Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[C:20]1([CH2:26][CH2:27][C:28](=O)[CH3:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH3:29][C:28]1([CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:6][C:1](=[O:7])[CH2:2][C:3](=[O:5])[O:4]1
Reactant: CC(=O)CCc1ccccc1
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC1(CCc2ccccc2)OC(=O)CC(=O)O1
Reaction time: 0.33 h

Procedure:
To a solution of malonic acid (56.7 g, 0.55 mol) and acetic anhydride (73 ml), sulfuric acid (2 ml) was added dropwise at 5°-10° C. and stirring was continued for 20 min at the same temperature. To this mixture, 4-phenyl-2-butanone (105 g, 0.7 mol) was added dropwise at 15°-20° C. and stirring was continued for 15 h at the same temperature. The reaction mixture was taken up into H2O, extracted with chloroform, then the organic extract was washed with H2O, dried over anhydrous MgSO4 and evaporated. The resultant solid was recrystallized from aqueous acetone to give the title compound as a white amorphous solid; yield: 68.0 g; mp. 63.0°-65.0° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:30]([C:32]1[C:36]([CH:37]=O)=[CH:35][NH:34][N:33]=1)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:28]=[CH:29][C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:37][C:36]3[C:32]([CH2:30][CH3:31])=[N:33][NH:34][CH:35]=3)[CH2:6][CH2:5]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: CCc1n[nH]cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1n[nH]cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Reaction time: 24 h

Procedure:
tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 395 mg, 1.0 mmol) and 3-ethyl-1H-pyrazole-4-carbaldehyde (149 mg, 1.2 mmol) were stirred at ambient temperature in dichloromethane (10 ml) for 1 hour. Sodium triacetoxyborohydride (297 mg, 1.4 mmol) was added and the mixture stiffed at ambient temperature for 24 hours. The resulting solution was absorbed onto an SCX-2 column which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give the product as a white foam. This was purified by chromatography on silica eluting with 10% methanol in dichloromethane. The residue was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (1 ml) was added and the mixture stirred for 3 hours at ambient temperature. The resulting solution was absorbed onto an SCX-2 column which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give the title compound (232 mg, 75%). NMR Spectrum: (DMSO d6) δ 1.18 (t, 3H), 1.65 (m, 2H), 1.77 (m, 2H), 2.00 (m, 2H), 2.57 (m, 3H), 2.95 (m, 2H), 3.34 (s, 2H), 4.86 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (m, 1H), 7.17 (d, 1H), 7.29 (br s, 1H), 7.37 (d, 2H), 7.91 (d, 2H), 9.55 (s, 1H), 12.39 (s, 1H); Mass Spectrum: M+H+ 404.
Reaction SMILES: [CH2:1]([C:4]1[N:13]=[C:12]([SH:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+].[CH3:17]I>O>[CH3:17][S:14][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:13]=1
Reactant: CI
Reactant: CCCc1nc(S)c2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(SC)c2ccccc2n1
Reaction time: 0.17 h

Procedure:
A mixture of 2-propyl-4-mercaptoquinazoline (3.3 g.) and sodium hydroxide (0.68 g.) in water (7 ml.) was stirred for 10 minutes at 25°. Methyl iodide (1.1 ml.) was added and stirring was continued for 1 hour. The precipitate was recrystallised from hexane to give 4-methylthio-2-propylquinazoline; n.m.r. in CDCl3 :-1.1(t, 3H); 1.95(m, 2H); 2.7(s, 3H); 3.0(t, 2H); 7.2-8.1(complex, 4H).
Reaction SMILES: [Cl:1][CH:2]=[CH:3]Cl.N1CCCCC1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)#[CH:12]>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.[Cu]I.C1COCC1>[Cl:1]/[CH:2]=[CH:3]/[C:12]#[C:11][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: ClC=CCl
Reactant: C#Cc1ccc(C=O)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: O=Cc1ccc(C#C/C=C/Cl)cc1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 59 %

