Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:14])C.C(C1C=CC=CC=1O)CCC>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([OH:14])[C:8](=[CH:7][CH:6]=1)[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OO
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: CCCCc1ccccc1O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(O)c(O)c1
Yield: 77 %

Procedure:
After the manner of the procedure of Comparative Example 1, the reaction was carried out by using 20 ml of ethyl acetate as a solvent for para-tert.-butyl phenol and 0.5% by weight of Na5R'5 (P3O10)2 (R' = 2-ethylhexyl, tradename "Victor Wet 35B") as a peracetic acid stabilizer based on the amount of butyl phenol used. Consequently, the conversion of parta-tert.-butyl phenol was 7.2%, 4-tert.-butyl pyrocatechol was formed in a yield of 77% based on the converted butyl phenol and the conversion of peracetic acid was 98.5%.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Benzoyl chloride (0.295 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 17 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.308 g, 91%). 1H NMR (Acetone d6, 400 MHz) δ 8.21-8.14 (m, 2 H), 8.03 (d, J=9 Hz, 2 H), 7.96 (d, J=9 Hz, 1 H), 7.81 (t, J=8 Hz, 1 H), 7.65-7.59 (m, 2 H), 7.55-7.49 (m, 2 H), 7.01 (d, J=9 Hz, 1 H), 5.94-5.85 (m, 1 H), 5.64 (dd, J=9 and 6 Hz, 1H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.34 (s, 3 H), 1.62 (d, J=6 Hz, 3 H).
Reaction SMILES: [N:1]1([C:10](=O)[CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@@H:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22]N=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:27]1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][O:19][C:20]3[CH:27]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(CN1CCO[C@@H](COc2ccccn2)C1)N1CCc2ccccc21
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(OC[C@@H]2CN(CCN3CCc4ccccc43)CCO2)cc1
Yield: 41.4 %

Procedure:
Compound 19s was synthesised by essentially the same procedure as compound 18s (Example 16), using compound 51 (Example 12; 52 mg, 0.2 mmol), phenol (28 mg, 0.3 mmol), triphenylphosphine (78 mg, 0.3 mmol), DEAD (0.05 ml, 0.3 mmol), THF (1 ml). The crude residue was purified twice by flash chromatography to afford the title compound as a colourless oil (28 mg; 41%). Analyses were performed on the free base, and it was converted to the HCl salt for testing.
Reaction SMILES: [H-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:24][OH:25])([S:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26]I>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]([CH2:24][O:25][CH3:26])([S:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(SC2(CO)CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: CI
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1(Sc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of potassium hydride (0.18 g, dry weight, 4.5 mmol; obtained from washing 0.52 g of 35% potassium hydride dispersion in mineral oil with hexanes and drying under a stream of argon) in anhydrous THF (25 mL), N-tert-butoxycarbonyl-4-(3-tolylsulfanyl)-4-hydroxymethylpiperidine (0.96 g, 2.8 mmol; Example 106, Step B) in THF (5 mL) was added. The resultant mixture was stirred at room temp. for 1 h., and treated with methyl iodide (0.31 mL, 4.97 mmol). The reacting mixture was stirred at room temp. overnight. The product mixture was cooled to 0° C., quenched with water, and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([SH:27])[N:3]=1.Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH:39][CH3:40])=[O:38])[CH:32]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:27][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH:39][CH3:40])=[O:38])[CH:32]=2)[C:5]([C:25]#[N:26])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21][C:20]([CH3:23])([CH3:24])[O:19]3)=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1cc(CCl)ccn1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(OC[C@H]4COC(C)(C)O4)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
450 mg (1.178 mmol) of 2-amino-4-(4-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}phenyl)-6-mercaptopyridine-3,5-dicarbonitrile (Example 18A), 286 mg (1.29 mmol) of 4-(chloromethyl)-N-methylpyridine-2-carboxamide hydrochloride (Example 41A) and 395 mg (4.71 mmol) of sodium bicarbonate were dissolved in 7.1 ml of DMF and the mixture was stirred at RT for 1.5 h. Water was added to the reaction mixture. The precipitate was filtered off and washed with water.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:15]2[C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Cl[C:48](=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:48](=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]([CH2:26][NH:27][C:28]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:34])=[C:15]2[C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(NCCNC(=O)OC(C)(C)C)cc23)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)N(CCNC(=O)OC(C)(C)C)c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To a solution of tert-butyl [6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.50 g, 0.89 mmol) in ethyl acetate (50 ml) was added saturated aqueous sodium hydrogen carbonate (50 ml), and the mixture was vigorously stirred at room temperature. Ethyl chloroglyoxylate (0.30 g, 2.2 mmol) was added dropwise to the obtained mixture and the mixture was vigorously stirred for 30 min. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl {{2-[(tert-butoxycarbonyl)amino]ethyl}[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]amino}(oxo)acetate (0.53 g, yield 90%) as a white powder.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][C@@H:15]([C:17]2[CH:28]=[CH:27][C:20]3[O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24][C:19]=3[CH:18]=2)[O:14][C:13]1=[O:29])[CH2:2][C:3]#[CH:4].Br[C:31]1[CH:32]=[C:33]([S:37]([N:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>N1CCCC1>[CH3:26][C:22]1([CH3:25])[O:21][C:20]2[CH:27]=[CH:28][C:17]([C@H:15]3[O:14][C:13](=[O:29])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][C:3]#[C:4][C:35]4[CH:34]=[C:33]([S:37]([N:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])[CH:32]=[CH:31][CH:36]=4)[CH2:16]3)=[CH:18][C:19]=2[CH2:24][O:23]1
Reactant: CN(C)S(=O)(=O)c1cccc(Br)c1
Reactant: C#CCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Solvent: C1CCNC1
Product: CN(C)S(=O)(=O)c1cccc(C#CCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Reaction time: 0.75 h
Yield: 61.7 %

