Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH:18]([F:20])[F:19]>CN(C)C=O.O>[F:19][CH:18]([F:20])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: FC(F)Cl
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OC(F)F)c(O)c1
Yield: 25 %

Procedure:
To a well stirred suspension of 3,4-dihydroxy benzaldehyde (100 gm) and anhydrous potassium carbonate (120 gm) in dry N,N-dimethylformamide (1.0 lit) was passed chlorodifluoromethane gas for about 30 minutes at about 80-85° C. After an hour another lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The third lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The reaction mixture was then stirred for about 5-6 hours at an ambient temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified through silica gel column to give 4-difluoromethoxy-3-hydroxy benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[NH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[N:11]([CH3:24])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1-c1cnc(-c2ccccc2)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CI
Product: COc1ccccc1-c1cnc(-c2ccccc2)n(C)c1=O

Procedure:
A mixture of 5-(2-methoxyphenyl)-2-phenyl-3H-pyrimidin-4-one (0.4 g, example 9), methyl iodide (0.134 ml), potassium carbonate (0.398 g) and tetrabutylammonium bromide (0.048 g) in toluene (60 ml) and water (10 ml) was refluxed for 2 hours and then evaporated. The residue was taken up in diethyl ether and insolubles were filtered off. The ether solution was evaporated, and the residue was purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 6:4), to give the title compound in a pure form as a white solid (0.22 g).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.CN([CH:31]=[O:32])C>>[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:31]=[O:32]
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Yield: 76 %

Procedure:
To a stirred solution of benzimidazole (2.00 g, 16.9 mmol) in anhydrous DMF (25 mL) was added N,N-diisopropylethylamine (7.3 mL, 42.2 mmol) followed by 2-(trimethylsilyl)ethoxymethyl chloride (3.3 mL, 18.6 mmol) and the resultant solution was heated to 80 □C for 4 hours. Purification of the crude brown oil through a plug of silica gel (CH2Cl2/MeOH, 19:1) provided the 1-(2-trimethylsilylethoxymethyl)-benzimidazole (3.19 g, 76%) as an orange oil. 1H NMR (CDCl3) −0.05 (s, 9H), 0.90 (t, 2H, J=9 Hz), 3.51 (t, 2H, J=9 Hz), 5.55 (s, 2H), 7.32-7.37 (m, 2H), 7.55 (br d, 1H, J=6 Hz), 7.83 (br d, 1H, J=6 Hz), 7.98 (s, 1H).
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:27][Cl:28]>>[Cl-:28].[C:1]([NH:20][CH2:21][CH2:22][CH2:23][N+:24]([CH3:27])([CH3:26])[CH3:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCl
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCN(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCC[N+](C)(C)C
Product: [Cl-]

Procedure:
A synthetic operation was carried out using oleoylaminopropyl-N,N-dimethylamine synthesized in the above Synthetic Example 15 and methyl chloride in the same manner as in Synthetic Example 13 to obtain the target N-oleoylaminopropyl-N,N,N-trimethylammonium chloride (a″-6).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:13][CH:14]=1)=[O:21])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C#CCCCO)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ccc(C#CCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
A solution of 3.02 g (10.44 mmol) of [4-(5-Hydroxy-pent-1-ynyl)-phenyl]-methyl-carbamic acid tert-butyl ester in 70 ml CH2Cl2 was treated at 0° C. with 0.89 ml (11.48 mmol) methanesulfonylchloride, 1.26 ml (15.66 mmol) pyridine and 1.28 g (10.44 mmol) DMAP. The reaction mixture was warmed up over night to room temperature, water (10 ml) was added and the reaction mixture was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×) the organic phases were washed with aqueous KHCO3 (2×), aqueous 10% NaCl, dried (Na2SO4) and evaporated to yield 3.74 g (97%) of Methanesulfonic acid 5-[4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-pent-4-ynyl ester, mp: 85-87° C.; MS: 367 (M).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH3:15][SH:16].CCN(C(C)C)C(C)C>>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[S:16][CH3:15]
Reactant: CS
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 39a was used, starting from 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c), methanethiol and DIEA to give 6-iodo-4-methylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 327 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]=[CH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:16])[NH:7]2.Cl.[C:18](=[O:21])([O-])[O-].[K+].[K+].C(OCC)(=O)C.[CH3:30][CH2:31][CH2:32][CH2:33]CC>O1C=CCCC1>[O:21]1[CH2:18][CH2:33][CH2:32][CH2:31][CH:30]1[O:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]=[CH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:16])[NH:7]2
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1ccc(O)c2c1NC(=O)CC2
Reactant: CCCCCC
Agent: C1=COCCC1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(OC2CCCCO2)c2c1NC(=O)CC2

