to afford 0.066 g (57%) of 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 439.15 (M+1)+, 97.26%, 1H NMR (DMSO-d6): δ 8.62 (t, 1H), 7.95 (m, 2H), 7.55 (m, 3H), 7.4 (s, 1H), 7.25 (dd, 1H), 7.2 (m, 2H), 6.85 (d, 1H), 6.6 (t, 1H), 4.9 (d, 1H), 4.4 (d, 1H), 4.2 (d, 2H), 3.9 (d, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 2.8 (m, 2H), 1.95 (t, 2H), 1.4 (m, 2H).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([NH:27][CH2:28][C:29](O)=[O:30])[CH:22]=[N:21]1>>[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([NH:27][CH2:28][C:29](=[O:30])[N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[C:3]([F:2])([F:17])[F:18])[CH2:8][CH2:9]2)[CH:22]=[N:21]1
Reactant: Cn1ncc(NCC(=O)O)cc1=O
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: Cl
Product: Cn1ncc(NCC(=O)N2CCC(Oc3ccccc3C(F)(F)F)CC2)cc1=O
Yield: 40 %

Procedure:
Compound 19 is prepared from intermediate 1a in base form and intermediate 4h following synthesis method 2 (yield: 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH2:34](I)[CH3:35].CN(C=[O:41])C>O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:41][CH2:34][CH3:35])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C=O
Reactant: CCI
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC1(c2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-difluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (200 mg) in DMF (4 mL) was added sodium hydride (60%, 28.4 mg) at room temperature, and the mixture was stirred at 60° C. for 30 min under a nitrogen atmosphere. Ethyl iodide (45.2 μL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (31.6 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:38])[CH2:32][CH2:33][O:34][CH:35]([CH3:37])[CH3:36]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:28][N:38]=[C:31]([CH2:32][CH2:33][O:34][CH:35]([CH3:37])[CH3:36])[N:30]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CC(C)OCCC(N)=NO
Product: CC(C)OCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
100 mg (0.25 mmol) of the compound from Example 99A and 61 mg (0.38 mmol) of the compound from Example 65A were reacted according to the General Method 2. Yield: 82 mg (61% of theory)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].[NH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([CH2:32][CH2:33][CH2:34][CH3:35])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1>C(O)(=O)C.C(O)C>[CH2:32]([CH:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][NH:15][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][CH:21]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Reactant: O=CCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC(Cc1ccc(OCCNCCCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-phenylpropionaldehyde (0.23 ml), sodium cyanoborohydride (117 mg) and acetic acid (one drop) were added to a solution of ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (500 mg), which is the product of Reference example 6, in ethanol (10 ml). The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel column using dichloromethane/methanol=19/1 as the eluant to afford the desired compound (460 mg) as a pale yellow oil.
Reaction SMILES: [ClH:1].Cl.Cl.[CH:4]([N:7]([CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[NH:28])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1)([CH3:6])[CH3:5].Cl.[C:34](=[NH:39])(OCC)[CH3:35].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:34]([N:18]1[CH2:17][CH2:16][CH:15]([O:14][C:11]2[CH:10]=[CH:9][C:8]([N:7]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:29])=[NH:28])[CH:4]([CH3:6])[CH3:5])=[CH:13][CH:12]=2)[CH2:20][CH2:19]1)(=[NH:39])[CH3:35]
Reactant: CC(C)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CO
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)C(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 231.7 %

Procedure:
To a solution of 3-[3-[N-isopropyl-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (310 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (229 mg) and triethylamine (0.52 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 15% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (259 mg, yield 77%) as a pale brown amorphous solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:27][CH:28]([CH3:33])[CH2:29]B(O)O.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:27][CH:28]([CH3:33])[CH3:29])[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)CB(O)O
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(CC(C)C)c2ccccc2c1OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of 4-Benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (207 mg, 0.5 mmol, see example D-86a), Pd(PPh3)4 (58 mg, 0.05 mmol), 2-methylpropylboronic acid (78 mg, 0.75 mmol), K2CO3 (207 mg, 1.5 mmol), and 1,4-dioxane (4 ml) was refluxed with stirring for 48 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (5 ml) and the mixture was extracted with EtOAc (2×20 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes EtOAc=88 12 as the eluent gave the title compound as a yellowish oil (136 mg); MS-(+)-ion M+1=392.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].Cl>ClCCl>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:22](=[O:23])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[F:8])[CH2:20][CH2:21]1)(=[O:15])[CH3:14]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reaction time: 3 h
Yield: 36 %

Procedure:
To a stirred of mixture of 56 ml of 1,3-difluorobenzene, 130 g of aluminium chloride and 147 ml of dichloromethane, a solution of 95 g of 1-acetyl-4-piperidinecarbonyl chloride in 50 ml of dichloromethane was added dropwise while cooling. Upon completion, stirring was continued for 3 hours at room temperature. The reaction mixture was poured out into a mixture of crushed ice and hydrochloric acid. The product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated, yielding 48 g (36%) of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine as a residue (interm. 1).