Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[H-]F.[NH4+].[C:5]1(=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH:7]=[CH:6]1.C([Si](CC)(CC)[C:20]([F:23])([F:22])[F:21])C.C1C2C(=CC=CC=2)C=CC=1>>[OH:16][C:5]1([C:20]([F:23])([F:22])[F:21])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH:7]=[CH:6]1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CC[Si](CC)(CC)C(F)(F)F
Agent: F[H-]F
Agent: [NH4+]
Solvent: c1ccc2ccccc2c1
Product: O=C1C=CC(O)(C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 74 mg (1.3 mmol) of ground ammonium bifluoride, 174 mg (1.1 mmol) of 1,4-naphthoquinone, and 1 mL of N,N-dimethylformam:ide was treated with 239 mg (1.3 mmol) of triethyltrifluoromethylsilane and stirred vigorously at room temperature for one hour. Gas chromatographic analysis of the reaction mixture showed that the major naphthalene-desired product was 1,4-dihydro-4-hydroxy-1-oxo-4-trifluoromethylnaphthalene.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([NH:34][C:35]([NH2:37])=[NH:36])[CH2:31][CH2:32][CH3:33]>>[CH2:30]([NH:34][C:35]1[N:37]=[C:16]([C:15]2[C:14]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[N:13][N:12]3[C:11]=2[CH:10]=[CH:9][N:8]=[C:7]3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:17]=[CH:18][N:36]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)nccc12
Reactant: CCCCNC(=N)N
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(NC4CCCC4)nccc23)n1
Yield: 72 %

Procedure:
In a similar manner as described in Example 1 above, 3-[2-(butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine (80 mg, 72%) was prepared from 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-one and N-butylguanidine. 1H NMR (CDCl3): δ 8.04 (d, 1H), 7.74 (d, 1H), 7.60 (dd, 2H), 7.48 (d, 1H), 7.13 (t, 2H), 6.36 (d, 1H), 6.25 (d, 1H), 5.05 (t, 1H), 4.51 (m, 1H), 3.42 (qt, 2H), 2.16 (m, 2H), 1.78 (m, 2H), 1.56–1.70 (m, 6H), 1.43 (m, 2H), 0.95 (t, 3H). MS m/z 446 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])[CH2:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[N:19]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: Cc1cccc(Cl)n1
Product: O=C(Cc1cccc(Cl)n1)c1ccc(Br)cc1
Yield: 78.9 %

Procedure:
In a similar manner as described in Example 1, from ethyl 4-bromobenzoate (12.8 mL, 78.3 mmol) and 6-chloro-2-picoline (4.3 mL, 39.2 mmol), 1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (9.6 g, 82%) was obtained as a crystalline solid existing as a keto-enol tautomeric mixture. 1H NMR (CDCl3): for the keto tautomer δ 7.95 (d, 2H), 7.74–7.56 (m, 3H), 7.27 (m, 2H), 4.47 (s, 2H); MS m/z 310 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCCNC2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CN1CCCC(c2ccccc2)C1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-phenyl-piperidine.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(OCC)C>[C:1]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)C(C)Br
Solvent: CCOCC
Product: CCOC(=O)C(C)C(=O)C(C)(C)C
Yield: 56.4 %

Procedure:
A 500 mL 3-neck round-bottom flask was equipped with a reflux condensor and thermometer and purged with nitrogen. To it was charged 100 mL dry, deoxygenated diethyl ether and 4.4 g of zinc strips. This mixture was agitated in a water-filled sonicating bath for 5 minutes. To this was slowly added a mixture of 12.06 g pivaloyl chloride (0.10 mole), 18.1 g of ethyl 2-bromopropionate (0.10 mole, synthesized by the method of Strunk, R. J.; DiGiacomo, P. M.; Aso, K.; Kuivila, H. G. J Am. Chem. Soc., 1970, 92, 2849-2856.) and 100 mL of ethyl ether. The resulting mixture was refluxed 6 hours and stirred at room temperature overnight. The mixture was then successively extracted with cold 20% aqueous sulfuric acid, water and brine before drying over sodium sulfate. The solution was stripped to obtain 12.8 g of crude oil. This was distilled under vacuum to yield 10.5 g of ethyl 2-pivaloylpropionate. 