Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[NH2:13][C:4]1[CH:3]=[C:2]([F:1])[C:11]([F:12])=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: CNC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(F)c(F)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4,5-difluoro-N-methyl-2-nitrobenzamide (1.33 g, 6.15 mmol) in methanol (50 mL) was added Pd/C (10% Pd in carbon, 200 mg, 15 wt %) under argon. A hydrogen balloon was used as hydrogen source. The reaction was stirred at room temperature overnight. The mixture was filtered through celite and the celite pad was washed several times. The solvent was removed the crude was purified by silica gel chromatography to obtain the desired product (quantitative yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:19][C:20](=[CH2:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[F:19][C:20](=[CH2:24])[C:21]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:22]
Reactant: C=C(F)C(=O)Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)Oc1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
27.5 g (0.169 mol) of 3-trifluoromethylphenol were dissolved in 100 ml of anhydrous methylene dichloride, and 17.1 g (0.169 mol) of triethylamine were added in portions to the solution; 20 g (0.184 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were then added dropwise, at a temperature of 5° C., with stirring and in the course of 20 minutes, and the reaction mixture was stirred for a further 60 minutes at the same temperature. The solid formed was filtered off and washed with 30 ml of methylene dichloride. The mixture of filtrate and wash solution was distilled, after adding 0.01 g of hydroquinone monomethyl ether. 27 g (68% of theory) of 3-trifluoromethylphenyl α-fluoroacrylate were obtained, boiling point 78° to 79° C. (under 4 mbar).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[OH:28][CH2:29][CH:30]1[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:34]3[C@H:30]([CH2:29][OH:28])[CH2:31][CH2:32][C:33]3=[O:35])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CCC(CO)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 50.1 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 110 and 5-hydroxymethylpyrrolidin-2-one (230 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (486 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)[CH:7]=1.C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:23][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=2)=[CH:7][C:6]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOCCOc1ccc(C(=O)Nc2cc(N)ccc2C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCCOc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)cc1
Yield: 19.2 %

Procedure:
A solution of N-(5-amino-2-methylphenyl)-4-(2-ethoxyethoxy)benzamide (0.141 g) and triethylamine (0.121 g) in methylene chloride (5 ml) was added to 3-trifluoromethylbenzoyl chloride (0.104 g) and the resultant mixture was stirred at ambient temperature for 18 hours. The mixture was washed in turn with a 1M aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and water. The organic solution was evaporated and the residue was triturated under a mixture of diethyl ether and ethyl acetate. The resultant solid was isolated and dried under vacuum. There was thus obtained the title compound (weight 0.042 g); Mass Spectrum: M+H+ 487.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (264 mg, 0.95 mmol) [prepared according to the procedure of Example 96], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (306 mg, 0.80 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (450 mg, 0.96 mmol) in chloroform (7 mL). DIEA (660 μl, 3.78 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (303 mg, 0.44 mmol, 56%): LC-MS (ES) m/z=607 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](O)=[N:6][C:7]=1[CH3:8].[ClH:13]>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5]([Cl:13])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(O)c(C#N)c(C)c1Br
Reactant: Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c(C#N)c(C)c1Br
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 9.0 grams (0.040 mole) of 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine in 40 mL of phosphorus oxychloride is stirred, and one drop (catalyst) of N,N-dimethylformamide is added. The reaction mixture is then stirred at ambient temperature for about five hours, and then allowed to stand for about 72 hours. After this time, the reaction mixture is poured into 1000 mL of ice containing about one mL of concentrated hydrochloric acid. The mixture is stirred until the ice melts. The resultant precipitate is collected by filtration and washed with water. The solid is then dried under reduced pressure at about 60° C. An NMR spectrum of the solid indicates that it contains a large amount of starting material. The solid is then dissolved in 25 mL of phosphorus oxychloride, and two drops of N,N-dimethylformamide are added. The mixture is heated to reflux where it is stirred for about 18 hours. After this time, the reaction mixture is poured into 600 mL of ice containing about two mL of concentrated hydrochloric acid. The mixture is stirred until the ice melts. The resultant precipitate is collected by filtration, washed with water, and dried under reduced pressure at about 60° C., yielding 8.6 grams of 5-bromo-2-chloro-3-cyano-4,6-dimethylpyridine. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH2:36])[CH:32]=2)[CH2:27]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:36][C:31]4[CH:32]=[C:33]5[C:28](=[CH:29][CH:30]=4)[CH2:27][N:26]([CH3:25])[CH2:35][CH2:34]5)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CN1CCc2cc(N)ccc2C1