Procedure:
1,2-Dichloroethylene (3.0 mL), tetrakis(triphenylphosphine)palladium (0.44 g), CuI (73 mg) and piperidine (1.1 mL) were added to a THF (20 mL) solution of 4-ethynylbenzaldehyde (1.0 g), and the mixture was stirred for 22.5 hours at room temperature in a nitrogen atmosphere. IPE was added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (hexane/ethyl acetate/chloroform=9/1/1) to obtain 4-((E)-4-chlorobut-3-en-1-yn-1-yl)benzaldehyde (light brown solid) (0.87 g, 59%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: COc1ccccc1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 67.8 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 13.04 mmol) with 2-methoxyphenylboronic acid (3.96 g, 26.09 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.532 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 3.63 g (68%) of (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. mp 151-153° C.; Anal. calcd. for C23H22O5S: C, 67.3; H, 5.4. Found: C, 66.95; H, 5.43.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)[CH:6]=[CH:5]2.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(Cl)Cl>C(N(CC)CC)C>[CH3:18][C:15]1([CH3:19])[O:16][CH2:17][C:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=4)[CH:3]=3)[CH:8]=2)[CH2:13][O:14]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(C)(C)OC1
Reaction time: 10 h
Yield: 62 %

Procedure:
[5-(6-Hydroxy-naphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (Example 13, 50.0 mg, 0.000134 mol), 3-(trifluoromethyl)phenylboronic acid (50.8 mg, 0.000268 mol), cupric acetate (24.3 mg, 0.000134 mol) were placed in a vial, purged with N2, following by methylene chloride (2 mL, 0.03 mol) and triethylamine to (0.0933 mL, 0.000669 mol) at 23° C. The reaction was allowed to stir for about for 10 hours, and filtrated. The crude material was then purified via chromatography (SiO2, 4 g, 0-35%) to give a pure product (43 mg, 62%). 1H NMR (CHLOROFORM-d) δ: 7.84 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.55 (dd, J=8.7, 1.6 Hz, 1H), 7.41-7.49 (m, 1H), 7.31-7.40 (m, 2H), 7.16-7.30 (m, 3H), 5.57 (br. s., 1H), 4.22-4.29 (m, 2H), 4.14 (d, J=11.3 Hz, 2H), 1.49-1.58 (m, 6H), 1.36 (br. s., 9H). MS (M-113): 404.20.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NCC1COc2ccccc2O1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1COc2ccccc2O1
Temperature: 25 °C

Procedure:
Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (4.4 g, 26 mmol) and sulfamide (5.1 g, 53 mmol) were combined in 1,4 dioxane (100 mL) and refluxed for 2 h. The reaction was cooled to room temperature and a small amount of solid was filtered and discarded. The filtrate was evaporated in vacuo and the residue was purified using flash column chromatography (DCM:Methanol-10:1) to yield a white solid. The solid was recrystallized from DCM to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].C(N(CC)CC)C.N1C=CC=N1>C1C=CC=CC=1>[C:8]([N:3]1[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]1)(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)Cl
Reactant: Cc1cc(C)[nH]n1
Agent: c1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)n1nc(C)cc1C
Temperature: 10 °C
Reaction time: 4 h

Procedure:
N-acrylyl-3,5-dimethyl pyrazole was prepared by reacting 3,5-dimethylpyrazole with acrylyl chloride in the presence of triethylamine. 19.2 grams (0.2 mole) of 3,5-dimethylpyrazole and 20.2 grams (0.2 mole) of triethylamine were dissolved in 125 milliliters of benzene and the solution put into a dropping funnel. The acrylyl chloride, 18.1 grams (0.2 mole) was dissolved in 25 milliliters of benzene and this solution put into a flask equipped for stirring and cooled at 10°C. The pyrazole solution was then added to the acrylyl chloride solution over a period of 45 minutes with constant stirring. Temperature of the reaction mix was held at 8°C. to 15°C. throughout the addition. Following the addition, the reaction mix was allowed to warm to room temperature and let stand for 4 hours. The mix was then filtered to remove triethylamine-hydrochloric acid salt which was formed in the reaction. The filtrate was heated to evaporate off volatiles, leaving 24.5 grams of an amber-colored liquid residue. The residue was then cooled to about 0°C. and 12.1 grams of a white crystalline precipitate was filtered out. After standing 16 hours at about 0°C., 2.5 more grams of crystalline solid was filtered out. The solids were combined and twice recrystallized from a solution of 18 milliliters of methanol and 2 milliliters of water to yield 9.4 grams of a crystalline solid having a melting point of 36°-37°C. The nuclear magnetic resonance (NMR) spectra of the solid conformed with that of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1)=[O:5].Cl[C:30]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:31].N1C=CC=CC=1>O1CCCC1>[C:13]1([C:10]2[N:11]=[CH:12][C:7]([NH:6][C:4]([C:3]3[CH:19]=[C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:2]=3[NH:1][C:30]([C:32]3[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:31])=[O:5])=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (138 mg, 0.37 mmol, 1.00 equiv) in tetrahydrofuran (6 mL) was added methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (112 mg, 0.41 mmol, 1.10 equiv) and pyridine (60 mg, 0.76 mmol, 2.00 equiv) and the resulting solution was stirred for 5 h at room temperature. The reaction progress was monitored by LCMS. The crude product was used directly in the next step.
Reaction SMILES: [CH:1]12[O:12][CH:4]([CH:5]([S:7]([O:10][CH3:11])(=[O:9])=[O:8])[CH2:6]1)[CH:3]=[CH:2]2.ClC1C=CC=C(C(OO)=[O:21])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:21]1[C:3]2[CH:4]3[O:12][CH:1]([CH2:6][CH:5]3[S:7]([O:10][CH3:11])(=[O:8])=[O:9])[C:2]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COS(=O)(=O)C1CC2C=CC1O2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COS(=O)(=O)C1CC2OC1C1=C2O1
Temperature: 4 °C
Yield: 85.5 %