1H NMR (CDCl3): δ4.103 (q, J=7.1 Hz, 2H), 3.959 (q, J=6.9, 1 Hz), 1.287 (d, J=7.0 Hz, 3H), 1.196 (t, J=7.1 Hz, 3H), 1.157 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][N:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:14][C:15]1[C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([NH:28][C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)=[O:13])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1ccc2c(C(=O)O)c[nH]c2c1
Reactant: Nc1ccc(Oc2cccnc2Cl)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(C(=O)Nc3ccc(Oc4cccnc4Cl)nc3)c[nH]c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
The 6-methyl-1H-indole-3-carboxylic acid (50 mg, 0.28 mmol) in Example 16 and the 6-(2-chloropyridine-3-yloxy)-pyridine-3-amine (60 mg, 0.28 mmol) in Example 22 were dissolved in DMF (5 ml), HBTU (100 mg, 0.28 mmol) and triethylamine (0.11 ml, 0.84 mmol) were added to the solution, and the mixture was stirred at 80° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (18 ml, 34%) by chromatography (methanol:dichloroinethane=1:30).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([O-:4])=O.[K+].P(Cl)(Cl)(Cl)=O.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]3[CH:31]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]3[C:31]=2[C:2](=[O:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(=O)[O-]
Reactant: Cc1ccc(-c2cn3cc(C)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Temperature: 10 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A suspension of potassium monoethyl oxalate (84.3 g; 0.54 mols) in methylene chloride (395 mL) is added dropwise with phosphorous oxychloride (82.8 g; 0.54 mols) keeping the temperature at about 30° C. After 4÷6 hours, 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine (100.0 g; 0.45 mols) is added, keeping the temperature below 35° C. The resulting suspension is added dropwise with triethylamine (50.5 g; 0.50 mols) keeping the mixture at the reflux temperature. After one hour under these conditions, the reaction mixture is cooled to 5÷10° C. and poured into a suspension of sodium carbonate (95 g; 0.89 mols) in water (500 mL) keeping the temperature below 35° C. The phases are separated and the upper aqueous phase is reextracted with methylene chloride (45 mL). The combined organic phases are washed with water (45 mL) and concentrated to a residue under vacuum. The solid residue is taken up in ethanol (590 mL), heated to dissolution and left to crystallize. After cooling to about 0° C. the solid is filtered, washed with ethanol and dried at 50° C. under vacuum to obtain ethyl 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-glyoxalate (141.5 g, 99.5% titre, 97.5% yield).
Reaction SMILES: [C:1]([NH:8][C:9]([N:18]1C=CC=N1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:24][O:25]N.CO.C(N(CC)CC)C>C1COCC1>[CH3:24][O:25][NH:18][C:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[N:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CON
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CONC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of N,N′-di-Boc-1H-pyrazole-1-carboxamidine (450 mg, 1.45 mmol) and methoxyamine hydrochloride (151 mg, 1.81 mmol) in THF (3 mL) aid methanol (3 mL) was slowly added triethylamine (183 mg, 1.81 mmol). After stirring at room temperature for 64 hours, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The salts were removed by filtration. The filtrate was concentrated under reduced pressure and triturated with ether to provide the crude product that was used without further purification.
