Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7](Cl)=[O:8].[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:17]1)=[O:8]
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(Cl)C(c1cccs1)c1cccs1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C(c1cccs1)c1cccs1
Yield: 23.9 %

Procedure:
2,2-Di(2-thienyl)acetyl chloride (0.67 g) and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.42 g) were reacted under the same conditions as in Example 53 to give (S)-2,2-di(2-thienyl)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)acetamide (0.2 g), melting point 96-98° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[C:8](=[O:13])[NH:9][CH:10]=[CH:11][CH:12]=1.[C:14]([O:17][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][CH:19]1Br)(=[O:16])[CH3:15].[Al]>ClCCl.C(=O)([O-])[O-].[Ag+2]>[C:14]([O:17][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@H:19]1[O:13][C:8]1[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1OC(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN1CCCC1c1ccc[nH]c1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ncccc2C2CCCN2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(±)-3-(1-methyl-2-pyrrolidinyl)-2-pyridone (1)(2.0 g) and 2,3,4,6-tetra-O-acetylglucopyranosyl bromide (4a)(5.6 g) were dissolved in dichloromethane (40 ml). To this solution, silver carbonate (1.8 g) was added. The mixture was stirred at room temperature for 24 hours while the vessel was shielded from light by an aluminum sheet. Solid material was filtered off, and the filtrate was concentrated under reduced pressure. As a result, (±)-3-(1-methyl-2-pyrrolidinyl)-2-pyridyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (5a) was obtained. The compound (5a) obtained as above was subjected to the experiment of the following example without purification.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH:14]=[CH:15][CH:16]=1)C=O)C1C=CC=CC=1.OO.S([O-])([O-])=O.[Na+].[Na+]>S(=O)(=O)(O)O.CO>[CH2:18]([O:17][C:10]1[CH:11]=[C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][C:9]=1[OH:8])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: OO
Solvent: CO
Product: Oc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 41.6 %

Procedure:
Concentrated sulphuric acid (2-3 drops) is added to a stirred solution of dibenzyloxybenzaldehyde (1.5 g) in methanol (50 mL), resulting in a thick precipitate. The mixture is stirred for 5 minutes then hydrogen peroxide (1 g; 27.5% in water) is added in one portion and stirring is continued for 2 hours. The resulting brown solution is treated with 10% aqueous sodium sulphite solution (10 mL) then evaporated to low bulk. The residue is treated with water (50 mL), the solid washed with water, dried and crystallised from cyclohexane, with charcoal treatment, to give 2,4-dibenzyloxyphenol (0.3 g) as a white powder, m.p. 82-83° C. [Elemental analysis:- C,78.2; H,5.79%. Calculated:- C,78.4; H,5.92%].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccnc(-c2ccc(C=O)cc2)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 21.1 %

Procedure:
To a suspension of 2-bromo-4-methylpyridine (2.0 g), 4-formylphenylboronic acid (2.27 g) and tetrakis(triphenylphosphine)-palladium (0.67 g) in 1,2-dimethoxyethane (40 ml) was added 2M aqueous solution of sodium carbonate (15.1 ml). The mixture was stirred at 90° C. for 6 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 75 g, dichloromethane) to give 4-(4-methylpyridin-2-yl)benzaldehyde (483 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:9]1[N:20](S(C2C=CC=CC=2)(=O)=O)[C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]2[CH:10]=1)[CH3:8].C(OCC)(=O)C>CO.O>[CH2:7]([C:9]1[NH:20][C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]2[CH:10]=1)[CH3:8]
Reactant: CCc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 80 °C
Yield: 99.1 %

Procedure:
Potassium carbonate (1.02 g, 7.394 mmol) was added to a solution of 2-ethyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.245 g, 0.739 mmol) in methanol (6.5 mL) and water (2.2 mL). The reaction mixture was heated at 80° C. overnight. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were then separated. The organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated to afford 2-ethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.14 g, 74% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH2:24][CH2:25][CH3:26])[N:3]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C.Cl.[NH2:45][C@H:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:45][C@H:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH2:24][CH2:25][CH3:26])[N:3]=1
