Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1.[CH3:15]C1C(C2C=CC=CN=2)=NC(C)=CC=1.CC1C(C2C=CC=CN=2)=NC=C(C)C=1.[CH2:43]([OH:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)P(=O)(N(C)C)N(C)C>[CH2:43]([OH:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[CH:1]([C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1)=[CH2:15]
Reactant: Cc1ccc(C)c(-c2ccccn2)n1
Reactant: Cc1cc(C)nc(-c2ccccn2)c1
Agent: Cc1cnc(-c2ccccn2)c(C)c1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: OCc1ccccc1
Product: C=Cc1cc(C)nc(-c2ccccn2)c1
Reaction time: 0.75 h
Yield: 61 %

Procedure:
500 g (2.75 mols) of a mixture of isomers, consisting of 4,6-dimethyl-2,2'-bipyridine (45% by weight), 3,6-dimethyl-2,2'-bipyridine (45% by weight) and 3,5-dimethyl-2,2'-bipyridine (10% by weight), are reacted in accordance with the procedure of Example 1(a). The crude product formed is heated under 133 to 400 Pa for 2 hours at 120° to 125° C. and then for 45 minutes at 170° C. (bath temperature). 299 g of a distillate are thus obtained which has a boiling range of 65°-107° C. and which is composed of 65% by weight of 3,6-dimethyl-2,2'-bipyridine, 7% by weight of 3,5-dimethyl-2,2'-bipyridine as well as 17% by weight of benzyl alcohol and 10% by weight of hexamethylphosphoric acid triamide. The residue is heated under 0.1 Pa and, in a boiling range of 48° -170° C., a mixture distils off which is subjected to a fractional redistillation after di-tert.-butyl-p-cresol has been added as a polymerisation inhibitor. Thus, 51 g of (4-(2-benxyloxy)-ethyl)-6-methyl-2,2'-bipyridine, 11 g of 3,6- and 3,5-dimethyl-2,2'-bipyridine, 105 g of benzyl alcohol and 147 g of 4-vinyl-6-methyl-2,2'-bipyridine (61% of theory) are obtained.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(C1C=CC=CC=1)(=O)CCCC.O1CCCC1>[CH2:11]([C:8]1([C:18]2[CH:17]=[CH:16][CH:21]=[CH:20][CH:19]=2)[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]1)[CH2:12][CH2:13][CH3:14]
Reactant: [Li]CCCC
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCC
Agent: CCCCC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC1(c2ccccc2)CC(O)=CC(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.7 mL of methyl acetoacetate, 1.1 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 5.1 mL of valerophenone and 125 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 10 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 124°-126° C.). 1H NMR (CDCl3) δ 0.85 (t, 3 H), 1.28 (m, 4 H), 1.97 (m, 2 H), 2.90 (dd, 2 H), 3.30 (dd, 2 H), 7.28-7.42 (m, 5 H).
Reaction SMILES: [P:1]([O-:6])([O:4]C)[O:2]C.O.[CH:8]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9]1>CO>[CH3:8][P:1](=[O:6])([O-:4])[O-:2].[CH:8]1([NH3+:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH:8]1([NH3+:13])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COP([O-])OC
Reactant: NC1CCCC1
Solvent: CO
Solvent: O
Product: CP(=O)([O-])[O-]
Product: [NH3+]C1CCCC1
Yield: 99 %