Procedure:
A mixture of (5R)-3-[6-(but-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.256 g) and 3-bromo-N,N-dimethylbenzene sulphonamide (0.208 g) in pyrrolidine (4 ml) was degassed using vacuum/nitrogen cycle. Cuprous iodide (0.005 g) and dichlorobis(triphenylphosphine)palladium (0.037 g) were added and the mixture was stirred at 80° for 45 min under nitrogen. The mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc and the combined organic phases washed with brine, dried (Na2SO4) and evaporated to dryness. The residue was dissolved in CH2Cl2 and applied to a silica Bond Elut Cartridge (10 g). The cartridge was eluted with CH2Cl2, cyclohexane/Et2O, Et2O and EtOAc. Evaporation of the ether fractions gave an oil which was repurified by silica Bond Elut to give the title compound (0.23 g), ES+ve 585 (MH)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.C(N(CC)CC)C.[C:32]([O:36][C:37](=[O:49])[N:38]([CH2:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([CH:47]=O)[CH2:43][CH2:42]1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([O:36][C:37](=[O:49])[N:38]([CH2:40][C@H:41]1[CH2:42][CH2:43][C@H:44]([CH:47]=[C:21]([Br:24])[Br:20])[CH2:45][CH2:46]1)[CH3:39])([CH3:35])([CH3:33])[CH3:34]
Reactant: BrC(Br)(Br)Br
Reactant: CN(C[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C[C@H]1CC[C@H](C=C(Br)Br)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 257.6 g (982 mmol) triphenylphosphine in 1 l CH2Cl2 was treated with 162.8 g (491 mmol) tetrabromomethane (the reaction heated up to reflux and was then cooled with an ice bath) and after 40 min at RT with 157.4 ml (1129 mmol) triethylamine (the reaction heated up to reflux and became dark violet). After cooling (0° C.), 77.96 g (corresponds to 245.5 mmol) of crude trans-(4-Formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester in 600 ml CH2Cl2 were added during 20 min. The solution was stirred for 20 h at RT, evaporated and filtered through silica gel (deactivated with hexane/0.5% Et3N) with hexane/Et2O 99:1 to 4:1 as eluent to yield 61.5 g (61%) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester, MS: 409 (M, 2Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]2([CH2:17][OH:18])[CH2:16][CH2:15]2)=[N:11][C:10]=1[C:19]1[N:24]=[C:23]2[O:25][C:26]([NH:28][C@@H:29]([CH3:34])[CH2:30][O:31][CH2:32][CH3:33])=[N:27][C:22]2=[CH:21][CH:20]=1.[CH3:35][S:36](O)(=[O:38])=[O:37]>ClCCl.CO.CO>[CH3:35][S:36]([O:18][CH2:17][C:14]1([C:12]2[NH:13][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[C:10]([C:19]3[N:24]=[C:23]4[O:25][C:26]([NH:28][C@@H:29]([CH3:34])[CH2:30][O:31][CH2:32][CH3:33])=[N:27][C:22]4=[CH:21][CH:20]=3)[N:11]=2)[CH2:15][CH2:16]1)(=[O:38])=[O:37]
Reactant: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(CO)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Reactant: CS(=O)(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(COS(C)(=O)=O)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
[1-[5-(2,4-Difluorophenyl)-4-[2-[[(1S)-2-ethoxy-1-methyl-ethyl]amino]oxazolo[5,4-b]pyridin-5-yl]-1H-imidazol-2-yl]cyclopropyl]methanol (0.56 g, 1.19 mmol) is dissolved in a 1:1 mixture of dichloromethane/methanol (12 mL total). A 0.5 M solution of methanesulfonic acid in methanol (2.37 mL) is added dropwise to the solution. The mixture is stirred at RT for 30 min and then the solvent is evaporated under reduced pressure. The residue is mixed with methanol and concentrated twice to afford the title compound (0.64 g, 96%). LC-ES/MS m/z 470.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2([OH:21])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:23][C:24](=[O:47])[C@@H:25]([C@H:44]([CH3:46])O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[C:1]1([C:7]2([O:21][C@@H:44]([CH3:46])[C@H:25]([C:24]([OH:47])=[O:23])[NH2:26])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)c2ccccc2Oc2ccccc21
Reactant: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C)O
Product: C[C@H](OC1(c2ccccc2)c2ccccc2Oc2ccccc21)[C@@H](N)C(=O)O

