Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH3:6].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(OCC)C>[F:3][C:4]([F:14])([F:15])[C:5]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([O:7][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)(c1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC(C)(c2ccccc2)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 49.9 %

Procedure:
0.9 g (30 mmol) of sodium hydride (80% strength dispersion in mineral oil) was added to 5 g (26 mmol) of 1,1,1-trifluoro-2-phenylpropan-2-ol in 125 ml of diethyl ether at room temperature. The mixture was stirred for about 1 hour, and 4.75 g (25 mmol) of toluene-4-sulfonyl chloride were then added in portions. Stirring was carried out for 60 hours at room temperature, after which the undissolved constituents were filtered off and the solution was then cooled. 4.3 g of 1,1,1-trifluoro-2-phenyl-2-(toluene-4-sulfonyloxy)-propane were obtained (colorless crystals, m.p.: 102° C. [recrystallized from diethyl ether]). After the mother liquor had been evaporated down, a further 1.6 g of the desired compound could be isolated.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH3:13])[N:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:17][CH:14]([CH3:16])[CH3:15])[N:3]=[C:4]([NH:11][CH2:12][CH3:13])[N:5]=1
Reactant: CCNc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CC(C)N
Solvent: CC(C)=O
Product: CCNc1nc(Cl)c(C#N)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a stirred solution of 6.5 grams of 4,6-dichloro-2-ethylamino-5-pyrimidinecarbonitrile in 100 ml of acetone was added dropwise 7.4 grams of isopropylamine in 30 ml of acetone. Upon complete addition, the reaction mixture was stirred at room temperature for 16 hours. The acetone was removed by evaporation under reduced pressure, and the solid residue was washed with water. The resultant solid was collected by filtration to give 6.8 grams of 4-chloro-2-ethylamino-6-isopropylamino-5-pyrimidinecarbonitrile; mp 160°-165°. Recrystallization from a mixture of benzene and methylcyclohexane gave purified product; mp, 163°-165°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37]([OH:39])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40][O:41][CH2:42][C@H:43]1[CH2:47][CH2:46][CH2:45][NH:44]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]2[CH2:11][C@@H:10]([C:37]([N:44]3[CH2:45][CH2:46][CH2:47][C@@H:43]3[CH2:42][O:41][CH3:40])=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: COC[C@H]1CCCN1
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2COC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (102 mg), (2R)-2-(methoxymethyl)pyrrolidine (64 mg), HOBt (20 mg) and triethylamine (104 μl) were dissolved in DMF (5 ml), WSC.HCl (107 mg) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:0) was concentrated under reduced pressure to give the object compound (91 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].O[CH2:8][C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.C(OCC)(=O)C>ClCCl.O>[Cl:2][CH2:8][C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)C1=Cc2cccc(CO)c2OCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)C1=Cc2cccc(CCl)c2OCC1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Under nitrogen atmosphere, phosphorus pentachloride (1.6 g) was added to a mixture of methyl 2,3-dihydro-9-hydroxymethyl-1-benzoxepin-4-carboxylate (1.2 g) and pyridine (0.62 ml) in dichloromethane (24 ml) under ice-cooling and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added a mixture of ethyl acetate and water. The separated organic layer was washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give methyl 2,3-dihydro-9-chloromethyl-1-benzoxepin-4-carboxylate (1.19 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl>[Br:13][CH2:12][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1CBr
Temperature: 80 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
A mixture of methyl 5-chloro-2-methylbenzoate (3.13 g, 17.0 mmol), N-bromosuccinimide (3.17 g, 17.8 mmol), benzoyl peroxide (0.41 g, 1.70 mmol), and carbon tetrachloride (80 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was diluted with dichloromethane (200 mL) and washed with saturated sodium hydrogen carbonate aqueous (150 mL), and brine (150 mL). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (60:1) to afford 1.13 g (25%) of the title compounds as colorless oil: 1H-NMR (CDCl3) δ 7.96 (1H, d, J=2.2 Hz), 7.46–7.40 (2H, m), 4.92 (2H, s), 3.96 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][N:6]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:5]3=[O:19])=[CH:23][CH:22]=1