Procedure:
A mixture of 11 g. (0.1 moles) of dimethyl phosphite, 20 ml. of water and 20 ml. of methanol is reacted with a mixture of 8.51 g. (0.1 moles) of cyclopentyl amine and 30 ml. of methanol as described in Example 1. 18.0 g. of cyclopentyl ammoniummethyl phosphonate are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([NH:16][OH:17])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C.CN(C=O)C.C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([N:16]([OH:17])[C:25]([NH2:24])=[O:26])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ON[C@@H]1COc2cc(OCc3ccccc3)ccc21
Agent: C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)N(O)[C@@H]1COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a 5 L, 3-necked flask equipped with a mechanical stirrer, thermometer and condenser with CaCl2 drying tube was added under a N2 atmosphere (S)-N-[6-benzyloxy-2,3-dihydrobenzofuran-3-yl]hydroxylamine (129.0 g, 0.501 mol) in THF (2.6 L). The resulting mixture was stirred at room temperature for 0.5 h, at which time was added in one portion, trimethylsilylisocyanate (107.2 mL, 86.6 g, 0.752 mol). The mixture was then heated at reflux for 15 min, then was cooled to 5° C. with an ice bath. The precipitate which formed was collected by filtration to afford a white solid. A second crop of peach-colored solid was obtained from concentration of the filtrate. This was taken up in a minimum of DMF, heated and treated with Darco. Filtration and cooling afforded a white solid which was collected, dried and combined with the first crop. The combined solids were dissolved in EtOH (20 vol), heated to reflux, cooled, collected and dried to afford the title compound (105.4 g, 70.2%); m.p. 192.5°-193° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[N:12][C:13]([CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1.[OH-].[Li+]>O1CCCC1.O>[C:23]([Si:20]([CH3:22])([CH3:21])[O:19][CH:17]([C:13]1[N:12]=[CH:11][C:10]2[C:15](=[CH:16][C:7](/[CH:6]=[CH:5]/[C:4]([CH3:28])([CH3:27])[C:3]([OH:29])=[O:2])=[CH:8][CH:9]=2)[N:14]=1)[CH3:18])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)C(C)(C)/C=C/c1ccc2cnc(C(C)O[Si](C)(C)C(C)(C)C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc2ccc(/C=C/C(C)(C)C(=O)O)cc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
A solution of (E)-4-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-quinazolin-7-yl}-2,2-dimethyl-but-3-enoic acid methyl ester (1.07 g, 2.58 mmol) in tetrahydrofuran (50 mL) was cooled to 0° C. before adding an aqueous solution of lithium hydroxide (1 M, 8 mL, 8 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 20 h. The reaction mixture was diluted with water (50 mL) then washed with diethyl ether (60 mL) before acidifying to pH 2 with a saturated solution of potassium bisulfate. The resulting mixture was extracted with diethyl ether (3×30 mL). The extract was dried over anhydrous sodium sulfate, filtered and evaporated to yield the title product (0.605 g, 59%) as a yellow gum. 1H NMR (300 MHz, CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.53 (s, 6H), 1.64 (d, J=6.5 Hz, 3H), 5.22 (q, J=6.5 Hz, 1H), 6.64-6.81 (m, 2H), 7.73, 7.87 (ABq, J=8.5 Hz, 2H), 7.99 (s, 1H), 9.40 (s, 1H). LCMS (m/z) 401.2 [M+H], Tr=3.43 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH:8]([CH2:10][CH3:11])[CH3:9])=[CH:4][CH:3]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]([CH2:10][CH3:11])[CH3:9])[C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:22])=[CH:12][CH:13]=1
Reactant: CCC(C)NCc1ccc(Cl)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Product: CCC(C)N(Cc1ccc(Cl)cc1)C(=O)Nc1ccccc1
Yield: 92.6 %

