Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH2:3]1.CCOCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.Cl>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2([OH:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)CC(O)(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 51.42 g (333.3 mmoles) of 3,3,5,5-tetramethylcyclohexanone in 200 ml of tetrahydrofuran (THF) was added dropwise to an ice cold solution made up of 200 ml of a 2M ether solution of 4-fluorophenyl magnesium bromide (400 mmoles) and 100 ml of THF. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then poured onto ice and 500 ml of 1N HCl. After stirring for 0.5 hour, the layers were separated. The aqueous layer was extracted once with ether and the combined organic layers were evaporated in vacuo to obtain the title compound in the form of an oil.
Reaction SMILES: [C@H:1]1([F:12])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.[Ag]=O>[CH2:13]([O:3][C@@H:2]1[C@@H:4]([O:5][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:6]([O:7][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:8]([CH2:10][O:11][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@@H:1]1[F:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OC[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: F[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -20 °C
Reaction time: 5 h

Procedure:
α-D-galactopyranosyl fluoride (2.30 g, 12.62 mmol) was dissolved in dry DMF (40 ml) and, at −20° C., benzyl bromide (12.95 g, 75.72 mmol) and silver oxide (10 g) were added. The reaction mixture was stirred at −20° C. for 5 h and then at room temperature for 24 h. The salts were then filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (350 g) with 15:1 petroleum ether/ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3Cl)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (0.89 g), 2-chloro-4-methylphenol (1.0 g), and 4-dimethylaminopyridine (1 g) were suspended in o-dichlorobenzene (10 ml), and the mixture was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, and water was then added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (0.92 g, yield 70%).
Reaction SMILES: C([O:5][C:6]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[O:7])(C)(C)C.[H-].[Na+].I[CH3:32].O>CN(C=O)C>[CH3:32][N:19]([C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:12][C:8]=1[C:6]([OH:5])=[O:7]
Reactant: CI
Reactant: Cc1ccc(C(=O)Nc2nc(-c3ccccc3)sc2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)N(C)c2nc(-c3ccccc3)sc2C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
4-(4-methyl-benzoylamino)-2-phenyl-thiazole-5-carboxylic acid t-butyl ester (50 mg) was dissolved in anhydrous DMF (5 mL). NaH (16 mg, 60% dispersion oil) was added. The mixture was stirred for 10 min., followed by adding iodomethane (25 μL). Stirring was continued for overnight and poured into water. The aqueous solution was extracted with methylene chloride, washed with water, brine and dried over MgSO4. Solvent was removed under reduced pressure. The residue was purified on silica gel using hexane:EtOAc 95:5. 9:1 and 85:5 as eluent. It yielded 25 mg of desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([C:15]1[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=1)=[O:14])[CH:7]=[CH:6]2.[F:39][C:40]([Si](C)(C)C)([F:42])[F:41].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(O)(C)C>[NH:18]1[CH:19]=[C:15]([C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)([OH:14])[C:40]([F:42])([F:41])[F:39])[N:16]=[CH:17]1
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(F)(F)F)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) was dissolved in THF (10 ml) and to the solution was added trifluoromethyltrimethylsilane (1.40 g). The reaction mixture was cooled to 0° C., and tetrabutylammonium fluoride (0.4 ml) was added. The mixture was stirred at room temperature for 2 h. To the mixture were added 1 N-hydrochloric acid (10 ml) and isopropanol (5 ml), and the mixture was stirred at room temperature for 24 h. The reaction mixture was neutralized, and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (eluent, chloroform methanol=20:1→10:1). Recrystallization from ethyl acetate gave the titled compound (0.40 g) as a colorless powder.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOCC1.[Br:31]Br>C(Cl)(Cl)Cl>[Br:31][C:8]1[O:9][C:10]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)coc12
Reactant: BrBr
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c(Br)oc12

Procedure:
A solution of 4.0 g. (0.013 mole) of the product of step D in 50 ml. of dioxane is treated with 2.4 g. of bromine in 450 ml. of chloroform, and the mixture is heated at its reflux temperature overnight. The solution is cooled, washed with water, dried and then evaporated. The residue is triturated with hexane to provide 2-bromo-3,5-diphenylbenzofuran-7-carboxylic acid as a white solid, m.p. 232°-236° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cc(F)ccc4F)cc3c2C1
Yield: 79.4 %