Procedure:
A four-neck flask having an internal capacity of 1,000 mL and fitted with a stirrer, a dropping funnel and a thermometer was charged sequentially with 22.0 g of methyl 7-oxabicyclo[2.2.1]hept-2-ene-5-sulfonate and 450 g of methylene chloride, the temperature was cooled to 4° C., and 22.9 g (0.17 mol) of m-chloroperbenzoic acid was added gradually to the flask under constant stirring so that the temperature did not exceed 10° C. Following stirring for 4 hours at 5 to 7° C., 100 g of a saturated aqueous solution of sodium sulfite was added, and the resulting mixture was stirred for 30 minutes. After standing and separating, the organic layer was washed three times with 100 g samples of saturated sodium hydrogen carbonate. The organic layer was then concentrated under reduced pressure, yielding 20.2 g of methyl 2,3-epoxy-7-oxabicyclo[2.2.1]hept-2-ene-5-sulfonate.
Reaction SMILES: [C:1]1([C:7]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]([CH3:10])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O.O>[N:17]([CH:9]([CH3:10])[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])=[N+:18]=[N-:19]
Reactant: CC1OC1(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])C(O)(c1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of 9.35 g (44.5 mmol) 2,2-diphenyl-3-methyloxirane and 9.00 g (138 mmol) NaN3 in 100 ml of 2:1 N,N-dimethylformamide-water was heated at reflux for 72 hours. The solution was concentrated and the residue was partitioned between ether and water. The ether layer was washed with NaHCO3, then water, dried over Na2SO4 and concentrated. HPLC (5% EtOAc-hexane) afforded 7.86 g (70%) of 2-azido-1,1-diphenylpropanol as a clean oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: C1COCCN1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCOCC2)c1OCCC(C)c1ccc(F)cc1

Procedure:
Example 8a (100 mg, 0.21 mmol) was reacted with morpholine (6.0 eq.) as described under General Procedure G. The title compound was afforded as an oil (72 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 7.18-7.13 (m, 2H), 6.99-6.89 (m, 2H), 4.05 (t, J=5.7 Hz, 2H), 3.94 (t, J=6.7 Hz, 2H), 3.82 (s, 3H), 3.70-3.67 (m, 4H), 3.02-2.95 (m, 1H), 2.59 (t, J=5.7 Hz, 2H), 2.49 (s, 3H), 2.47-2.44 (m, 4H), 2.17 (s, 3H), 2.03-1.96 (m, 2H), 1.28 (d, J=7.0 Hz, 3H). MS (ES+) m/z 493.9 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][N:31]([CH3:42])[S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:41][C:38]4[CH:39]=[CH:40][C:35]([S:32](=[O:34])(=[O:33])[N:31]([CH3:30])[CH3:42])=[CH:36][CH:37]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Product: CN(C)S(=O)(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Yield: 86 %