Procedure:
6 Grams of 5-hydroxy-3,4-dihydro-8-allyloxy-2(1H)-quinolinone was dissolved in 20 ml of dihydropyran, to this solution was added 2 ml of concentrated hydrochloric acid, then refluxed by heating for 1 hour. To this reaction mixture was added 5 g of potassium carbonate powder and stirred, then concentrated under reduced pressure. The residue thus obtained was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, again concentrated under reduced pressure to obtained pale yellow oily product. A mixed solvent of ethyl acetate-n-hexane was added to the oily product and allowed to stand for crystallization. There was obtained 8 g of 5-tetrahydropyranyloxy-8-allyloxy-3,4-dihydro-2(1H)-quinolinone as white amorphous product.
Reaction SMILES: [OH:1][C:2]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:18]>COC(OC)C1C=CC=CC=1>[CH3:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[N:8]3[CH2:16][CH2:15][CH2:14][CH:9]3[C:10](=[O:13])[N:11]3[CH:18]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:12][CH:2]=4)[O:1][C:2]=1[C:12]=23
Reactant: Cc1ccc2c(c1O)NC(=O)C1CCCN1C2=O
Agent: COC(OC)c1ccccc1
Product: Cc1ccc2c3c1OC(c1ccccc1)N3C(=O)C1CCCN1C2=O
Yield: 176.8 %

Procedure:
2.0 g of 2,3,5,10,11,11a-hexahydro-9-hydroxy-8-methyl-1H-pyrrolo[2,1-C] [1,4]benzodiazepin-5,11-dione was admixed with 300 ml of benzaldehyde dimethyl acetal and heated at 190° to 200° C. for 2 hours with stirring under a stream of nitrogen gas. The liquid reaction mixture was concentrated at 130° to 150° C. under reduced pressure. The concentrate was dissolved in a small quantity of chloroform, passed through a silica gel chromatographic column and eluted with ether. Thus, there was obtained 2.4 g of 6,8,9,10,10a,11-hexahydro-3-methyl-1-phenyl-1H-oxazolo[5,4,3-jk]pyrrolo[2,1-C] [1,4]benzodiazepin-6,11-dione as a colorless crystal. Recrystallization of the resulting product from ether gave a colorless needle-like crystal having a melting point of 158.5° to 162.5° C.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:14]([OH:22])(=[O:21])[C@H:15]([CH2:17][C:18]([OH:20])=[O:19])[OH:16]>C(O)C>[C:14]([OH:22])(=[O:21])[CH:15]([CH2:17][C:18]([OH:20])=[O:19])[OH:16].[C:2]1([C@@H:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CN)c1ccccc1
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](CN)c1ccccc1
Product: O=C(O)CC(O)C(=O)O
Temperature: 75 °C
Reaction time: 1.6 h
Yield: 118.6 %

Procedure:
Charge 2-phenyl-1-propylamine HCl (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) washed with additional ethanol (500 mL) to a dry 3-L round bottom flask under nitrogen. Stir the mixture for 1.6 hours. Filter and add a solution of L-malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) dropwise to the yellow filtrate. Heat the solution to 75° C., then stir at 75° C. for 30 minutes. Remove heat and allow the solution to cool slowly. Allow the resulting thick precipitate to stir overnight. Filter the precipitate, rinse with ethanol (325 mL) and dry under reduced pressure to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5%) as a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1-propylamine reveals 83.2% e.e. enriched in the R-isomer. (Configuration is assigned via spectrometric comparison with commercial 2-phenyl-1-propylamine.) 1H NMR (CDCl3, 300 MHz) δ 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:18])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:14]2[CH2:15][CH2:16][CH2:17][C:12]([CH3:18])([CH3:11])[CH2:13]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CC1(C)CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCCN(C(=O)c2cccc(Br)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After 6-bromopicolinic acid (200 mg, 0.99 mmol) was suspended in acetonitrile (8 ml), 3,3-dimethylpiperidine (0.17 ml, 1.19 mmol), N,N-diisopropylethylamine (0.26 ml, 1.49 mmol), and HBTU (0.45 g, 1.19 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.Br[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[NH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[C@H:22]1([NH:21][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[O:1][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:7]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: BrCc1cccnc1
Reactant: Oc1cccc2nc(Cl)ccc12
Reactant: N[C@@H]1CCc2ccccc21
Product: c1cncc(COc2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)c1

