Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C:7]1[C:8]([C:22]([O:24]C)=[O:23])=[N:9][C:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[C:11]([F:13])[CH:12]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:6][C:7]1[C:8]([C:22]([OH:24])=[O:23])=[N:9][C:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[C:11]([F:13])[CH:12]=1
Reactant: COC(=O)c1nc(-c2c(F)cccc2F)c(F)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-amino-5-fluoropicolinate (1.0 equiv.) in DME/2M Na2CO3 (3:1, 0.05 M) equipped with microwave vial was added 2,6-difluorophenylboronic acid (3.0 equiv.) and Pd(dppf)Cl2-DCM (0.1 equiv.). The reaction mixture was heated to 140° C. for 10 min in microwave reactor. After 2,6-difluorophenylboronic acid (3.0 equiv.) was added more, the reaction mixture was heated once more to 140° C. for 10 min in microwave reactor. After the reaction mixture was cooled to room temperature, H2O and EtOAc were added and the organic phase was washed with brine, then dried with Na2SO4, and concentrated. The crude material was purified via preparative HPLC. The pure methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate was obtained after the pure fractions were neutralized with NaHCO3, extracted with EtOAc, and concentrated (34%). The methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate (1.0 equiv.) was dissolved in THF and MeOH (2:1, 0.2 M) followed by addition of LiOH (1.8 equiv., 1 M aqueous solution). After the reaction mixture was stirred for 1.5 h at room temperature, the reaction mixture was quenched with 1 N HCl solution (1.8 equiv.) and extracted with EtOAc. The organic phase was washed with brine, then dried with Na2SO4, and concentrated. The crude 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid was used for the next step without further purification (88%). LCMS (m/z): 269.0 (MH+); LC Rt=3.26 min.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([O-])([OH:13])=[O:12]>>[Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2nc(Cl)[nH]c2c1
Reaction time: 8 h

Procedure:
To 210 mL of fuming HNO3, 2-chlorobenzimidazole (13.42 g, 87.95 mmole) was added portionwise over a period of 10 min with stirring and ice-H2O cooling. After the addition, the cooling bath was removed and stirring was continued at room temperature overnight. This reaction mixture was cooled to ~ 0° C., poured into 300 mL of ice, and neutralized carefully with conc. NH4OH to ~ pH 8. The resulting suspension was filtered. The yellowish solid product was washed with portions of H2O and air-dried. The filtrate and washings were combined and extracted with EtOAc (200 mL×2). The EtOAc solution was washed with sat. NaCl solution (200 mL×2), dried (Na2SO4), and evaporated to give 1.3 g of a yellowish solid. The solid was combined with the major part of the product and was recrystallized from MeOH to give 16.34 g (5 crops, 94%) of 19 as yellowish crystals. mp 235°-237° C. MS (El) m/e 196.9984 (100%, M+ =196.9992). 1H NMR (DMSO-d6) d 14.06 (br. s, 1, 1-NH), 8.41 (s, 1, 4-H), 8.14 (dd, 1, 6-H, J6-4 =2.0 Hz, J6-7 =9.0 Hz), 7.71 (d, 1, 7-H).