Procedure:
The title compound was prepared in 86% yield from compound (10) and 4-(N,N-dimethylsulfamoyl)phenylamine using the method described for Preparation 35. 1H-NMR (d6-DMSO, 500 MHz): δ 1.48 (s, 9H), 1.60 (s, 9H), 2.58 (s, 9H), 6.87 (d, J=0.63 Hz, 1H), 7.61 (d, J=9.14 Hz, 2H), 7.65 (s, 1H), 7.90 (d, J=8.83 Hz, 2H), 8.05 (d, J=0.63 Hz, 1H), 8.49 (d, J=0.63 Hz, 1H), 8.57 (d, J=0.95 Hz, 1H), 9.67 (s, 1H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]#N>C(#N)C1C=CC=CC=1>[C:27]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C#CCCCCCC
Reactant: N#Cc1ccc2ccccc2c1
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: CCCCCCC#Cc1ccc2ccccc2c1
Reaction time: 22 h
Yield: 99 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-naphthonitrile (0.306 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 22 h at 65° C. showed the presence of 1.98 mmol (99% yield) of 2-(1-octynyl)naphthalene and no remaining 2-naphthonitrile in the reaction mixture.
Reaction SMILES: N#N.Cl[CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Cl:11][C:12]1[CH:13]=[C:14]([S:18][CH2:19][C:20]2[C:21]([C:26](N(OC)C)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:16][CH:17]=1.CCOC(C)=O>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([S:18][CH2:19][C:20]2[C:21]([C:26]([CH:4]3[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]3)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN1CCC(Cl)CC1
Reactant: CON(C)C(=O)c1ncccc1CSc1cccc(Cl)c1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(C(=O)c2ncccc2CSc2cccc(Cl)c2)CC1
Temperature: -40 °C
Reaction time: 1.25 h
Yield: 64 %

Procedure:
Anhydrous CeCl3 (1.1 g, 4.46 mmol) was placed in a 50 ml 2-necked flask and flamed out under vacuum. The vacuum was replaced with N2, and dry THF (20 ml) was added. The CeCl3/THF solution was stirred at room temperature for 16 hours and then cooled to -40° C., and the Mg-Grignard reagent from 4-chloro-1-methyl-piperidine (3 ml of an 0.8M stock solution in THF) was added. The resulting solution was stirred at -40° C. for 75 minutes, and then 3-[(3-chlorophenyl)thiomethyl]-N-methoxy-N-methyl-2-pyridinecarboxamide (345 mg, 1.07 mmol) was added dropwise. After 40 minutes, the mixture was poured into 5% HCI/EtOAc, stirred for 5 minutes, and then basified to pH ~8. The organic product was extracted with EtOAc (6×100 ml), the extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The product was chromatographed on silica and eluted with 5-10%MeOH/CH2Cl2 to afford [3-[(3-chlorophenyl)thiomethyl]-2-pyridinyl][1-methyl-4-piperidinyl]methanone (251 mg, 64%); HRMS, FAB, calcd. 361.1141; found. 361.1141.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])=[CH:10][CH:9]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Cl:29][CH2:30][C:31]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:20])([F:21])[CH:17]([F:18])[F:19])=[CH:10][CH:9]=1)=[O:32]
Reactant: CCOC(=O)CNc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(=O)CCl)c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2.1 g of the resulting N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline, 1.1 ml of triethylamine and 50 ml of dichloromethane was added dropwise a solution of 0.6 ml of chloroacetyl chloride in 6 ml of dichloromethane with ice cooling and the resulting mixture was stirred at room temperature for five hours. To the reaction solution was added 50 ml of dichloromethane and 100 ml of ice water to factionate. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane (1:2 v/v!) to give 2.4 g of N-chloroacetyl-N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1.O.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:5]1[N:4]([CH2:11][CH2:12][OH:13])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Solvent: O
Product: O=[N+]([O-])c1c(Br)nn(CCO)c1NCc1ccccc1
Yield: 59 %

Procedure:
6.3 g (20 mmoles) 3,5-dibromo-1-(2'-hydroxyethyl)-4-nitropyrazole are heated in 20 ml benzylamine for 2 hours at 60° C. After cooling, the reaction mixture is poured on 50 ml of water, the separated product is filtered and recrystallized once from toluene/ligroine (1:1). 4 g (59 percent of theory) of 5-benzylamino-3-bromo-1-(2'-hydroxyethyl)-4-nitropyrazole are obtained in the form of yellow crystals with a melting point of 133° to 135° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:70][CH2:71][C:72]([NH2:74])=[O:73]>CN(C=O)C>[NH2:74][C:72](=[O:73])[CH2:71][NH:70][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=4[F:25])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:37][CH3:38])[N:9]=2)[CH:28]=1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NCC(N)=O
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: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(N)=O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and glycinamide (11.1 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 31%).