Reactant: O=c1c2cc(Br)ccc2ncn1Cc1cccnc1
Reactant: Oc1ccc(Cl)cc1
Product: O=c1c2cc(Oc3ccc(Cl)cc3)ccc2ncn1Cc1cccnc1

Procedure:
The titled compound was prepared in the same manner as in Example 1 (1) c) from 6-bromo-3-(3-pyridylmethyl)-4 (3H)-quinazolinone and 4-chlorophenol.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[CH2:37]([O:36][C:34]([CH:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:35])[CH3:38]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=C(OCc1ccccc1)n1ccc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1cccc2c1ccn2C(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
The indole 11 (10.69 g, 40 mmol) was added to a suspension of anhydrous potassium carbonate (8.29 g, 60 mmol) in acetone (400 mL) and the mixture was stirred at room temperature for 15 min. Diethyl bromomalonate (11.47 g, 48 mmol) was added and the mixture was heated under reflux for 17 h. The solid was filtered off and washed with acetone and the combined filtrates were evaporated. The residue was dissolved in diethyl ether (150 mL), washed with 0.5 M aq. sodium hydroxide and brine, dried and evaporated to a brown viscous oil (16.87 g). After trituration with diethyl ether, the precipitated white solid was filtered off and the filtrate was evaporated. The residue was flash chromatographed [ethyl acetate-hexanes (15:85)] to give more solid and the combined solids were recrystallised to give 12 as white crystals (13.83 g, 81%), mp 77-78° C. (from ethyl acetate-hexanes); 1H NMR (500 MHz) δ 7.86-7.92 (br d, 1H), 7.57 (d, J=3.7 Hz, 1H), 7.47-7.49 (m, 2H), 7.36-7.43 (m, 3H), 7.20 (t, J=8.1 Hz, 1H), 6.86 (d, J=3.9 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 5.45 (s, 2H), 5.30 (s, 1H), 4.29-4.37 (m, 4H), 1.30 (t, J=7.1 Hz, 6H). Anal. Calcd for C23H23NO7: C, 64.93; H, 5.45; N, 3.29. Found: C, 65.06; H, 5.64; N, 3.21.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)[CH:2]=[CH2:3].[N:25]1C=[CH:29][CH:28]=[CH:27][C:26]=1CCN>>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([NH:4][CH2:1][CH2:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[N:6][C:7]([C:23]#[N:24])=[C:8]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Reactant: NCCc1ccccn1
Product: COc1ccc2c(NCCc3ccccn3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (2-pyridin-2-ylethyl)amine in place of allylamine and heating for 35 min instead of 1 h, the title compound was synthesized.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[Cl:28][C:29]1C=[CH:35][CH:34]=[CH:33][C:30]=1CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:35]=[CH:34][CH:33]=[CH:30][C:29]=3[Cl:28])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCc1ccccc1Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1Cl)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 90 h

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg of powdered potassium cyanide and 14.20 g (100 mmol) of 2-chlorobenzyl alcohol is stirred at 130° for 90 hours, the mixture is diluted with about 30 ml of methylene chloride and chromatographed on about 300 g of silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there is obtained o-chlorobenzyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 192°-193°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([O:10][CH2:11][C@@H:12]([OH:15])[CH2:13][OH:14])[CH3:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].O>O1CCCC1.CN(C)C1C=CN=CC=1>[C:22]([Si:26]([CH3:28])([CH3:27])[O:14][CH2:13][C@H:12]([OH:15])[CH2:11][O:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([CH3:16])[CH3:9])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(OC[C@@H](O)CO)c1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(OC[C@@H](O)CO[Si](C)(C)C(C)(C)C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of (S)-3-[1-(4-fluoro-phenyl)-1-methyl-ethoxy]-propane-1,2-diol (0.46 g) in tetrahydrofuran (6 ml) were added imidazole (0.32 g) and 4-dimethylaminopyridine (catalytic amount). The mixture was cooled to 0° C. and a solution of tert-butyl(chloro)dimethylsilane (0.32 g) in tetrahydrofuran (2 ml) was added dropwise. After 2 hours at 0° C., the reaction mixture was allowed to stir at room temperature for 16 hours. Water was added and the mixture was extracted twice with diethylether. The combined organic layers were dried (MgSO4) and evaporated. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 90:10->75:25) to give (R)-1-(tert-butyl-dimethyl-silanyloxy)-3-[1-(4-fluorophenyl)-1-methyl-ethoxy]-propan-2-ol (0.57 g, 83%) as a colorless liquid. 1H NMR (300 MHz, CDCl3, δ): 0.00 (s, 6H), 0.82 (s, 9H), 1.48 (s, 6H), 2.49 (bs, 1H), 3.15 (d, J=4 Hz, 2H), 3.56 (t, J=4 Hz, 2H), 3.68 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[C:12]#N.[H-].C([Al+]CC(C)C)C(C)C.C(C1C([O:34]C)=NC(C)=CC=1)#N>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH:12]=[O:34]
Reactant: COc1nc(C)ccc1C#N
Reactant: Cc1nc(Cl)c(C#N)c2c1CCCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1nc(Cl)c(C=O)c2c1CCCC2

Procedure:
3-Chloro-1-methyl-5,6,7,8-tetrahydroisoquinoline-4-carboxaldehyde was prepared from 3-chloro-4-cyano-methyl-5,6,7,8-tetrahydroisoquinoline by reduction with diisobutylaluminium hydride following essentially the same procedure as that described in J. Org. chem., 1980, 45, 1354 for the reduction of 3-cyano-2-methoxy-6-methylpyridine. Pmr spectrum (CDCl3 ; δ in ppm): 1.79 (4H,m); 2.47 (3H,s); 2.59-3.18 (4H,m); 10.52 (1H,s).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Cl[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][N:30]=1>CS(C)=O>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][N:30]=1)[C:7]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cn1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
A solution of potassium tert-butoxide in dimethylsulfoxide was treated with dibenzyl malonate. This mixture was stirred at 95° C. for 10 min. At this time, the reaction was treated with a solution of 2-chloro-5-nitropyridine. The resulting mixture was stirred at 95° C. for 1.5 h. At this time, the reaction mixture was poured into ice/water and extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 20/80 ethyl acetate/hexanes) afforded 2-(5-nitro-pyridin-2-yl)-malonic acid dibenzyl ester (45%) as a bright yellow solid; LRMS for C22H18N2O6 (M−H)+ at m/z=405.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[C:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)(=[O:10])[CH3:9].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>C(#N)C.O>[OH:4][CH2:9][C:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(C(=O)CO)cc1

Procedure:
Trifluoroacetic acid (3.5 mL; 47.1 mmol) was added to a solution of 4-acetylbenzonitrile (3.40 g; 23.4 mmol) and [bis-(trifluoroacetoxy)iodo]benzene (20.1 g; 46.7 mmol) in acetonitrile/water (5:1; 300 mL). The reaction mixture was heated under reflux for 18 hours. The solvent was removed in vacuo and the residue partitioned between DCM and 10% aqueous potassium carbonate. The organic phase was poured through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography eluting with iso-hexane/EtOAc (10:1 to 4:1) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.04 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 4.91 (d, J=2 Hz, 2H), 3.37 (t, J=2.0 Hz, 2H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C@H:14]([C:16]3O[CH:18]=[CH:19][CH:20]=3)[CH3:15])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH:23]=[CH:22]1>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:24](=[O:25])[C:23]4[C:22]([C:21]([OH:26])=[O:27])=[CH:18][CH:19]=[CH:20][C:16]=4[C@@H:14]3[CH3:15])[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=CC(=O)O1
Reactant: C[C@H](NC1CCN(C2CCCCC2)CC1)c1ccco1
Solvent: Cc1ccccc1
Product: C[C@H]1c2cccc(C(=O)O)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-Cyclohexyl-N-[(1S)-1-(furan-2-yl)ethyl]piperidin-4-amine (0.3 gr, 1.08 mmol) and maleic anhydride (0.13 gr, 1.3 mmol) in toluene (10 mL) were stirred at reflux for 16 hours. Solvent was evaporated and the residue was dissolved in aqueous 37% hydrochloric acid (5 mL) and stirred at 100° C. for 2 hours. Volatiles were evaporated affording crude title product that was used for the next step without further purification
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K6) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (332 mg).