Reaction SMILES: [C:1]1(OB(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)(O)O>O.[Pd](Cl)Cl.C(OCC)(=O)C>[C:12]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:14][CH:13]=1
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)Oc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: OB(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture containing phenylboric acid (6.1 g; 50 mmol), 4′-bromopropiophenone (10.65 g; 50 mmol), sodium carbonate (5.3 g; 50 mmol) and palladium chloride (500 mg, 2.8 mmol) in 300 ml of water is heated under reflux for 4 hours. Boric acid (1 g; 0.8 mmol) is then added followed by heating for 30 minutes. Once the mixture has been returned to 23° C., 250 ml of ethyl acetate is added followed by filtering on frit then on GFA paper. The filtrate is decanted and the organic phase is washed with a saturated solution of NaCl before being dried over MgSO4 and concentrated using a rotary evaporator. The precipitate is stirred for 30 minutes in 100 ml of isopentane and 5 ml of dichloromethane. After filtration on frit, the solid is rinsed with isopentane. A cream coloured powder is obtained (8.7 g; 83%). Melting point: 98-99° C. MH+=211.1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+].O.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCc1ccc(Br)cc1F
Temperature: 70 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-fluoro-benzene (8.15 g, 30.4 mmol) dissolved in DMF (16 mL) were added sodium cyanide (2.24 g, 45.6 mmol) and water (2 mL). The reaction was stirred for one hour at 70° C. To the reaction was added 130 mL water; 120 mL saturated NaHCO3, and 100 mL EtOAc. The layers were separated, and the aqueous layer was extracted with 3×100 mL EtOAc. The combined organics were washed with 100 mL water, and then dried over Na2SO4. After filtering off the solids, the mother liquor was concentrated to the desired product by rotary evaporation (6.5 g, 99% yield). MS (APCI): 240 (M+H), 242 (M+2+H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].[CH2:18](O)CCCC=C>>[CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:18])=[O:6]
Reactant: C=CCCCCO
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Product: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
3-Methyl-N-[(hex-5-enyloxy)carbonyl]-L-valine was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine by using 5-hexenol instead of 4-pentenol. LRMS (ESI) m/z 258 [(M+H)+; calcd for C13H24NO4: 258].
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[C:20]([NH:23][CH2:24][C:25](O)=[O:26])(=[O:22])[CH3:21].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:20]([NH:23][CH2:24][C:25]([NH:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17])=[O:26])(=[O:22])[CH3:21]
Reactant: CC(=O)NCC(=O)O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)NC[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-C-(Aminomethyl)thymidine (4) (0.025 g, 0.1 mmol), N-acetylglycine (0.023 g, 0.2 mmol) and TSTU (0.09 g, 0.3 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL) at ambient temperature. Diisopropylethylamine (0.065 g, 0.5 mmol, 0.087 mL) was then added and the reaction mixture stirred for 18 hours at ambient temperature. The solvent was then removed under vacuum and the residue re-dissolved in 9:1 dichloromethane:methanol and eluted through a flash silica gel column with 9:1 dichloromethane:methanol. The title compound (19) was obtained as an amorphous solid on removal of solvent from the appropriate fractions (0.023 g). δH(300 MHz, CD3OD) 7.78(1H, s, H-6), 6.26(1H, dd, H-1′), 4.48(1H, dd, H-3′), 3.83(2H, s, glycyl CH2), 3.60(2H, 2d, H-5′), 3.58(1H, d, 4′-C—CH2), 3.42(1H, d, 4′-C—CH2), 2.33(2H, m, H-2′), 2.00(3H, s, CH3CO), 1.86(3H, s, 5-CH3); ES +ve m/z 393(M+Na)+.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1.S(Cl)([Cl:13])=O>>[Cl:13][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1
Reactant: CCCn1cc(CO)nn1
Reactant: O=S(Cl)Cl
Product: CCCn1cc(CCl)nn1
Temperature: 25 °C

Procedure:
To a solution of aluminum lithium hydride (0.58 g) in THF (51.4 ml) was added dropwise a solution of methyl 1-propyl-1,2,3-triazole-4-carboxylate (2.6 g) in THF (26 ml) at 0° C. The mixture was stirred for 1 hour at room temperature, and an aqueous solution of saturated sodium thiosulfate was added to the mixture at 0° C. The mixture was filtered with Celite, and washed with ethanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-hydroxymethyl-1-propyl-1,2,3-triazole (1.9 g). To 4-hydroxymethyl-1-propyl-1,2,3-triazole (1.9 g) was added thionyl chloride (32 ml) at 0° C., and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, to give 4-chloromethyl-1-propyl-1,2,3-triazole (1.75 g).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:22][C:23]1[CH:43]=[CH:42][C:26]([O:27][CH2:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:25][CH:24]=1.