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[C@H:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])[C:9]([O:11][CH3:12])=[O:10].Cl.[N-:23]=[N+:24]=[N-].[Na+]>O>[C:19]([NH:18][C@@H:16]([C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N:5]=[N+:23]=[N-:24])[CH3:17])(=[O:21])[CH3:20]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(N=[N+]=[N-])c1
Reaction time: 0.5 h

Procedure:
Sodium nitrite (440 mg) was added to a mixture of methyl (R)-3-amino-4-(1-acetylaminoethyl)benzoate (1.38 g), conc. hydrochloric acid (3 ml) and water (9 ml) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. A solution of sodium azide (420 mg) in water (5 ml) was added, and the mixture was stirred for 30 minutes. After the reaction, the mixture was extracted with ethyl acetate, and washed with water. The mixture was dried, and the solvent was evaporated to give methyl (R)-4-(1-acetylaminoethyl)-3-azidobenzoate as white crystals.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15](Cl)=[N:16][C:17]([S:19][CH3:20])=[N:18][C:11]=2[NH:10][CH2:9][CH2:8]1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1OB(O)O>>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH3:31])=[N:16][C:17]([S:19][CH3:20])=[N:18][C:11]=2[NH:10][CH2:9][CH2:8]1
Reactant: Cc1ccccc1OB(O)O
Reactant: CSc1nc(Cl)c2c(n1)NCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Product: CSc1nc2c(c(-c3ccccc3C)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCN2
Yield: 99.7 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (Compound of Reference Example 8; 2.36 g) was reacted with 2-methylphenylboric acid (816 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-4-(2-methylphenyl)-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (2.63 g, 100%).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[C:5](=O)[C:4]=2[S:3][CH:2]=1.[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[CH2:19][Mg]Cl>C1COCC1>[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[CH:19]=[C:5]1[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[CH2:8][CH2:9][C:10]2[CH:1]=[CH:2][S:3][C:4]1=2
Reactant: O=C1c2ccccc2CCc2ccsc21
Reactant: Cl[Mg]Cc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: Clc1ccc(C=C2c3ccccc3CCc3ccsc32)c(Cl)c1
Yield: 32.4 %

Procedure:
Following the procedures essentially as described in Example 238 and using 9,10-dihydro-3-thia-benzo[f]azulene-4-one (23.3 mg, 0.108 mmol) and solution of 2,4-dichlorobenzyl magnesium chloride (0.325 mmol) in THF provides, after dehydration, 12.5 mg (32%) of the title compound as a 3:1 mixture of E- and Z-isomers: 1H NMR (CDCl3) δ 2.88-3.40 (m, 4 H), 6.26 (d, J=4.8 Hz, 1/4 H), 6.50 (d, J=8.2 Hz, 3/4 H); 6.63 (s, 1/4 H, Z), 6.74 (s, 3/4 H), 6.76 (td, J=8.6 Hz, 2.0 Hz, 3/4 H), 6.88 (td, J=8.2 Hz, 1.2 Hz, 3/4 H), 6.96 (s, 3/4 H), 6.95-6.98 (m, 15/4 H), 7.28 (d, J=2.0 Hz, 3/4 H), 7.34 (d, J=2.4 Hz, 1/4 H), 7.35-7.38 (m, 1/4 H); TLC shows >95% purity: Rf=0.20 hexanes).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2O[CH:24]2C(OCC)=O)=[CH:19][CH:18]=1.C(O)C>O.CO.CCCCCC.C1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]2[C:5]3[CH2:6][CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:19][CH:18]=1
Reactant: NCCC1=CCCc2ccccc21
Reactant: CCOC(=O)C1OC1c1ccc(OC)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(CC2NCCC3=C2CCc2ccccc23)cc1
Reaction time: 16 h
Yield: 56 %

Procedure:
A mixture 28.4 g. (0.138 mole) of the hydrochloride salt of 2-aminoethyl)-1,2-dihydronaphthalene (II) in water (800 ml.) was acidified to pH 3 by the addition of hydrochloric acid. The resulting mixture was heated under reflux under a nitrogen atmosphere and with vigorous stirring, a solution of 38.0 g. (0.172 mole) of ethyl 3-(4-methoxyphenyl)-2,3-epoxypropionate in 200 ml. of ethanol was added dropwise over a period of 8 hours. Reflux was continued for 16 hours, then 300 ml. of concentrated hydrochloric acid was added. After a further 4 hours under reflux, the mixture was allowed to cool, and benzene (800 ml.), hexane (200 ml.) and methanol (200 ml.) were added, the mixture was shaken and the aqueous layer separated. The aqueous layer was basic and extracted with methylene chloride to give a 56 percent yield of product (III). The nuclear magnetic resonance spectrum of the product was consistent with the structure.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:6]1([NH:5][C:3](=[O:4])[CH2:2][N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccccc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
N-Chloroacetylaniline (0.5 g, 2.95 mmol), 1-(2-pyridinyl)piperazine (0.72 g, 4.42 mmol), and N,N-diisopropylethylamine (1.03 mL, 5.9 mmol) were combined in toluene and heated at reflux overnight. The mixture was allowed to cool to room temperature, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 60% ethyl acetate:hexanes) to provide 400 mg (46% yield) of the title compound as a hygroscopic white solid. 1H NMR (300 MHz, CDCl3) δ 2.60 (m, 4H), 3.18 (s, 2H), 3.55 (m, 4H), 6.65 (dd, 1H, J=12, 6 Hz), 6.85 (d, 1H, J=9 Hz), 7.05 (t, 1H, J=6 Hz), 7.3 (t, 2H, J=9 Hz), 7.51 (ddd, 1H, J=9, 7.5, 3 Hz) 7.68 (d, 2H, J=9 Hz) 8.1 (dd, 1H, J=6, 3 Hz) 9.75 (br s, 1H); MS (DCI/NH3) m/e 297 (M+H)+; Anal. calcd for C17H20N4O: C, 68.89; H, 6.80; N, 18.90. Found: C, 68.97; H, 6.87; N, 19.01.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(Cl)cccc2o1
Product: Clc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 11.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (15 mg, 97 μmol) and 2-(but-3-ynyl)-4-chlorobenzo[d]oxazole (20 mg, 97 μmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 3 mg (11 μmol, 11%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][Si](C)(C)C)[N:4]=1.C1C=CC(O[C:22](Cl)=[S:23])=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]=[C:22]=[S:23])[N:4]=1
Reactant: COc1nc(C)nc(N[Si](C)(C)C)n1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1C
Product: COc1nc(C)nc(N=C=S)n1
Temperature: 25 °C
Yield: 23.3 %

Procedure:
A solution of 15.0 g of 4-methoxy-6-methyl-2-trimethylsilylamino-1,3,5-triazine and 12.2 g of phenyl chlorothionocarbonate in 50 ml of xylene is stirred for 6.5 hours at ca. 140° C. The reaction solution is cooled to room temperature, and filtered to remove insoluble substance, and the resulting filtrate is concentrated under reduced pressure. The residue is purified by silica gel column-chromatography (eluent: ethyl acetate:toluene =1:3) to give 3.0 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH:9]1[CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]([S:24][CH2:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[CH3:22]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[CH2:7][N:8]([C:27](=[O:28])[CH:26]([CH3:30])[CH2:25][S:24][C:21](=[O:23])[CH3:22])[CH:9]1[CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)CNC1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCC1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a chilled (0.5° C.) methylene chloride solution of N-cyclobutyl-glycine t-butyl ester (63.2 g, 0.34 mol) and triethylamine (26 g, 0.4 mol) was added dropwise 3-acetylthio-2-methylpropanoyl chloride (61.4 g, 0.34 mol). After stirring overnight the reaction mixture was filtered and the filtrate was concentrated. The residue was redissolved in ethyl acetate, washed with 5% HCl (3×500 ml), brine (500 ml) and saturated aqueous sodium bicarbonate (6×600 ml), dried over MgSO4, filtered, and concentrated yielding 80.6 g (72%) of the product as a brown oil.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][CH2:22][O:23][C@@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C.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.CO>[CH2:1]([C:8]1[C:13]([C:25]#[C:24][C@:26]2([OH:34])[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][CH2:22][O:23][C@@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc(N2C[C@H]3OCCO[C@@H]3C2)nc1Cc1ccccc1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CO
