Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[N:21][C:22]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)=[CH:23][CH:24]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)nn2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(-c3ccc(OC(F)(F)F)cc3)nn2)cs1
Yield: 79.8 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(6-chloropyridazin-3-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (500 mg) synthesized in Example 213-1 and 4-trifluoromethoxyphenylboric acid (300 mg) were dissolved in dioxane (6 mL) and 2 mol/L sodium carbonate (3 mL), tetrakis(triphenylphosphine)palladium (70 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:2) to give the title compound (520 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C@@H:13](O)[CH2:12]2)[C:7]1=[O:25].CCN(S(F)(F)[F:36])CC>C(Cl)Cl.C(=O)(O)[O-]>[F:36][C@@H:13]1[C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:15][CH2:16][N:11]([CH:8]2[CH2:9][CH2:10][N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:2]([F:1])[CH:3]=3)[C:7]2=[O:25])[CH2:12]1
Reactant: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(O)cc4)[C@@H](O)C3)C2=O)cc1F
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(O)cc4)[C@@H](F)C3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 1-(3-fluoro-4-methylbenzyl)-3-((3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one (from step F, 1.9 g, 4.8 mmol) in DCM (35 mL) at 0° C. was added DAST (3.2 mL, 23.8 mmol) under nitrogen. The reaction mixture was allowed to warm to rt and stirred for 2 h, and then diluted with saturated bicarbonate solution and extracted with 200 mL of DCM. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to give a crude product which was purified via preparative HPLC (method J) to yield 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (1.1 g, 2.6 mmol) as a pair of diastereomers. LCMS (Method F) RT: 2.13 min, m/z 401. (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)(=[O:14])[CH3:13].Cl>CCOCC>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)=[O:14]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)C1=CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C1C=CCCC1)C(F)F
Yield: 93 %

Procedure:
Ethyl difluoroacetate (4.71 g, 38 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (20 mL). To the stirred solution was added 25 weight % sodium methoxide (9.68 g, 45 mmol) followed by 1-acetyl-1-cyclohexene (4.27 g, 34 mmol The reaction was stirred at room temperature overnight 17.5 hours), then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a brown oil (6.48 g, 93%). 1H NMR (CDCl3) 300 MHz 15.00 (br s, 1H), 6.09 (s, 1H), 5.92 (t, J=54.4 Hz, 1H), 2.31 (m, 4H), 1.64 (m, 4H); 19F NMR (CDCl3) 300 MHz: -126.94; M+202.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Br
Reactant: Cc1nc(C=O)cs1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Br)cs1
Temperature: 25 °C
Yield: 52 %

Procedure:
Anhydrous zinc chloride (0.150 g, 1.1 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (5 mL) was then added. To this mixture was added 3-(2-bromo-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.182 g, 0.55 mmol), acetic anhydride (0.156 mL, 1.65 mmol), and 2-methylthiazole-4-carboxaldehyde (0.209 g, 1.65 mmol in 3 mL of dioxane). The reaction was refluxed 3 hours, and was then cooled to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The combined chloroform layers were washed with water and brine, then dried over magnesium sulfate and then concentrated to yield a dark residue. This residue was triturated with ether, filtered and dried to afford 0.116 g (52% of 3-(2-bromo-phenyl)-6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[CH3:12][C:13](=[CH:15][CH2:16]Br)[CH3:14]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])[CH:4]=1
Reactant: CC(C)=CCBr
Reactant: COc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cccc(SCC=C(C)C)c1
Yield: 90.4 %