Procedure:
30 g (0.15 mole) of N-(4-chlorobenzyl)N-sec.-butylamine were dissolved in 500 ml of ether. To the resulting solution, a solution of 18 g (0.15 mole) of phenyl isocyanate in 50 ml of ether was added dropwise, under cooling and stirring. After the dropwise addition, the temperature of the solution was gradually raised, and the solution was then stirred at room temperature for about 10 hours. The crystals which had been formed were separated by filtration. After recrystallization with a solvent mixture of hexane and ethyl alcohol, 44 g of N-(4-chlorobenzyl)-N-sec.-butyl-N'-phenylurea were obtained. Yield: 93%. Melting point: 80°-81.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15])=[CH:4][CH:3]=1.CS[C:25]([NH:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH:36]=1)=[CH:26][N+:27]([O-:29])=[O:28].C(OCC)(=O)C.CO>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:25]([NH:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:36]=2)=[CH:26][N+:27]([O-:29])=[O:28])[CH3:16])=[CH:4][CH:3]=1
Reactant: CN(CCCN)CCC(c1ccc(F)cc1)c1ccccn1
Reactant: CSC(=C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCNC(=C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
A mixture of 0.74 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and an equimolar amount of 1-methylthio-1-[3-[3-(piperidinomethyl)phenoxy]propyl]amino-2-nitro-ethene is heated under reflux for 12 hours in 20 ml of acetonitrile. The batch is then freed from solvent and the title compound is isolated in the form of a viscous oil by means of preparative thick-layer chromatography (eluant: ethyl acetate/methanol 9+1, ammoniacal atmosphere); MS (+FAB method): m/z (rel. int.[%])=619 ([M+H]+ 2), 214 (100). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 102° C. with decomposition.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.C(N(C(C)C)C(C)C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].Cl>C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=3[N:6]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1ccc2oc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(C#N)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of 2-chloro-benzooxazole-5-carbonitrile (5.0 g, 28.0 mmol, 1.0 equiv; prepared as described in A. Batista-Parra, S. Venkitachalam, W. D. Wilson, D. W. Boykin Heterocycles 2003, 60, 1367-1376) in acetonitrile (65 mL) was added N-ethyl diisopropylamine (36.0 mL, 27.1 g, 210.0 mmol, 7.5 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.61 g, 28.0 mmol, 1.0 equiv). The reaction mixture was stirred at rt for 18 h under Ar, poured on crashed ice and the pH adjusted by addition of a solution of 37% HCl to pH 3.0. The reaction mixture was extracted with ethyl acetate (3×100 mL), the combined organic phases washed with water and dried over MgSO4. The organic solvent was evaporated under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with a gradient of dichloromethane/methanol (100:0→95:5) to give 7.31 g (76%) of the title compound. MS (ESI): 343.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[OH-].[Na+].[CH3:15]I.CN(C)[CH:19]=[O:20]>O>[CH3:15][O:8][C:9]1[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]=1/[CH:5]=[CH:6]\[C:7]([O:20][CH3:19])=[O:12]
Reactant: Cc1ccc2oc(=O)ccc2c1
Reactant: CN(C)C=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)/C=C\c1cc(C)ccc1OC
Reaction time: 0.25 h

Procedure:
A stirred solution of 6.0 g (37.46 mmol) of 6-methylcoumarin in 100 ml of dimethylformamide was treated with 3.29 g (82.41 mmol) of sodium hydroxide in 10 ml of water. After 15 minutes, 26.6 g (187.3 mmol) of methyl iodide was added. After an additional 6 hours, ether extraction provided the title compound as an oil. NMR in CDCl3 (δ units): 2.28 (singlet, 3); 3.66 (singlet, 3); 3.79 (singlet, 3); 5.97 and 7.13 (doublet, J=12 Hz, 1); 6.76 (doublet, J=8 Hz, 1); 7.09 (broad doublet, 1); 7.35 (broad singlet, 1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:27](=O)[CH2:28][CH2:29][CH2:30][CH3:31])[C:23](OC)=[O:24])=[CH:17][CH:16]=1)#[N:8]>ClC1C=CC(Cl)=CC=1Cl>[CH2:28]([C:27]1[N:2]2[N:1]=[CH:5][N:4]=[C:3]2[NH:6][C:23](=[O:24])[C:22]=1[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[C:9]([C:7]#[N:8])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][CH:19]=1)[CH2:29][CH2:30][CH3:31]
Reactant: Nc1nc[nH]n1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Yield: 52.6 %

Procedure:
A solution of 1H-1,2,4-triazol-3-amine (1.5 g) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (7.1 g) in 1,2,4-trichlorobenzene (70 mL) was stirred at 190° C. for 6 hr. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the obtained residue. The precipitated solid was collected by filtration to give the title compound as a colorless solid (3.6 g, 44%).
Reaction SMILES: IC.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[OH:14].[C:15](=O)([O-])[O-].[K+].[K+].N>O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:15])[CH:9]=[CH:8][C:7]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccnc2ccc(F)cc12
Agent: N
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ccc(=O)c2cc(F)ccc21
Reaction time: 18 h