Reactant: CCCc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A mixture of 3.2 g (0.0091 mole) of 4-[4-(2,4-diamino-6-propyl-5-pyrimidinyl]-1-piperazinyl]benzoic acid, 4.9 g (0.030 mole) of diethyl phosphorocyanidate and 4.2 ml (0.030 mole) of triethylamine in 200 ml of of N,N-dimethylformamide (dried over 4 Å molecular sieves overnight) was stirred at room temperature for two hours. To the resulting clear solution was added a mixture of 2.4 g (0.010 mole) of diethyl glutamate hydrochloride and 1.4 ml (0.010 mole) of triethylamine in 10 ml of N,N-dimethylformamide, and the solution was stirred for another hour. The solvent was removed under high vacuum (0.1 mm, dry ice-2-propanol trap) at 40° C. The gummy residue was poured into 100 ml of ice water. The solid was collected and recrystallized from N,N-dimethylformamide to give 1.9 g of the product as an off-white powder; mp 175°-180° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C(OCC)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: Fc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.6 g. of 2-tetralone, 20 g. of p-fluorophenyl magnesium bromide, and 200 ml. of diethyl ether is stirred for 4 hours and then refluxed for 1 hour. The mixture is acidified with the addition of 200 ml. of 1N hydrochloric acid, filtered, and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, filtered, dried and evaporated. The residue, containing 2-p-fluorophenyl-3,4-dihydronaphthalene is mixed with 25 g. of 5% palladium-on-charcoal catalyst; the resulting mixture is heated to 200°C for 6 hours, cooled, diluted with 250 ml. of chloroform, filtered, and evaporated to give 2-p-fluorophenylnaphthalene.
Reaction SMILES: CS(Cl)(=O)=O.[N+:6]([C:9]1[C:10]([NH:18][C@H:19]2[CH2:23][CH2:22][C@@H:21]([CH2:24]O)[CH2:20]2)=[C:11]2[S:17][CH:16]=[CH:15][C:12]2=[N:13][CH:14]=1)([O-:8])=[O:7].[CH2:26]([N:28](CC)CC)C.S([O-])(=O)(=O)C.[C-]#N.[Na+]>C(Cl)Cl.[Cl-].[Na+].O.CCOC(C)=O.CS(C)=O>[N+:6]([C:9]1[C:10]([NH:18][C@H:19]2[CH2:23][CH2:22][C@@H:21]([CH2:24][C:26]#[N:28])[CH2:20]2)=[C:11]2[S:17][CH:16]=[CH:15][C:12]2=[N:13][CH:14]=1)([O-:8])=[O:7]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@@H](CO)C1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [C-]#N
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC[C@@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
Methanesulfonyl chloride (24.0 μL, 0.310 mmol) was added to a solution of {(1R,3S)-3-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclopentyl}methanol (70 mg, 0.2 mmol) and triethylamine (66.5 μL, 0.477 mmol) in methylene chloride (2.1 mL) at about 0° C. with stirring. The resulting mixture was allowed to warm to room temperature and stir overnight. The mixture was diluted with dichloromethane then washed with water and brine. The organic was dried (MgSO4), filtered, and concentrated to give a bright yellow gum. To the crude mesylate was added dimethyl sulfoxide (2.0 mL) and sodium cyanide (22 mg, 0.45 mmol). The resulting mixture was stirred at room temperature. After 2 h, the temperature was increased to 80° C. and stirred for 3 h. After cooling, EtOAc and brine were added. The layers were separated and the organic washed with water (2×), dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel, eluted with 10-70% EtOAc in hexanes to give 8 mg (10%) of the desired product. LCMS calculated for C14H15N4O2S (M+H)+: m/z=303.1. Found: 303.0.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[CH2:16][Cl:15])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCl)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8.60 g (0.05 mol) of 4-bromoaniline, 10.60 g (0.10 mol) of Na2CO3, and 6.78 g (0.06 mol) of chloroacetyl chloride in 100 mL of acetone was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and H2O. The organic layer was separated, washed with H2O, dried over Na2SO4, filtered, and evaporated in vacuo to give 11.4 g of analytically pure title compound as light crystals.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][O:10][C:11]2[N:16]=[C:15]([NH:17]C=O)[C:14]([F:20])=[CH:13][N:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.NN>CCOCC>[CH:1]1([C:6]([O:8][CH2:9][O:10][C:11]2[N:16]=[C:15]([NH2:17])[C:14]([F:20])=[CH:13][N:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CNc1nc(OCOC(=O)C2CCCC2)ncc1F
Agent: NN
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: Nc1nc(OCOC(=O)C2CCCC2)ncc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36.6 %

Procedure:
A 25 mL vial was charged with (5-fluoro-4-formamidopyrimidin-2-yloxy)methyl cyclopentanecarboxylate (34.0 mg, 0.120 mmol), ethanol (1 mL), and hydrazine monohydrate (23.3 μL, 0.479 mmol). The resulting clear, colorless solution was then agitated on an orbital shaker at room temperature for 45 min. The crude reaction mixture was diluted with Et2O (50 mL) and was washed with saturated aqueous NaCl solution (50 mL×2). The organic was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (11.2 mg, 36%) as a white solid: mp 101-104° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=3.4 Hz, 1H), 7.44 (bs, 1H), 5.86 (s, 2H), 2.69-2.83 (m, 1H), 1.42-1.91 (m, 8H); MS (ESI) m/z 256 (M+H)+, 254 (M−H)−.