Procedure:
50.45 g (360.0 mmol) of 3-methoxythiophenol, 360 ml of acetone and 14.40 g (360.0 mmol) of sodium hydroxide pellets are introduced into a one liter round-bottomed flask under a nitrogen atmosphere and the mixture is heated at reflux for three hours. A solution composed of 53.65 g (360.0 mmol) of 2-methyl-4-bromo-2-butene and of 60 ml of acetone is added dropwise. Reflux is maintained for sixteen hours and the reaction mixture is evaporated to dryness. Water is added, extraction is carried out with ethyl acetate, the organic phase is washed with water and then using a saturated sodium chloride solution, dried over magnesium sulphate and filtered, and the solvents are evaporated. The residue obtained is distilled under reduced pressure (5×10-2 bar/113° C.) to produce 67.81 g (90%) of the expected compound in the form of a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](O)=[O:7])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[S:31][C:30](=[S:32])[NH:29][N:28]=1>C1COCC1>[S:32]=[C:30]1[S:31][C:27]([NH:26][C:6]([CH:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:7])=[N:28][NH:29]1
Reactant: Nc1n[nH]c(=S)s1
Reactant: CCOC(=O)C(C(=O)O)C(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)Nc1n[nH]c(=S)s1)C(C)(C)C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of tert-butylmalonic acid monoethyl ester (3.0 g, 16.0 mmol) in THF (100 mL) is added carbonyldiimidazole (2.85 g, 17.6 mmol) and the reaction is stirred overnight. 5-Amino-(3H)-1,3,4-thiadiazole-2-thione (864 mg, 6.5 mmol) is added and stirring continued for an additional 72 hours. The reaction mixture is 35 poured into pH 4 buffer, extracted with methylene chloride, and the organic layers combined, dried (anhydrous sodium sulfate) and concentrated. Chromatography of the residue on silica gel (elution with 5% methanol/methylene chloride) gave 1.2 g (25%) of the title compound as an amorphous solid.
Reaction SMILES: N1C=CC=CC=1N1[C:12](=[S:13])[N:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]2=[N:9]C1=S.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:12](=[S:13])[N:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]3=[N:9][C:27]2=[O:28])=[CH:22][CH:21]=1
Reactant: S=c1nc2ccccn2c(=S)n1-c1ccccn1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CC#N
Product: O=c1nc2ccccn2c(=S)n1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
544 Mg. of 3-(2-pyridyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione is combined with p-chloro phenylisocyanate and 10 ml. of acetonitrile. The reaction mixture is heated at 70° C. for 1 hour with a precipitate appearing after 1/2 hour. The reaction mixture is allowed to cool to room temperature with stirring. The solid material is filtered, washed twice with acetone, once with ether and dried in vacuo affording 3-(4-chlorophenyl) pyrido (1,2-a) 1,3,5-triazine-2-one-4-thione m.p. 209°-212° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)=[O:8]>O.C(Cl)Cl.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[N:1]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: CCOC(=O)Cc1ccc(C(=O)CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sodium azide (32.5g.) in water (200ml.) was added to a solution of ethyl 4-(chloroacetyl)-phenylacetate (24.05g.) in methylene dichloride (200ml.). Benzyltrimethylammonium chloride (0.1g.) was added, and the bisphasic mixture was shaken for 4 hours at room temperature. The organic phase was separated, washed with distilled water (3 × 30ml.) dried and evaporated to give ethyl 4-(azidoacetyl)-phenylacetate as an oil showing a peak at 2120 cm-1 in its I.R. spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([OH:11])=O.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:11]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetic acid (0.051 g, 0.10 mmol) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (0.022 g, 0.18 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.033 g, 0.17 mmol), methanesulfonamide (0.016 g, 0.17 mmol) and triethylamine (0.040 mL, 0.29 mmol). The reaction was stirred at ambient temperature for 3 days. The reaction mixture was then diluted with dichloromethane and washed with 10% aqueous acetic acid. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica gel followed by trituration with methylene chloride/hydrogen chloride in diethyl ether gave the title compound as the hydrochloride salt (0.015 g, LRMS: 542.1, 544.1).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11]1[O:19][CH:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O>[OH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: c1ccc(C2CO2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc(SCC(O)c2ccccc2)cc1
Temperature: 120 °C