Procedure:
Beginning with 10.4 mg (0.046 rmMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 2,5-difluorobenzoyl chloride, 13.3 mg (78%) of the title compound were recovered as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])=[CH:5]2.C(N(CC)CC)C.[CH:35]12[CH2:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][CH:36]2[CH2:42][C:43](Cl)=[O:44]>C1COCC1.Cl>[CH:35]12[CH2:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][CH:36]2[CH2:42][C:43]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])=[CH:5]2)=[O:44]
Reactant: Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CCc1ccccc1
Reactant: O=C(Cl)CC1CC2CCC1C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC1CC2CCC1C2)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon, 78 mg (0.22 mmol) of 5-amino-N-phenyl-1-(2-phenylethyl)-1H-indole-2-carboxamide (Example LI) are dissolved in 2 ml of THF, and 24.4 mg (0.24 mmol) of triethylamine are added. The solution is cooled to 0° C., and a solution of 37.9 mg (0.22 mmol) of bicyclo[2.2.1]hept-2-ylacetyl chloride in 0.2 ml of THF is added dropwise. The reaction mixture is stirred at RT for 2 h and then diluted with 1-molar hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution and once with sodium bicarbonate solution, dried over sodium sulphate and filtered. The residue obtained after removal of the solvent under reduced pressure is purified chromatographically on silica gel (mobile phase: dichloromethane/ethyl acetate). 31.5 mg (29% of theory) of the product are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:12][C:13]([CH3:15])=[O:14]>>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:13]([CH3:15])([OH:14])[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CC(C)=O
Product: CC(C)c1ccc(CC(C)(C)O)cc1

Procedure:
The reaction of a Grignard compound, prepared from 20 g (119 mmol) 4-isopropylbenzyl chloride, with 11.4 mL (155 mmol) acetone yields the target compound as a colorless oil. Yield: 13.0 g (57%); mass spectrometry: [M+H]+=193.
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6](=O)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])[CH3:4].O.[NH2:21]N>C(O)(=O)C>[CH2:13]([C:11]1[C:10]([O:15][CH3:16])=[N:9][C:8]([CH3:17])=[C:7]([C:6]2[N:5]=[C:3]([CH3:4])[NH:2][N:21]=2)[CH:12]=1)[CH3:14]
Reactant: CCc1cc(C(=O)N=C(C)N(C)C)c(C)nc1OC
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(-c2n[nH]c(C)n2)c(C)nc1OC
Temperature: 90 °C
Reaction time: 12 h
Yield: 79.7 %

Procedure:
In a round bottom flask under a nitrogen atmosphere N-(1-dimethylaminoethylidene)-5-ethyl-6-methoxy-2-methyl-nicotinamide (synthesized on 0.567 mmol scale) prepared in accordance with the procedures of Step 1, Example 19 is treated with glacial acetic acid (1 mL), followed by hydrazine hydrate (36 μL, 0.742 mmol). The resulting mixture is stirred at 90° C. for 12 hr. The reaction mixture is evaporated and the residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (49:1). Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (99:1). Fractions containing the product are combined and the solvent evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyridine (105 mg, 80% yield, 2 steps) as a orange-red. MS: m/e=233 (M+H); 1H NMR (CDCl3, δ, ppm): 9.8-11.6 (1H, br.s), 7.81 (1H, s), 3.97 (3H, s), 2.69 (3H, s), 2.59 (2H, q), 2.52 (3H, s), 1.19 (3H, t).
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15]>>[O:15]=[C:7]1[NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:11][C:10]=2[O:6]1
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]c2ccccc2o1
Product: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 25.7 %