Product: CN1CCc2cc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)ccc2C1
Yield: 52.2 %

Procedure:
N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (0.109 g, 0.316 mmol) and 2-Methyl-1,2,3,4-tetrahydro-isoquinolin-6-ylamine (0.064 g, 0.39 mmol) were reacted in an analogous manner to Example 908D at rt for 16 h. The reaction mixture was concentrated, taken up in EtoAc, and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting solid was purified by ISCO silica gel chromatography (0-10% MeOH in CH2Cl2) to afford title compound (81 mg, 52%). HPLC purity=96%, rt=2.654, LCMS=491.0 (M+H) 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.48 (s, 1H), 9.04 (s, 1H), 8.50 (d, J=7.9 Hz, 1H), 8.39 (s, 1H), 7.84 (d, J+7.4 Hz, 1H), 7.73 (dd, J=7.9 Hz, 7.9 Hz, 1H), 7.61 (s, 1H), 7.58 (s, 1H0, 7.48 (dd, J=8.3 Hz, 1.67 Hz, 1H), 7.18 (d, J=4.7 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 7.00 (d, J=4.8 Hz, 1H), 3.67-3.61 (m, 2H), 2.85 (s, 3H), 2.80-2.70 (m, 2H), 2.48-2.42 (m, 2H), 1.11 (s, 9H).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]1>>[C:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCOC(=O)CCC1CCNCC1
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCC(CCC(=O)OCC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl 3-(4-piperidyl)propionate hydrochloride as starting raw materials, to produce ethyl 3-(1-((E)-2-decenoyl)-4-piperidyl)propionate (ethyl ester of Compound 36).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12]Br.[C-:14]#[N:15].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:14]#[N:15]
Reactant: [C-]#N
Reactant: BrCc1ccc2ccccc2c1Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CCc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 99 parts of 1-bromo-2-(bromomethyl)naphthalene, 103 parts of potassium cyanide and 1 part of benzyl triethylammonium chloride in 150 parts by volume of methylene chloride and 30 parts by volume of water is stirred at room temperature for about 72 hours. The mixture is then diluted with additional quantities of methylene chloride and water, the organic layer separated, dried over calcium sulfate, and concentrated to give α-(1-bromo-2-naphthyl)acetonitrile, as a solid.
Reaction SMILES: [O:1]=[C:2]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14](C(OC(C)(C)C)=O)[CH:15]=[C:16]([C:17]([O:19]C)=[O:18])[C:9]=12)[CH2:4][CH3:5].CO.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)[C@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:9]=12)[CH2:4][CH3:5]
Reactant: CC[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1
Temperature: 53 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
To a 20 mL round bottom flask with a stirrer was added (R)-1-tert-butyl 3-methyl 4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (150 mg, 0.337 mmol), MeOH (1 mL) and THF (1 mL). Aqueous NaOH (12 N, 1 mL) was added and the reaction mixture was stirred at 53° C. for 16 h. The solvent was removed and the resulting residue was further purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (8.7 mg, 0.026 mmol, 7.80%). [M+H] calc'd for C17H22N4O3, 331; found, 331.6.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([F:25])=[C:6]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:7]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([F:25])=[C:6]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
The whole of the diethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylmalonate [(XIV), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] [prepared as described in step (a) above] was dissolved in 200 ml of dioxane, and then 4.52 g (0.0238 moles) of p-toluene-sulfonic acid monohydrate were added to the resulting solution. The mixture was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. 100 ml of water and 2.52 g (0.03 moles) of sodium bicarbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 5.66 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylacetate as a reddish brown liquid.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].CN([Si](C)(C)C)C(=O)C.CC([O:23][CH2:24][C:25]1[C:38]2[C:33](=CC=CC=2)[C:32](COC(C)=O)=[C:31]2[C:26]=1C=CC=C2)=O>ClCCl>[OH:4][CH2:3][CH:2]([NH:1][C:24](=[O:23])[C:25]1[CH:38]=[CH:33][CH:32]=[CH:31][CH:26]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: N[C@@H](CO)c1ccccc1
Agent: CC(=O)N(C)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(NC(CO)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A slurry of (R)-2-amino-2-phenylethanol (1.0 g, 7.4 mmol) in 50 mL dichloromethane was allowed to stir with N-methyl-N-(trimethylsilyl)acetamide (3.4 mL, 21.1 mmol) until a homogenous solution occured. The solution was cooled to 0° C. to 5° C. and a solution of 2,2'-dithiobis[benzoyl chloride] (1.0 g, 2.9 mmol) in 20 mL dichloromethane was added. The solution was stirred for 2 hours and 1 mL of 50% aqueous acetic was added causing the crude product to precipitate from solution. This solid was collected by filtration, washed with 1N HCl, water, and recrystallized from dimethylformamide/water to afford 1.2 g of the title compound, mp 235°-236° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:43])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[O:41][N:40]=[C:39]([CH3:42])[CH:38]=4)[CH:32]=3)[CH2:28][C:27](=[O:43])[NH:20][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C5CC5)c(Cl)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(cyclopropyl-methyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example J11) (156 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (170 mg, 0.56 mmol) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (49 mg).