Procedure:
4-Mercaptophenol (63 grams) and 0.5 gram of KOH were combined in a flask equipped with an agitator, water condenser and thermometer. The combination was heated to 120° C. under nitrogen. Styrene oxide (66 grams) was added dropwise at 100° C. to 135° C. The combination was neutralized with one millimeter of hydrochloric acid and the volatiles stripped off to a pot temperature of 170° C. at 28 millimeters of mercury. The weight of product was 131 grams.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.C>C(O)C.[OH-].[Na+]>[CH:24]1([NH:27][C:3]2[N:8]=[C:7]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]3=[CH:5][N:4]=2)[CH2:26][CH2:25]1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NC3CC3)ncc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and cyclopropylamine (1.2 ml) in ethanol (20 ml) was heated for 18 hours at 90° C. in a pressure vessel. Further cyclopropylamine (1 ml) was added and the reaction mixture was stirred in a pressure vessel for 18 hours at 100° C. and then for 20 hours at 120° C. The cooled reaction mixture was evaporated under reduced pressure to yield a residue which was dissolved in 1 Normal sodium hydroxide. The resultant solution was treated with charcoal, filtered, and the filtrate neutralized by the addition of concentrated hydrochloric acid which caused the precipitation of a crude product. The crude product was eluted from a silica column with chloroform as eluant, and the combined fractions containing product were evaporated under reduced pressure to yield a residue. This was twice recrystallized from methanol to yield the title compound, 0.23 g, m.p. 207.5-208.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.BrBr.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])O.[Na+]>O.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: Nc1ccccn1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cccc(-c2cn3ccccc3n2)c1
Yield: 25.6 %

Procedure:
Dissolving 10 g (50 mmol) of 3′-bromoacetophenone into 20 milliliter of acetic acid and adding 7.0 g (44 mmol) of bromine at the temperature of about 5 to 10° C., stirred at the temperature of about 5 to 10° C. for 4 hours until the color of bromine disappeared. After completion of the reaction, adding water and an extraction was carried out using dichloro-methane. Further, washing with water, dried with the use of sodium sulfate. The solvent was removed by distillation and the resultant crude 2,3′-dibromo acetophenone was dissolved into 30 milliliter of ethanol, adding 5.0 g (53 mmol) of 2-aminopyridine and 7.0 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 8 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 3.5 g of 2-(3-bromo-phenyl)-imidazo [1,2-a] pyridine (yield: 26%).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[N+:44]([O-:46])=[O:45])[CH:39]=O>O1CCCC1>[C:2]([O:6][C:7](=[O:8])/[CH:9]=[CH:39]/[C:38]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[C:36]([F:35])[CH:37]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc([N+](=O)[O-])c(F)c1
Yield: 86 %

Procedure:
To a suspension of (tert-butoxycarbonylmethyl)triphenylphosphonium chloride (1.6 g, 3.9 mmol; [35000-37-4]) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (0.44 g, 3.9 mmol). After stirring for 15 min 3-fluoro-4-nitrobenzaldehyde (0.60 g, 3.5 mmol; [160538-51-2]) was added. After 1.5 h the suspension was poured on water, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash-chromatography using a gradient of n-heptane:tert-butyl methyl ether (100:0 to 80:20) to give the title compound (804 mg, 3.01 mmol; 86%) as light brown solid. MS: m/e=194.0 [M−C4H9O+].
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=2)=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.C1C[O:32]CC1>>[F:18][C:16]([F:19])([F:17])[C:13]1[N:14]=[CH:15][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:32])=[CH:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: C=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 137 %