Procedure:
Sulfurochloridic acid (70 g, 603.45 mmol) was cooled to 0° C. and benzo[d]oxazol-2(3H)-one (1.8 g, 13.33 mmol) was added in several batches, maintaining the temperature at about 0° C. The resulting solution was stirred at room temperature for 3 hours, then quenched by the addition 400 mL of iced water. The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:10 ethyl acetate/petroleum ether solvent system to afford 0.8 g (26%) of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride as a white solid. 1H NMR (CDCl3) δ 8.26 (s, 1H), 8.00 (d, 1H), 7.98 (d, 1H), 7.32 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>[Pd]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=2[CH:10]=[O:11])=[CH:15][CH:14]=1
Reactant: CC1(C)CCC(Cl)=C(C=O)C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
reacting the 2-chloro-5,5-dimethylcyclohex-1-enecarbaldehyde, 4-chlorophenylboronic acid, a first phase transfer catalyst, a fifth base, and a first palladium catalyst to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde.
Reaction SMILES: [NH2:1][CH:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35]([NH:1][C@H:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C@H:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:36]
Reactant: CCCCCN1CC(C(=O)OCC)C(N)C1=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN1C[C@@H](C(=O)OCC)[C@@H](NC(=O)c2ccc3ccccc3c2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
To a solution of the aminopyrrolidinone of Example R (120 mg, 0.495 mmol) and triethylamine (0.35 ml, 2.48 mmol) in CH2Cl2 was added a solution of 2-naphthoyl chloride (94 mg, 0.495 mmol) in CH2Cl2 dropwise via syringe. After stirring for 12 h at room temperature the reaction mixture was evaporated in vacuo to give a residue which was chromatographed on silica gel eluting with EtOH/CH2Cl2 (2%-5%) to give the title compound (172 mg, 69%) as a colorless solid. MS M+1 calcd for C23H28N2O4 397; found 397.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]2=1)#[N:4].Cl.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=1>CN(C=O)C>[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=1)[C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:9][C:8]2=1)#[N:4]
Reactant: Fc1ccc(CCl)nc1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccc(F)cn2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
Suspend sodium hydride (60% in oil, 80 mg, 1.99 mmol) in DMF (2 mL) and chill to 0° C. Add a solution of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (253 mg, 0.90 mmol) in DMF (2 mL) slowly via syringe, and allow to stir 30 min before warming to ambient temperature for 60 min. Add 2-chloromethyl-5-fluoro-pyridine hydrochloride salt (180 mg, 0.99 mmol) and stir the reaction for about 12 h. Quench the reaction with saturated aqueous ammonium chloride (5 mL). Add ethyl acetate (50 mL) and wash the solution with water (50 mL), then brine (2×50 mL). Separate the organic phase and dry over magnesium sulfate, filter, and evaporate under reduced pressure. Titurate the resulting residue with diethyl ether (10 mL) for 5 min and then filter to afford 187 mg (53%) of the title compound as a light yellow solid. mp 235-238° C. (dec); MS (ESI): m/z [391 C23H23FN4O+H]+; 1H NMR (300 MHz, CDCl3): δ 8.43s, 1H), 7.78 (s, 1H), 7.38-7.25 (m, 3H), 6.67 (dd, J=8.6, 4.2 Hz, 1H), 5.58 (d, J=7.8 Hz, 1H), 5.35 (s, 2H), 4.40 (br s, 1H), 3.14 (dd, J=15.4, 5.0 Hz, 1H), 2.79 (br s, 2H), 2.60 (dd, J=15.4, 7.6 Hz, 1H), 2.34 (pentet, J=6.8 Hz, 1H), 2.15 (br s, 1H), 2.02-1.95 (m, 1H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:24])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:24])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:32][C:33](=[O:34])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(O)cc2)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(OCC(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
a mixture of 4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (100 mg, 0.28 mmol), cesium carbonate (140 mg, 1.5 eq) and α-bromoacetophenone (84 mg, 1.5 eq) in DMF was shaken at ambient temperature for 16 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic extracts were washed with water (30 mL), dried (MgSO4) and condensed to give the desired product (129 mg, 96%) as a yellow oil: NMR δH(400 MHz; d6-DMSO) 1.40 (9H, s), 3.30–3.36 (4H, m), 3.43 (4H, br s), 4.07 (2H, s), 5.54 (2H, s), 6.86–6.91 (2H, m), 7.20–7.26 (2H, m), 7.54–7.60 (2H, m) and 7.66–7.72 (1H, m); HPLC (XTERRA, 50/80, 220 nm) 96.1% (6.56 min).
Reaction SMILES: [N:1]1[C:6]2[N:7]([C:10]3([CH2:13][OH:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:14][CH2:13][C:10]1([N:7]2[C:6]3[N:1]=[CH:2][N:3]=[CH:4][C:5]=3[CH:9]=[CH:8]2)[CH2:11][CH2:12]1
Reactant: OCC1(n2ccc3cncnc32)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: c1ncc2ccn(C3(COC4CCCCO4)CC3)c2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a stirred solution of (1-Pyrrolo[2,3-d]pyrimidin-7-yl-cyclopropyl)-methanol (Preparation 247, 240 mg, 1.27 mmol) in THF (12 mL) was added 3,4-dihydro-2H-pyran (0.46 mL, 5.07 mmol) followed by addition of PTSA (24 mg, 0.13 mmol). The reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution (15 mL) and extracted with dichloromethane (3×25 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 98:2) to afford the title compound as a light brown gum in 90% yield, 320 mg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]2=[O:21])[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:35][C:31]1[CH:32]=[N:33][CH:34]=[C:29]([N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:30]=1)=[C:3]([CH3:22])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]1=[O:21])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCN(C)CC2=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C)CC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-methylpiperazin-2-one (25.0 mg, 0.077 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-4-methyl-2-piperazinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.92 (1H, br. s.), 7.88 (1H, br. s.), 7.47 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 7.23 (1H, d, J=14.9 Hz), 7.01 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.53 (1H, t, J=2.1 Hz), 4.41 (1H, ddd, J=11.8, 5.2, 5.1 Hz), 3.75-3.89 (4H, m), 3.53-3.67 (1H, m), 3.29-3.43 (1H, m), 3.11-3.27 (5H, m), 2.82-2.96 (2H, m), 2.44 (3H, s), 1.95 (3H, s). Mass Spectrum (ESI) m/e=326.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=S)([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(=[O:25])C>C1(C)C=CC=CC=1.OO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:25])([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: S=P(c1ccccc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: OO
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 92 %