Procedure:
The title compound, MS: m/e=367.5 (M+H+), was prepared in accordance with the general method of example 2 from 5-hydroxy-2-chloroquinoline, 3-bromomethyl-pyridine and (R)-1-aminoindane.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]>S(=O)(=O)(O)O>[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:8]=1[CH:9]=[O:10]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 240 h
Yield: 34.5 %

Procedure:
Potassium nitrate (578 mg, 5.71 mmol) was dissolved in concentrated sulfuric acid (4.5 mL) and added dropwise to a stirred solution of 2,3-dichlorobenzaldehyde (1.0 g, 5.71 mmol) at room temperature. The mixture was left without stirring for 10 days at room temperature. Material that had crystallized out of the reaction mixture was collected by filtration to afford 2,3-dichloro-6-nitrobenzaldehyde (196MBT36, 433 mg, 34%) as yellow needles. Regioselectivity was confirmed by the Bayer-Drewson indigo synthesis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:20])[C:12]1([C:17](O)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:17]([C:12]2([N:11]([CH3:20])[CH3:10])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:18])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN(C)C1(C(=O)O)CCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)C1(C(=O)NNc2ccc(F)cn2)CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 200 mg, 1.57 mmol) in DMF (10 mL) were added Intermediate 99a (247 mg, 1.57 mmol), EDC (333 mg, 1.73 mmol) and HOBt (21 mg, 0.16 mmol). The reaction mixture was stirred at RT for 18 h and then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-8% (2M NH3 in MeOH) in DCM, to give the title compound (282 mg, 67%). 1H NMR (400 MHz, CDCl3): 1.54-1.73 (4H, m), 1.76-2.04 (4H, m), 2.25 (6H, s), 6.46 (1H, s), 6.64 (1H, dd, J=9.0, 3.5 Hz), 7.23-7.33 (1H, m), 8.04 (1H, d, J=3.0 Hz), 8.94 (1H, s).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][C:33]([O:37][CH3:38])=[CH:32][C:31]=1[Cl:39]>C1COCC1.O.CCOCC>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:29][C:30]1[C:31]([Cl:39])=[CH:32][C:33]([O:37][CH3:38])=[CH:34][C:35]=1[Cl:36])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=CC[C@@H](Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -60 °C
Yield: 76 %

Procedure:
Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (5.0 g, 19.3 mmol) and tetrahydrofuran (75 mL) in a 250 mL round bottom flask at −75° C. Transfer 2 M LDA (14.5 mL) to the flask via syringe and add at a rate such that the internal temperature does not reach above −60° C. After the addition is complete, allow the reaction to stir at −25° C. for 30 min then cool to about −60° C. At this point, add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene (7.76 g, 28.96 mmol) in THF (25 mL). After the addition is complete, the reaction vessel is allowed to slowly warm up to 0° C., and maintain the internal reaction temperature at 0° C. for 4 hr. Quench the reaction with 30 mL aqueous 1N hydrochloric acid. Transfer the mixture to a 500 mL separatory funnel and dilute with 100 mL water and 100 mL ether. Separate the layers and extract the aqueous layer with ether. Dry the combined organic phase over anhydrous sodium sulfate, filter and concentrate to give a thick oil. Purify by silica gel chromatography using hexanes:ethyl acetate to obtain 6.65 g, (76%) of a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[Br:20]Br>C(O)(=O)C>[Br:20][C:12]1[C:11]([F:14])=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3](=[O:17])[C:2]([F:1])([F:18])[F:19])[CH:13]=1
Reactant: BrBr
Reactant: COc1cc(F)ccc1C(C)(C)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1cc(F)c(Br)cc1C(C)(C)CC(=O)C(F)(F)F
Yield: 97.4 %