Solvent: CCN(CC)CC
Product: O[C@]1(C#Cc2ccc(N3C[C@H]4OCCO[C@@H]4C3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of 5.12 g of 2-benzyl-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]-3-iodopyridine, 1.83 g of (3R)-3-ethynyl-3-quinuclidinol, 140 mg of tetrakis(triphenylphosphine)palladium(0), 115 mg of cuprous iodide, 3.4 ml of triethylamine and 12 ml of methanol was stirred at room temperature overnight in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and the mixture was extracted with ethyl acetate/tetrahydrofuran (1:1). Then, the organic phase was washed with brine and the solvent was removed. The residue was crystallized from tetrahydrofuran/methanol/ethyl acetate, to give 3.59 g of the target compound.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:25])=[C:10]([F:24])[C:11]([N:16]3[CH2:21][CH:20]([CH3:22])[O:19][CH:18]([CH3:23])[CH2:17]3)=[C:12]([CH:15]=2)[CH:13]=[O:14])=[N:6][CH:7]=1.[C:26](=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.CB(O)O>CCOC(C)=O.O>[CH3:23][CH:18]1[O:19][CH:20]([CH3:22])[CH2:21][N:16]([C:11]2[C:10]([F:24])=[C:9]([F:25])[C:8]([C:5]3[CH:4]=[N:3][C:2]([CH3:26])=[CH:7][N:6]=3)=[CH:15][C:12]=2[CH:13]=[O:14])[CH2:17]1
Reactant: O=C([O-])[O-]
Reactant: CC1CN(c2c(C=O)cc(-c3cnc(Br)cn3)c(F)c2F)CC(C)O1
Agent: CB(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cnc(-c2cc(C=O)c(N3CC(C)OC(C)C3)c(F)c2F)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a suspension of 5-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde (0.375 g, 0.91 mmol) and sodium carbonate (0.29 g, 2.7 mmol) in previously degassed acetonitrile/water (1/1) mixture (4 mL) was added methyl boronic acid (0.11 g, 1.8 mmol) under nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.026 g, 0.036 mmol) was added at room temperature and the reaction was heated for 5 hours at 85° C. Analysis indicated that starting material had not fully been consumed so an additional 1 equivalent of methyl boronic acid was added to the reaction and stirred overnight at 85° C. The mixture was cooled to room temperature, diluted with EtOAc and water then neutralized. The phases were separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated. Purified by column chromatography eluting with ethyl acetate in hexanes (5-35%) to obtain 132 mgs of product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H), 2.61 (s, 3H), 3.00 (m, 2H), 3.38 (m, 2 H), 4.19 (m, 2H), 8.26 (dd, J=8.2, 2.1 Hz, 1H), 8.54 (d, J=1.2 Hz, 1H), 8.89 (dd, J=2.3, 1.6 Hz, 1H), 10.33 (s, 1H); MS(APCl+) m/z 348 (MH+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C@:26]2([O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]2[O:29][C:30](=[O:32])[CH3:31])[OH:27])=[CH:22][C:21]=1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][Si](C(C)(C)C)(C)C)=[CH:53][CH:52]=1.C(O)(=O)C.C(OCC)(=O)C>O1CCCC1.O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C@:26]2([O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]2[O:29][C:30](=[O:32])[CH3:31])[OH:27])=[CH:22][C:21]=1[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.02 mL of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution of 1.3 g 1-methyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos1-yl)-2-[4-(tert-butyl-dimethyl-silyloxy)-benzyl]-benzene and 0.12 mL acetic acid in 10 mL of tetrahydrofuran. The solution is stirred for 30 min at ambient temperature, and then 50 mL ethyl acetate and 10 mL water are added. The organic layer is separated, washed with aqueous NaHCO3 solution, and dried over MgSO4. After removal of the solvent, the residue is recrystallized from a mixture of ethyl acetate and petrol ether.