Procedure:
from 9-phenyl-9H-xanthen-9-ol (Example 1f) and Nα -(9-fluorenylmethoxycarbonyl)-D-threonine methyl ester;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([OH:27])[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([OH:27])[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: N#Cc1cc(O)c2ccn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cc(O)c2ccn(-c3ccc(O)c(F)c3)c2c1
Yield: 73.3 %

Procedure:
A solution of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-hydroxy-1H-indole-6-carbonitrile (D14) (320 mg, 0.89 mmol) in ethanol (25 mL) and ethyl acetate (5 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated and the product purified by silica gel chromatography eluting with 2-60% ethyl acetate in hexane to yield the title compound (E8), (175 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>FC(C1C=CC=CC=1)(F)F>[Br:12][CH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][N:3]=1
Reactant: Cc1cnc(C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: FC(F)(F)c1cnc(CBr)cn1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
To a solution of 2-methyl-5-(trifluoromethyl)pyrazine (1 g) in trifluoromethylbenzene (10 ml) was added N-bromosuccinimide (1.21 g) at room temperature, and the mixture to was stirred at 90° C. for 30 min. To the obtained reaction mixture was added azobisisobutyronitrile (0.051 g), and the mixture was stirred at the same temperature for 7 hr. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (404 mg).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: OCC=Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCC=Cc1ccccc1

Procedure:
1.26 ml (10.0 mmol) of methyl 3-oxovalerate, 2.57 ml (20.0 mmol) of cinnamyl alcohol and 122 mg (1.0 mmol) of 4-dimethylaminopyridine were heated under reflux in 20 ml of toluene overnight. A phosphate buffer solution was added to the reaction liquid. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous salt solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:50](=[O:51])[CH2:49][O:48][CH3:47])=[CH:42][CH:41]=2)=[N:17]1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 9 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.302 g, 0.50 mmol) in tetrahydrofuran (4.5 mL) was added methoxyacetyl chloride (0.07 mL, 0.75 mmol) and triethylamine (0.35 mL, 2.52 mmol). The final crude product was purified by preparative HPLC (5–100% acetonitrile to H2O, 30 min.) (0.015 g, 9% yield): 1H NMR (CD3OD) δ 8.75 (d, 1H), 8.40 (s, 1H), 8.10 (dd, 1H), 8.02 (d, 2H), 7.83 (d, 2H), 7.68 (dd, 1H), 4.09 (s, 2H), 3.52 (s, 3H); ES-MS (m/z) 349 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[N:11]([C:28](=[O:29])[NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2n[nH]c(-c3ccccc3C)n2)c1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: COc1cccc(-c2nc(-c3ccccc3C)n(C(=O)Nc3ccccc3)n2)c1
Reaction time: 8 h