Procedure:
7.26 g (20 mmol) of bis(4-chlorophenyl)phenylphosphine sulfide, dissolved in 12.5 ml of glacial acetic acid/12.5 ml of toluene, and 0.72 g (21.1 mmol) (1.81 ml of a 35% solution) of hydrogen peroxide gave 6.4 g (92% of theory) of bis(4-chlorophenyl)phenylphosphine oxide after a reaction time of 60 minutes at 50° C. and working-up as in Example 8.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([OH:15])=O.[NH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH2:34][C:33]1=[O:42]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[N:35]1([C:13]([C:16]2[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:15])[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:32][C:33](=[O:42])[CH2:34]1
Reactant: CN(Cc1cccc(C(=O)O)c1)C(=O)OC(C)(C)C
Reactant: O=C1CNc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(Cc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 27.2 %

Procedure:
WSC.HCl (640 mg, 3.4 mmol) and 4-(dimethylamino)pyridine (330 mg, 2.7 mmol) were added to a solution of tert-butyl N-(3-carboxybenzyl)-N-methylcarbamate (700 mg, 2.6 mmol) and 1,2,3,4-tetrahydroquinoxalin-2-one (440 mg, 2.9 mmol) in dichloromethane (20 ml). The mixture was stirred for 18 h, reduced in vacuo and taken up in ethyl acetate. This solution was washed with 0.3N potassium hydrogen sulphate and saturated sodium hydrogen carbonate solutions, dried and reduced. Chromatography (50% EtOAc/50% 60-80 pet.ether) afforded tert-butyl N-(3-(1,2,3,4-tetrahydroquinoxalin-3-on-1-carbonyl) benzyl)-N-methylcarbamate (280 mg, 27%) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:13][CH3:14])[CH:3]=1.[CH:15]([Mg]Br)=[CH2:16]>C1COCC1>[CH3:1][C:2]1[C:9]2[NH:10][CH:16]=[CH:15][C:8]=2[C:5]([C:6]#[N:7])=[C:4]([S:13][CH3:14])[CH:3]=1
Reactant: CSc1cc(C)c([N+](=O)[O-])cc1C#N
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: CSc1cc(C)c2[nH]ccc2c1C#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methyl-2-(methylthio)-5-nitrobenzonitrile (1.6 g, 7.68 mmol) in THF (80 mL) at −78° C. under nitrogen, was added rapidly 1M vinylmagnesium bromide in THF (30.7 mL, 30.7 mmol). After addition was complete, the reaction was stirred at −78° C. for 30 min. The reaction was then quenched with sat. aq. NH4Cl and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated. The pure title compound was isolated using FCC (0-50% EtOAc in heptanes). MS (ESI−) m/z 201.2 (M−H).