Reaction SMILES: [S:1]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1.CCOC(C)=O>[C:20]([O:6][C@H:5]1[C@@H:7]([O:8][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]([CH2:11][O:12][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:10][C@@H:2]([S:1][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C@@H:3]1[OH:4])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A suspended mixture of p-Methylphenyl 1 -thio-β-D-galactopyranoside (Vargas-Berenguel, A. et al. J. Chem. Soc. Perkin Trans 1 1994, 3287) (100 mg, 0.350 mmol) and Bu2SnO (266 mg, 1.04 mmol) in toluene-benzene (1:1, 10 mL) was refluxed for 10 min. The mixture was concentrated to a volume of 2 mL by distillation under Ar, then the hot solution (about 100° C.) was treated with benzoyl chloride (130 μL, 1.12 mmol). After being stirred for 1 h at this temperature, the reaction mixture was diluted with EtOAc (20 mL), cooled to room temperature, filtered through Celite and concentrated. Chromatography of the residue (hexane/EtOAc, 4:1 to 2:1 to 1:1) furnished 15 (192 mg, 91.7%) as white white solid: [α]D22 +15° (c, 0.5, CHCl3); 1H-NMR (250 MHz, CDCl3), δ 5.91 (d, 1H, J=3.1 Hz, H4), 5.43 (dd, 1H, J=3.3, 9.7 Hz, H-3), 4.720 (d, 1H, J=9.6 Hz, H-1), 4.29 (bt, 1H, J=6.5 Hz, H-5), 4.62 (dd, 1H, J=6.6 Hz, H-6) 4.37 (dd, 1H each, J=11.5 Hz, H-6′), 4,03 (t, 1H, J=9.6 Hz, H-2), 2.38 (s, 3H, Me); 13C-NMR (270 MHz, CDCl3) δ 165.98, 165.90, 165.29, 88.26, 74.97, 74.47, 68.59, 67.34, 62.45, 21.28; HRMS for C40H44O8SiCs (M+Cs) calcd 845.1581, found 845.1609.
Reaction SMILES: Cl[C:2]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][N:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.C1COCC1.[NH3:40].CC(O)C>O>[NH2:40][C:2]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][N:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1
Reactant: N
Reactant: Cn1cnnc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cnnc1C(N)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 1 h
Yield: 57 %

Procedure:
6-[chloro(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (0.0045 mol) was added at 5° C. to THF (25 ml) under N2 flow. NH3/2-propanol saturated (25 ml) was added dropwise. The mixture was kept for 1 hour, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (2.6 g) was purified by column chromatography over silica gel (eluent: toluene/iPrOH/NH4OH; 50/50/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (1.6 g, 73%) was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried. The residue (1.3 g, 59%) was purified by column chromatography over kromasil 10 μm (eluent: CH3OH/H2O; 60/40). The pure fractions were collected and the solvent was evaporated. The residue (1.4 g, 63%) was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried, yielding 1.26 g (57%) of 6-[amino(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, mp. 210° C.