Reaction SMILES: C(NC(C)C)(C)C.C(N)CCC.[CH3:13][N:14]([CH3:18])[C:15](=[O:17])[CH3:16].C([O:21][C:22](=O)[CH2:23][C@H:24]([OH:38])[CH2:25][S:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[N:29][N:28]=1)C>C1COCC1>[OH:38][C@H:24]([CH2:25][S:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[N:29][N:28]=1)[CH2:23][C:22](=[O:21])[CH2:16][C:15]([N:14]([CH3:18])[CH3:13])=[O:17]
Reactant: CCOC(=O)C[C@H](O)CSc1nnnn1-c1ccccc1
Reactant: CC(=O)N(C)C
Solvent: CC(C)NC(C)C
Solvent: CCCCN
Solvent: C1CCOC1
Product: CN(C)C(=O)CC(=O)C[C@H](O)CSc1nnnn1-c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
1000 mL THF and 132.27 g diisopropyl amine were taken in round bottom flask at 25° C. The reaction mixture was cooled to −10° C. and 531 mL of n-butyl amine was added to it. The reaction mixture was stirred for 30 minutes and further cooled to −40° C. 113 g N,N-dimethylacetamide solution in 1000 mL THF was gradually added to the reaction mixture and stirred for 2 hours. 100 g (S)-Ethyl-3-hydroxy-4-(1-phenyl-1H-tetrazol-5-ylthio)butanoate (11a) solution in 200 mL THF was added to the reaction mixture and stirred for 2 hours. After the completion of the reaction as monitored by TLC, the reaction mixture was quenched with 20% 1000 mL ammonium chloride solution at about −25° C. The separated aqueous layer was extracted with 400 mL ethyl acetate. The separated organic layer was washed with 1000 mL 1N HCl solution followed by washing with 1000 mL of water at 25° C. The organic layer was distilled under vacuum below 50° C. to obtain 100 g residue as an oil. The oily residue was taken in 400 mL hexane and distilled to obtain oil.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=1)[C:9]([OH:11])=O)[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:48][C:49]1([CH3:69])[O:53][C@H:52]([CH2:54][O:55][C:56]2[C:65]([CH3:66])=[CH:64][C:59]([C:60]([NH:62]O)=[NH:61])=[CH:58][C:57]=2[CH2:67][CH3:68])[CH2:51][O:50]1>C1COCC1.CN(C=O)C.CC(=O)OCC>[CH3:48][C:49]1([CH3:69])[O:53][C@H:52]([CH2:54][O:55][C:56]2[C:65]([CH3:66])=[CH:64][C:59]([C:60]3[N:62]=[C:9]([C:8]4[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:7]=4)[O:11][N:61]=3)=[CH:58][C:57]=2[CH2:67][CH3:68])[CH2:51][O:50]1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1
Reactant: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid (190 mg, 732 μmol) in THF (10 mL) and DMF (2 mL), DIPEA (190 mg, 1.46 mmol) followed by TBTU (235 mg, 732 μmol) is added. The mixture is stirred at rt for 10 min before (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine 226 mg, 732 μmol) is added. The mixture is stirred at rt for 1 h before it is diluted with EA and washed with water. The org. phase is separated and concentrated. The remaining residue is dissolved in dioxane (10 mL) and heated to 105° C. for 18 h. The mixture is cooled to rt, concentrated and the crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give 4-{3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-2-(1-ethyl-propyl)-6-methoxy-pyridine (256 mg) as a yellow oil; LC-MS: tR=1.28 min, [M+H]+=496.23.