[OH-].[Na+].Cl>O1CCCC1.C(O)C.O.CN(C)C=O>[CH3:35][C:34]1[O:33][C:32]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[N:31][C:30]=1[CH2:29][CH2:28][O:27][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:11]2[CH:12]=[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:10]2)=[CH:43][CH:42]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Sodium hydride (60%, oily, 200 mg) was added to an N,N-dimethylformamide solution (15 ml) of ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (1.04 g) at 0° C., which was stirred at 0° C. for 30 minutes. 4-[2-(4-Chloromethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (1.43 g) was added to the reaction mixture, which was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the substance obtained, 1N aqueous sodium hydroxide solution (4 ml), ethanol (5 ml) and tetrahydrofuran (5 ml) was stirred for 2 hours at room temperature. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The crystals obtained were collected by filtration to yield 3-[1-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (930 mg, yield: 71%). This was recrystallized from acetone-hexane. Melting point: 142–143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClS([N:21]=[C:22]=[O:23])(=O)=O.O>C(OCC)(=O)C>[NH2:21][C:22]([N:13]1[CH2:14][CH2:15][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:12]1=[O:16])=[O:23]
Reactant: COc1ccc(N2CCNC2=O)cc1OC
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(C(N)=O)C2=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 13.33 g (60 mmol) of 1-(3,4-dimethoxyphenyl)-2-imidazolidinone in 150 ml of ethyl acetate was cooled to 0° C., and 8.92 g (63 mmol) of chlorosulfonylisocyanate was added dropwise. The mixture was stirred for one hour at room temperature. To the resulting thick suspension was added 50 ml of water, and the mixture was stirred until two clear layers were formed. The aqueous phase was separated and stored in the refrigerator overnight. The precipitate was filtered off by suction, washed with water and dried in vacuo; yield: 11.04 g; melting point 240° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>CCOCC>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCCOc1ccc(O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCCCCOc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 5.07 g of ethyl 4-(4-hydroxyphenoxy)butyrate in 23 ml of ether is added dropwise to a mixture of 1.72 g of lithium aluminum hydride in 90 ml of ether at a rate which maintains a gentle reflux. The mixture is stirred at ambient temperature for 6 hours, and then water is carefully added followed by 3N HCl to dissolve all solids. After separating the ether phase and extracting the aqueous phase twice with ether, the combined ether phases are washed with saturated NaHCO3, water, and brine and dried over MgSO4. Filtration and concentration yields 4-(4-hydroxyphenoxy)butan-1-ol as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](Cl)=[O:17])=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH:19]([N:22]([CH:25]([CH3:27])C)CC)([CH3:21])C.N1CCCC1>C(#N)C>[N:22]1([C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:2](=[O:1])[C:3]4[C:8]([O:9][C:10]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[O:17])[CH2:19][CH2:21][CH2:27][CH2:25]1
Reactant: O=C(Cl)c1ccc2c(=O)c3ccccc3oc2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCNC1
Product: O=C(c1ccc2c(=O)c3ccccc3oc2c1)N1CCCC1
Reaction time: 2 h

Procedure:
9-oxo-9H-xanthene-3-carboxylic acid (9 g, 37.4 mmol) was added to thionyl chloride (28 mL, 334 mmol). The mixture was refluxed for 5 h. At that time, the thionyl chloride was removed under vacuum and the remaining residue was diluted with toluene and concentrated to dryness to give 9-oxo-9H-xanthene-3-carbonyl chloride. A portion of 9-oxo-9H-xanthene-3-carbonyl chloride (0.25 g, 0.96 mmol) was dissolved in acetonitrile (7 mL). Diisopropylethylamine (335 μL, 1.9 mmol) was then added to the mixture with the subsequent addition of pyrrolidine (113 μL, 1.3 mmol). After stirring 2 h, the solvent was concentrated and the residue was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10%- 90%) in water with trifluoroacetic acid (0.1%) to afford the 3-(pyrrolidine-1-carbonyl)-xanthen-9-one. MS m/z (MH+) 294.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(O)C>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccc(C(N)=O)cc1
Solvent: CCO
Product: Cc1ccc(-c2nc(CCl)co2)cc1
Yield: 50.8 %

Procedure:
4-Methylbenzamide (10.0 g) and 1,3-dichloroacetone (9.4 g) were dissolved in ethanol (100 mL), and the mixture was refluxed for 8 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 7:1) to give the title compound (7.8 g) as a white solid.