Procedure:
To a solution of 300 mg (1.078 mmnol) of 1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 25) in 0.5 mL of acetic acid was added 70 μL (1.35 mmol) of bromine. The reaction was monitored by TLC (EtOAc-hexanes (1:9)) by partitioning an aliquot between saturated aqueous sodium bicarbonate and EtOAc. A new slightly more polar product was observed. The reaction was made basic with saturated aqueous sodium bicarbonate and extracted with three 15 mL portion of EtOAc. The combined organic layers were washed with two 10 mL portions of saturated aqueous sodium bicarbonate, 10 mL of brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in hexanes and passed through a pad of silica gel eluting with EtOAc-hexanes (0.5:99.5) to afford 375 mg (97%) of the title compound.
Reaction SMILES: Cl.FC(C1C=CC=CC=1C1(NC2C=C3C(=CC=2)NC(=O)CC3)C=CN=CN1)(F)F.[Cl:30]C1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.CO[C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][C:65]([NH:71][C:72]3[CH:77]=[C:76]([C:78]4[CH:83]=[CH:82][C:81]([C:84]([F:87])([F:86])[F:85])=[CH:80][CH:79]=4)[N:75]=[CH:74][N:73]=3)=[CH:66][CH:67]=2)[N:62]=1>O1CCOCC1>[Cl:30][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][C:65]([NH:71][C:72]3[CH:77]=[C:76]([C:78]4[CH:83]=[CH:82][C:81]([C:84]([F:87])([F:86])[F:85])=[CH:80][CH:79]=4)[N:75]=[CH:74][N:73]=3)=[CH:66][CH:67]=2)[N:62]=1
Reactant: COc1ccc2ccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cc2n1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: Cl
Agent: O=C1CCc2cc(NC3(c4ccccc4C(F)(F)F)C=CN=CN3)ccc2N1
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4ccc(Cl)nc4c3)ncn2)cc1
Temperature: 25 °C

Procedure:
7-[6-(4-(Trifluoromethylphenyl)pyrimidin-4-ylamino]-3,4-dihydro-1H-quinolin-2-one hydrochloride, Example 9(c), (500 mg, 1.2 mmol) was suspended in anhydrous 1,4-dioxane (10 mL), under N2, in a flame-dried, round-bottomed flask equipped with a reflux condenser. The suspension was magnetically stirred at 25° C. and treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (350 mg, 1.5 mmol, Aldrich) followed by bis(trimethylsilyl)trifluoroacetamide (1.4 mL, 5.3 mmol, Aldrich). The reaction mixture was stirred in a 105° C. oil bath for 15 min, then allowed to cool to 25° C. and partitioned between EtOAc (150 mL) and 1% aq NaHSO3 (100 mL). The resulting emulsion was allowed to settle, and the organic phase was separated and concentrated in vacuo to a brown solid (1.1 g). The solid was treated with phosphorous oxychloride (10 mL, Aldrich) and stirred in a 100° C. oil bath for 1 h. After cooling to room temp, the reaction was quenched by slow addition to MeOH (200 mL), then concentrated in vacuo. The residue was treated with a mixture of 30% NH4OH and ice (200 mL), then extracted with EtOAc (2×100 mL). The combined organic extract was washed with satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (30% EtOAc in hexane) provided a mixture of the title product and (2-methoxyquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine (Example 12), and the pure title product as a white solid. MS (ESI, pos. ion) m/z: 401 (M+1). MP: 233° C.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([OH:31])([CH3:32])[CH3:30])=[CH:27][CH:28]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(C)(C)O)cc1
Yield: 83 %

Procedure:
To a solution of 3-acetyl-2-(4-acetylbenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one (297 mg) in THF (10 ml) was added methyl magnesium bromide (1M tetrahydrofuran solution, 1.89 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hr. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1→3/2) to give the title compound (258 mg, 83%).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[C:15](=[S:17])=[S:16].Br[CH:19]([CH3:23])[C:20]([OH:22])=[O:21]>O1CCCC1.C(OCC)(=O)C>[C:2]1([CH2:1][C:15]([S:17][CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[S:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC(Br)C(=O)O
Reactant: S=C=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(SC(=S)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A solution of benzylmagnesium chloride in ether (1.0 M, 40 mL, 40 mmol) was added slowly with stirring to an ice-cooled solution of carbon disulfide (4.0 mL, 66 mmol) in dry tetrahydrofuran (40 mL) under nitrogen. After 30 min, 2-bromopropanoic acid (3.6 mL, 6.2 g, 40 mmol) was added and the reaction was stirred at ambient temperature. After 48 h, the mixture was poured into ethyl acetate (200 mL) and washed with water (3×100 mL), followed by saturated sodium chloride solution (100 mL). The organic layer was dried (magnesium sulfate) and evaporated. The remaining liquid was distilled (120°/0.13 Pa, Kugelrohr) to remove unreacted 2-bromopropanoic acid. The residue was then dissolved in ether (200 mL) and extracted with 5% sodium bicarbonate solution (4×50 mL). The combined aqueous extracts were washed with ether (100 mL), then acidified to pH<1 with 2 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were washed with water (2×50 mL), saturated sodium chloride (50 mL) and then dried with magnesium sulfate. Evaporation of the solvent gave the title compound (20) as a red liquid (3.73 g, 39%) which slowly solidified on standing.