Procedure:
A solution of 0.53 g (0.002 mole) of 3-(3-methoxyphenyl)-5-(2-methylphenyl)-1H-1,2,4-triazole and 0.22 ml. (0.002 mole) of phenylisocyanate in 5 ml of acetonitrile was strred for 7 hours at room temperature and, subsequently, it was left standing overnight. The solvent was evaporated off and the obtained residue was first taken up with hexane, then, after separating the liquid and the solid phase by decantation, it was recrystallized from acetonitrile. Yield: 0.25 g of the title compound. M.p. 123°-125° C. Δδ=-0.18.
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.Cl.C(O[CH:25](OCC)[CH2:26][NH:27][C:28]#[N:29])C>COCCOC.O>[NH:29]1[CH:25]=[CH:26][N:27]=[C:28]1[NH:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12
Reactant: CCOC(CNC#N)OCC
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3c[nH]nn3)CS[C@H]12
Agent: Cl
Solvent: O
Solvent: COCCOC
Product: O=C(O)C1=C(CSc2c[nH]nn2)CS[C@@H]2C(Nc3ncc[nH]3)C(=O)N12
Temperature: 51 °C
Yield: 10 %

Procedure:
To a suspension of 7-amino-3 (1H-1,2,3-triazol-4-yl)thiomethylceph-3-em-4-carboxylic acid (31.3 g., 0.1 moles) in a mixture of 1,2-dimethyoxyethane (250 ml.) and concentrated HCl (12 ml., 0.138 moles) in water (50 ml.) was added 2,2-diethoxyethylcyanamide (52.05 g., 0.3 moles). The mixture was stirred and heated at 51° C. for 4 hours and the resulting solution was evaporated under reduced pressure to remove the 1,2-dimethoxyethane. The residual oil was diluted with water (250 ml.), the pH of the resulting suspension was adjusted to 4.8 using sodium bicarbonate and then filtered. The filtrate was applied to a column of "Amberlite" XAD-2 (500 ml.) ("Amberlite" is a Trade Mark). The resin was first washed with water (2000 ml.) and then eluted with 40% v/v aqueous methanol. The required fractions were combined and evaporated to dryness to give 7-(imidazol-2-yl)amino-3-(1H-1,2,3-triazol-4-yl)thiomethylceph-3-em-4-carboxylic acid (3.79 g., 10%) having an n.m.r. spectrum identical to the product of Example 5.
Reaction SMILES: C(N)CC.CN.[ClH:7].[Cl:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]2[C:10]=1[C:11](=[O:27])[N:12]([CH2:24][CH2:25][CH3:26])[C:13]([CH2:21]NC)=[N:14]2>>[Cl:7][CH2:21][C:13]1[N:12]([CH2:24][CH2:25][CH3:26])[C:11](=[O:27])[C:10]2[C:15](=[C:16]([OH:20])[C:17]([Cl:19])=[CH:18][C:9]=2[Cl:8])[N:14]=1
Reactant: Cl
Reactant: CCCn1c(CNC)nc2c(O)c(Cl)cc(Cl)c2c1=O
Agent: CN
Solvent: CCCN
Product: CCCn1c(CCl)nc2c(O)c(Cl)cc(Cl)c2c1=O

Procedure:
Other 2,3-disubstituted-3H-quinazolin-4-ones (4-9B-4-9E) prepared via substitution of n-propylamine (Step 1) and methylamine (Step 3) in Example 3 for the appropriate amine(s) are given in Table 6.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Fc1ccc(-c2cnc(Cl)nc2)cc1

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (500 mg, 2 mmol), 4-fluorophenylboronic acid (430 mg, 3.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (1:1) (210 mg, 0.26 mmol) and potassium carbonate (1.8 g, 13 mmol) in 1,4-dioxane (6 mL) was irradiated under microwave at 120° C. for 30 min. After cooling, the solvent was evaporated. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes to give the desired product. (376 mg) LCMS: (M+H)=209.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.[Li]CCCC.C[O:17][B:18](OC)[O:19]C>C1COCC1>[CH2:8]([C:4]1[CH:3]=[C:2]([B:18]([OH:19])[OH:17])[CH:7]=[CH:6][CH:5]=1)[CH2:9][CH3:10]
Reactant: CCCc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
To a solution of Intermediate 214.1 (130 mg, 0.65 mmol) in 4 mL THF at −78° C., was added BuLi (1.4 M in hexanes, 0.557 mL, 0.78 mmol). The mixture was stirred 5 min at −78° C., then trimethylborate (0.109 mL, 0.975 mmol) was added. The reaction was stirred at −78° C. for 10 min, then was removed from the cooling bath and stirred 1 h. The reaction was quenched with 1 N HCl, then was diluted with EtOAc. The organic phase was washed with 1N HCl and brine, dried (Na2SO4) and concentrated to afford 83 mg of Intermediate 214.2 as a colorless oil, which was used without further purification in the following step.