Reaction SMILES: [C:1]1([C:6]2[O:7][C:8]3[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:9]=3[C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl[C:35]1[CH:36]=[CH:37][C:38]2[O:50][CH2:49][N:41]3[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=4[CH:48]=[C:40]3[C:39]=2[N:51]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:1]1([C:6]2[O:7][C:8]3[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([C:35]4[CH:36]=[CH:37][C:38]5[O:50][CH2:49][N:41]6[C:42]7[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=7[CH:48]=[C:40]6[C:39]=5[N:51]=4)=[CH:15][C:9]=3[C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Clc1ccc2c(n1)-c1cc3ccccc3n1CO2
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5ccccc5n3CO4)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
To a degassed solution of 2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (110 mg, 0.23 mmol), 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (70 mg, 0.27 mmol), K3PO4(123 mg, 0.46 mmol) in 1,4-Dioxane (5 mL) and H2O (0.5 ml) was added Pd(dba)3 (5 mg) and X-Phos (5 mg) under N2, then the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O, brine, extract with DCM, and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)benzofuran-3-carboxamide (30 mg, yield: 23%). 1H-NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.47 (s, 2H), 7.27˜7.33 (m, 2H), 7.14˜7.20 (m, 2H), 6.74 (s, 1H), 6.10 (s, 1H), 5.99 (s, 2H), 3.32 (s, 3H), 3.01 (d, J=4.8 Hz, 3H), 2.83 (d, J=6.8 Hz, 2H), 2.73 (s, 3H), 2.62 (t, J=6.8 Hz, 2H), 2.00˜2.08 (m, 2H). MS (M+H)+: 569.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:31])[N:8]2[C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[F:27])[C:14]([O:28][CH3:29])=[CH:13][C:12]=2[Cl:30])=[C:4]([O:32][CH3:33])[N:3]=1.[NH2:34][CH2:35][CH2:36][OH:37].C(O)C.[Cl-].[NH4+]>CN1CCCC1=O>[Cl:30][C:12]1[CH:13]=[C:14]([O:28][CH3:29])[C:15]([O:17][CH2:18][C:19]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[F:27])=[CH:16][C:11]=1[N:8]1[C:7](=[O:31])[NH:6][C:5]2[C:9]1=[N:10][C:2]([NH:34][CH2:35][CH2:36][OH:37])=[N:3][C:4]=2[O:32][CH3:33]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(Cl)nc32)cc1OCc1c(F)cccc1OC
Reactant: NCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(NCCO)nc32)cc1OCc1c(F)cccc1OC
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
A mixture of 2-chloro-9-[2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (50 mg), 2-aminoethanol (19 mg), ethanol (1 mL) and 1-methyl-2-pyrrolidone (0.5 mL) was stirred at 150° C. in a sealed tube under microwave irradiation for 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/3−ethyl acetate). The obtained product was suspended in a mixed solvent (n-hexane/ethyl acetate=2/1), and collected by filtration. The collected material was dried under reduced pressure to give the title compound (5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:29])[CH:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[N:15][CH:16]=3)[C:4]=2[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(OCC)(=O)C>C1(OC)C=CC=CC=1>[Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[N:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc(NC(C)=O)nc3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)cn1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
N-(5-(7-Chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)pyridin-2-yl)acetamide (210 mg, 0.366 mmol) was dissolved in anisole (1 mL) under nitrogen and AlCl3 (195 mg, 1.465 mmol) was added in one portion. The resulting orange solution was heated to 85° C. for 2 h then allowed to cool. Ice and ethyl acetate were added and the mixture was stirred for 30 min then partitioned and the organic layer was washed with water then brine and dried (MgSO4). Chromatography on silica gel eluting with 10%-50%-70% ethyl acetate in hexanes gave the product (120 mg, 72% yield). 1H-NMR (300 MHz, CDCl3) δ 7.62-7.5 (m, 3H), 7.5-7.20 (m, 7H), 6.49 (s, 1H), 6.47 (s, 1H), 4.31 (dd, 1H), 4.25-4.17 (m, 2H), 3.59 (dd, 1H), 3.35 (dd, 1H). HRMS (ES+) m/z calcd for C23H18Cl2N4O2 [M+H]+, 453.0885. found, 453.0872.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:21]([C:19]1[S:20][C:16]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:17][CH:18]=1)(=[O:22])=[O:23]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Cc2ccccc2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(Cc3ccccc3)s2)c1Br
Yield: 22 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-benzylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-benzyl-2-thiophenesulfonyl chloride in 22% yield. The product was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. 49-50° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH2:15][O:16][CH3:17]>[OH-].[Na+].O>[CH3:17][O:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: COCCCl
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cc(C)c(C(C)=O)c(C)c1
Temperature: 140 °C
Yield: 61.3 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (500 mg, 3.1 mmol, 1.0 equiv) and 1-chloro-2-methoxyethane (0.28 mL, 3.1 mmol, 1.0 equiv) in 50% aqueous NaOH solution (5.0 mL) was heated at 140° C. for 16 h. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to give 1-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)ethanone (430.9 mg, 1.9 mmol) as yellow oil in 64% yield: 1H NMR (CDCl3, 500 MHz) δ 6.58 (s, 2H), 4.09-4.10 (m, 2H), 3.72-3.74 (m, 2H), 3.44 (s, 3H), 2.45 (s, 3H), 2.23 (s, 6H); ESI-MS: m/z 223.6 (M+H)+.