Procedure:
Iodomethane (6.9 ml) was added to a stirred suspension of 6-fluoro-4-hydroxyquinoline (16.3 g) and anhydrous potassium carbonate (15.2 g) in dry tetrahydrofuran (100 ml) at ambient temperature and stirring was continued for 18 hours. More iodomethane (1.8 ml) and anhydrous potassium carbonate (3.8 g) were added and stirring was continued for 4 hours at ambient temperature. Concentrated aqueous ammonia (specific gravity 0.88; 100 ml) was added and the mixture was evaporated to dryness. The residue was treated with water (200 ml) and extracted with dichloromethane (2×400 ml). The extract was dried and evaporated to dryness. The residue was crystallised from ethyl acetate to give the novel compound 6-fluoro-1-methyl-4-quinolone, m.p. 88°-89°.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:1]([N:14]1[CH2:13][CH:12]=[C:11]([CH2:10][OH:9])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: OCC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
10.7 ml (0.0901 mol) of benzyl bromide were added to a solution of 8.9 g (0.0815 mol) of 4-hydroxymethylpyridine in 30 ml of dimethylformamide and the mixture was stirred at 100° for 2 hours. Subsequently, the reaction mixture was cooled to room temperature, diluted with 111 ml of ethanol and treated portion-wise with 3.9 g (0.103 mol) of NaBH4. The mixture was boiled under reflux for 3 hours and stirred at room temperature for a further 18 hours. Then, the solvent was distilled off, the residue was partitioned between dichloromethane/water, extracted and dried. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1 as the eluent. 9.26 g (56%) of (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol were obtained as yellow crystals; m.p. 57°-60°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:12]C2=O)[CH3:9])=[CH:4][CH:3]=1.S([C:37]#[N:38])(C1C=CC(C)=CC=1)(=O)=O.C(OO)(C)(C)C.C1([SiH3])C=CC=CC=1.C[CH2:53][OH:54]>[Co]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:24])([CH3:25])[C:37]#[N:38])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:12][C:53]2=[O:54])[CH3:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCO
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Agent: [Co]
Agent: CC(C)(C)OO
Agent: [SiH3]c1ccccc1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.5 %

Procedure:
Cobalt catalyst 1 (1.32 mg, 0.002 mmol, 1 mol %) was dissolved in EtOH (8 mL; absolute) at rt under argon, (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenyltetrahydropyrimidin-2(1H)-one (82.6 mg, 0.2 mmol), TsCN (54 mg, 0.3 mmol), tBuOOH (6 mg, 0.06 mmol), and PhSiH3 (21.6 mg, 0.2 mmol) were added. The resulting solution was stirred at rt for 3 h. The solvent was removed by evaporation, and the residue was purified by prep HPLC to afford 3-((R)-1-((S)-1-(4-bromophenyl)ethyl)-2-oxo-4-phenylhexahydropyrimidin-4-yl)-2,2-dimethylpropanenitrile (4 mg, 4.5%) as a white solid. 1H NMR (CD3OD): δ 1.24 (s, 3H), 1.36 (s, 3H), 1.47-1.48 (m, 3H), 2.04-2.07 (m, 2H), 2.07 (m, 1H), 2.22-2.26 (m, 2H), 2.98-3.02 (m, 1H), 5.65-5.67 (m, 1H), 6.95-6.97 (m, 1H), 7.25-7.30 (m, 3H), 7.33-7.37 (m, 4H).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.CO.[CH3:31][S-:32].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:31][S:32][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1)[C:12]#[N:13]
Reactant: C[S-]
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CSC(C#N)c1cccc(C(=O)c2ccccc2)c1
Yield: 80 %

Procedure:
979 mg of O-(p-toluenesulfonyl)-m-benzoylmandelonitrile was dissolved in 2 ml of DMF, and the mixture was stirred in an argon atmosphere under ice cooling. Then, 1.08 ml of a 2.3 M methanol solution of sodium methanethiolate was added dropwise to the solution over 5 minutes, and the mixture was further stirred under ice cooling. An aqueous solution of ammonium chloride (0.2 g/30 ml) was added, and the mixture was extracted with methylene chloride. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was separated by column chromatography (silica gel; methylene chloride) to afford 533 mg (yield 80%) of alpha-(methylthio)(m-benzoylphenyl)acetonitrile as a pale orange oil.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[CH:5][N:4]([CH:10]([CH3:12])[CH3:11])[N:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:8][C:7]([C:6]1[C:2]([I:1])=[N:3][N:4]([CH:10]([CH3:12])[CH3:11])[CH:5]=1)=[O:9]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cn(C(C)C)nc1I
Product: CC(C)n1cc(C(=O)C=CN(C)C)c(I)n1
Temperature: 155 °C