Procedure:
To the solution of 5-[(4-ethenylphenyl)oxy]-2-(trifluoromethyl)pyridine (1.83 g, 6.90 mmol) in dry THF (20 mL), was added 9-BBN (20.70 mL, 10.35 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (3M, 9 mL), and 30% H2O2 (8 mL). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (2.67 g, 9.43 mmol, 137% yield) as a colorless oil. LCMS: rt=2.97 min, [M+H+]=284
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([Br:11])[CH:3]=1.[CH:12]1[CH:13]=[CH:14][N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[NH:18][CH2:17][C:16]=12.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[CH2:21][N:15]3[CH:14]=[CH:13][CH:12]=[C:16]3[CH2:17]2)=[O:7])=[C:4]([Br:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1Br
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1Br)N1Cc2cccn2Cc2ccccc21
Reaction time: 16 h
Yield: 96.1 %

Procedure:
Step b) (4-Fluoro-2-bromophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzo-diazepin-10-yl)-methanone: A solution of 4-fluoro-2-bromobenzoyl chloride (5.32 g) from step a), in dichloromethane (35 ml), was added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (3.44 g) and triethylamine (2.27 g) in dichloromethane (80 ml) and cooled in an ice bath. The cooling bath was removed and after stirring for 16 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a pale purple foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1:1) resulted in the intermediate (4-fluoro-2-bromophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone as a tan foam (6.91 g), MS m/z: 384 (M)+. This material was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[N:8][C:9]([OH:13])=[C:10]([CH3:12])[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][C:9]1[N:8]=[C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]2=[N:11][C:10]=1[CH3:12])(=[O:26])=[O:25]
Reactant: Cc1nc2ccnc(Cl)c2nc1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2ccnc(Cl)c2nc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A solution of 5-chloro-2-methylpyrido[3,4-b]pyrazin-3-ol (1.88 g, 9.61 mmol) in DCM (30 mL) at 0° C. was treated with DIEA (3.34 mL, 19.22 mmol) followed by methanesulfonyl chloride (1.11 mL, 14.42 mmol) (Sigma Aldich). The reaction mixture was warmed to RT and stiffed for 1 h. The mixture was diluted with DCM and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a silica gel column (10-35% EtOAc in Hexanes) to give 5-chloro-2-methylpyrido[3,4-b]pyrazin-3-yl methanesulfonate (1.68 g, 6.14 mmol, 64% yield) as a brown solid. MS (ESI, pos. ion) m/z: 274.0 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (1H, d, J=5.7 Hz), 7.85 (1H, d, J=5.7 Hz), 3.83 (3H, s), 2.85 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([CH3:9])[N:3]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:1][C:2]1[C:7]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]([CH3:8])=[C:4]([CH3:9])[N:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1ncc(N)nc1C
Product: Cc1nc(N)c(OCc2ccccc2)nc1C

Procedure:
The known 2-amino-5,6-dimethylpyrazine can be brominated by Preparation 72, Step A method, and then reacted with benzyl alcohol by Preparation 45 method to provide 2-amino-3-benzyloxy-5,6-dimethylpyrazine. The 2-amino group is converted to the 2-hydroxy by the method described by Sharp et al, ibid., (see Route III) which when treated with phosphorus oxychloride by Preparation 13, Step B method, there is obtained 2-chloro-3-benzyloxy-5,6-dimethylpyrazine.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:16])=[O:4].[Na+].[NH2:19][CH2:20][C:21]([O-:23])=[O:22]>COCCO>[Cl:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[O:7][C:6](=[O:17])[C:5]([C:3]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:4])=[C:14]2[OH:15]
Reactant: COC(=O)c1c(O)c2cccc(Cl)c2oc1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2cccc(Cl)c2oc1=O
Yield: 76.9 %

Procedure:
A mixture of 8-chloro-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (150 mg, 0.59 mmol) and glycine sodium salt (286 mg, 2.95 mmol) in 2-methoxyethanol (6 mL) was heated to reflux overnight. Reaction mixture was concentrated and dissolved in water (25 mL). The solution was acidified by 1 N aq HCl to pH=2-3 and extracted with EtOAc. Organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated to give the title compound (135 mg). MS ESI(−) m/e: 296 (M−1).