Reaction SMILES: C(C1C=CC=CC=1)(=[O:3])C.C[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:15][C:14]=1[O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:12].Cl[O-]>>[F:28][C:27]([F:30])([F:29])[CH2:26][O:25][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:18][C:13]=1[C:11]([OH:12])=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [O-]Cl
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
replacing the methyl moiety of the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.S(=O)(=O)(O)O.[C:22](=O)(O)[O-].[Na+].O>CO.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:22])=[O:13])=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2ccc(C(=O)O)cc2)cn1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(N)nc2)cc1

Procedure:
The resulting 4-(2-aminopyridin-5-yl)benzoic acid (684 mg) was dissolved in methanol (50 ml) at room temperature, followed by the addition of concentrated sulfuric acid (1 ml). After heating under reflux for 2 hours, the reaction mixture was made weakly alkaline with an aqueous solution of sodium bicarbonate. Water and ethyl acetate were added to the resulting mixture to separate the organic layer. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off. Hexane was added to the residue for crystallization, whereby the title compound (243 mg, 23%) was obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl-].[Li+].C(N1C=C(C=O)N=C1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:40]([O:44][C:45]([NH:47][CH2:48][CH2:49][CH2:50]/[C:51](=[CH:59]\[C:60]1[N:61]=[CH:62][N:63](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:64]=1)/[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:46])([CH3:43])([CH3:42])[CH3:41].C(OC(NCCC/C(=C/C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)/C(OC(C)(C)C)=O)=O)(C)(C)C>C(#N)C.CO.[C].[Pd]>[C:40]([O:44][C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH:51]([CH2:59][C:60]1[N:61]=[CH:62][NH:63][CH:64]=1)[C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])=[O:46])([CH3:41])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCC/C(=C\c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)OC(=O)NCCC/C(=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OC(C)(C)C
Agent: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCC(Cc1c[nH]cn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound (8.35 g) obtained in Reference Example 1 in acetonitrile (100 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (4.58 mL) and lithium chloride (1.30 g) were added at room temperature. To this suspension, 1-trityl-1H-imidazole-4-carbaldehyde (6.90 g) was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure. To the residue, ethyl acetate and a 10% aqueous citric acid were added. This solution was separated into aqueous and organic layers. Then, the organic layer was washed with saturated sodium chloride solution, saturated aqueous sodium bicarbonate, and saturated sodium chloride solution in this order. The organic layer was dried over anhydrous sodium sulfate to obtain a mixture of tert-butyl (2E)-5-[(tert-butoxycarbonyl)amino]-2-[(1-trityl-1H-imidazol-4-yl)methylene]valerate and tert-butyl (2Z)-5-[(tert-butoxycarbonyl)amino]-2-[(1-trityl-1H-imidazol-4-yl)methylene]valerate (11.3 g). This mixture was suspended in methanol (500 mL). To this suspension, 10% palladium-carbon catalyst (hydrated, 4 g) was added, and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting solvent: methylene chloride/methanol=9/1) to obtain the title compound (5.60 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[Cl:11]Cl.CCOC(C)=O.CCCCCC>CCOC(C)=O>[Cl:11][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1ccc2ncsc2c1
Reactant: ClCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ccc2ncsc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 6-aminobenzothiazole (2.0 g, 13.4 mmol) in 100 mL of ACOH was added a solution of Cl2 saturated AcOH and the resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid which was dissolved in EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (10-50% EtOAc/n-Hexane) to obtain 7.8 g (34 mmol, 80% ) of the desired product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21](=[O:23])=[O:22]>O1CCCC1>[Cl:20][C:16]1[N:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=1[C:21]([OH:23])=[O:22]
Reactant: Clc1cccc(Cl)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine 3.76 g in tetrahydrofuran 25 ml is dropped at −78° C. n-butyllithium (23.2 ml). The mixture is stirred at 0° C. for 10 minutes and thereto is added 2,6-dichloropyridine 5.0 g in tetrahydrofuran 25 ml at −78° C. over a period of 20 minutes. The mixture is stirred at −78° C. for 3 hours. The reaction mixture is poured into powdered dry ice and is left at room temperature overnight. After removal of the solvent the residue is dissolved in a mixture of ethyl acetate and a 10% aqueous sodium hydroxide solution, and the water layer is separated and made acid with concentrated hydrochloric acid. The resulting colorless precipitate is filtered and washed with cold water to give 2,6-dichloronicotinic acid 4.50 g. mp 148–150° C., MS(ESI): 190(M−H)−