Procedure:
A mixture of Intermediate 1-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)ethanone (5.0 g, 18.0 mmol) and N,N-dimethyformamide dimethyl acetal (50 mL) was heated at 155° C. for 20 h. The mixture was concentrated under vacuum to provide the crude title compound. MS m/z 334.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[NH2:20][C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:20][C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Product: CC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and methyl (S)-2-aminobutanoate hydrochloride (prepared from (S)-(+)-2-aminobutyric acid (Aldrich) using General Procedure H), the title compound was prepared as a solid (mp=154-157° C.).
Reaction SMILES: CS(C)=O.[CH3:5][NH:6][C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17](F)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13].[CH2:36](N(CC)CC)C>[Cl-].[Na+].O>[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17]([N:9]2[CH2:10][CH2:11][C@@H:7]([N:6]([CH3:36])[CH3:5])[CH2:8]2)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13]
Reactant: CCN(CC)CC
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN[C@@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@@H](N(C)C)C2)c2oc(C(=O)N(C)C)nc2c1C#N
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution of (3R)-3-methylaminopyrrolidine (85 μl, 660 μmol) was added at 150° C. to a dimethyl sulfoxide (11 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (180 mg, 557 μmol) and triethylamine (101 μl, 724 μmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with chloroform. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (53 mg, 23%) as a white amorphous substance.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1)=[O:5])#[N:2].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2.C(OCC)(=O)C>COCCOCCO.O>[F:14][C:9]1[CH:8]=[C:7]([N:6]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: N#CCC(=O)Nc1cc(F)cc(F)c1
Reactant: CO/C=C/C(C)=O
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: COCCOCCO
Solvent: O
Product: Cc1ccc(C#N)c(=O)n1-c1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
A solution (30 mL) of 2-cyano-N-(3,5-difluorophenyl)acetamide (3.10 g, 16.0 mmol), (3E)-4-methoxybut-3-en-2-one (2.40 g, 24.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (2.70 g, 24.0 mmol) in 2-(2-methoxyethoxy)ethanol was stirred at 130° C. for 12 hr. After cooling to room temperature, the reaction solution was divided into two layers with ethyl acetate and water and subjected to extraction (3 times) with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (1.60 g, 40%) as a brown solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C=O)C>[C:18]([O:11][CH2:10][CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[CH:3])[CH2:5][CH2:6]1)(=[O:20])[CH3:19]
Reactant: C#CCC1CCC(CO)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#CCC1CCC(COC(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 960 mg (6.31 mmol) of 86 in 6 mL DMF was added 0.62 mL (7.57 mmol) pyridine and 0.78 mL (8.27mmol) acetic anhydride. The reaction was allowed to stir overnight at room temperature. After 16 hours, starting material still remained. The reaction mixture was heated at 75° C. for 3 hours. The solvent was removed under reduced pressure to yield a yellow oil which was purified by flash chromatography, on silica gel, eluting with 1:3 ether/petroleum ether to yield 1.12 g (91%) of 87 as an oil. 1H NMR (CDCl3) δ 3.87 (d, J=6.2Hz, 2H), 2.06 (d, J=4.3 Hz, 2H), 2.03 (s, 3H), 1.98–1.93 (m, 1H), 1.92–1.83 (m, 2H), 1.83–1.74 (m, 2H), 1.63–1.36 (m, 2H), 1.12–0.90 (m, 4H); 13C NMR (CDCl3) δ 171.7, 83.7, 69.9, 69.6, 37.4, 37.3, 32.1, 29.7, 26.5, 21.4; APCI m/z (rel intensity) 195 (M+, 30), 153 (M+, 70), 135 (M+, 100).