Reaction SMILES: [Li].[C:2](#[N:4])C.[N:5]1([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17](OC)=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.O1CCCC1>[N:5]1([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH2:17][C:2]#[N:4])[CH:21]=[CH:22][CH:23]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: COC(=O)c1cccc(OCCN2CCOCC2)c1
Reactant: CC#N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: O
Product: N#CCc1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylarmide (18.8 ml, 37 mmol, 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene) was added dropwise to a solution of acetonitrile (1.58 g, 37 mmol) in dry tetrahydrofuran (50 ml) at −78° C. After stirring the reaction mixture for 30 min., a solution of methyl 3-(2-morpholin-4-ylethoxy)benzoate in dry tetrahydrofuran (50 ml) was added dropwise over 10 min. After 15 min., water was added and the reaction mixture was allowed to warm to room temperature. The aqueous layer was separated and acidified with dilute hydrochloric acid to pH 7. The product was extracted into ethyl acetate and washed with water and brine and dried over magnesium sulfate. The organics were removed in vacuo to give 2-[3-(2-morpholin-4-ylethoxy)phenyl]acetonitrile (5.0 g) as an oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1>>[CH2:13]([C:7]1([CH2:15][CH3:16])[C:6]2[CH:17]=[C:2]([NH:1][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=3)[CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9](=[O:12])[O:8]1)[CH3:14]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: N#Cc1ccc(Br)cc1F
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(C#N)c(F)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromo-2-fluorobenzonitrile according to the coupling procedure described in example 2. 1H NMR (DMSO-d6): δ 9.15 (s, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.24 (dd, J=8.6, 2.3 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.76 (m, 2H), 3.29 (s, 3H), 1.99 (m, 4H), 0.81 (t, J=7.3 Hz, 6H); MS (ESI) m/z 354 ([M+H]+); MS (ESI) m/z 352 ([M−H]−); Anal. calcd for C20H20FN3O2: C, 67.97H, 5.70; N, 11.89. Found: C, 67.09; H, 5.64; N, 11.53.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:23]1[CH2:24][CH2:25][C:20]2[C:19](=[O:26])[O:18][C:17]([CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]=2[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Solvent: ClCCl
Product: CC(C)(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Benzyl isocyanate (0.02 g, 0.15 mmol) was added to a solution of 3-phenyl-3-neopentyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.043 g, 0.15 mmol prepared in a manner analogous to compound 2) in dichloromethane (10 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.041 g, 63%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.87 (s, 9H), 1.88 (d, J=14.88 Hz, 1H), 2.28-2.43 (m, 2H), 2.38 (d, J=14.88 Hz, 1H), 3.16-3.28 (m, 1H), 3.53 (s, 1H), 3.96 (dt, J=19.03, 2.50 Hz, 1H), 4.42 (d, J=5.65 Hz, 2H), 4.59 (s, 1H), 4.88-4.99 (m, 1H), 7.20-7.41 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:7][C:3]=1[C:4](O)=O.[NH2:19][C:20]1[C:25]([NH2:26])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:7][C:3]=1[C:4]1[NH:26][C:25]2[C:20]([N:19]=1)=[N:21][CH:22]=[C:23]([CH3:27])[CH:24]=2
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccco1
Reactant: Cc1cnc(N)c(N)c1
Product: Cc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)[nH]c2c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
In a 40 mL vial was transferred 2-chloro-5-(furan-2-carboxamido)benzoic acid (I-1) (1 g, 3.75 mmol) in polyphosphoric acid (10 mL), and the 2,3-diamino-5-methyl-pyridine (578 mg, 4.69 mmols, 1.25 eq) was added. The dark brown reaction mixture was heated at 150° C. for 4 hrs. The reaction mixture was then quenched with solid sodium carbonate and extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (0-100 EtOAC/Hex), afforded 80 mg (0.22 mmols, 6%) of the title compound (Example 1). 1H NMR (400 MHz, MeOD) δ 8.36-8.25 (m, 1H), 8.20 (s, 1H), 8.04-7.94 (m, 1H), 7.93-7.83 (m, 1H), 7.77 (s, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.31 (d, J=3.5 Hz, 1H), 6.67 (dd, J=1.7, 3.5 Hz, 1H), 2.53 (s, 3H). LCMS M/Z=353.0 (M+1). RT=1.39: Method B.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C[O-].[Na+].C(O)=O>C1(C)C(C)=CC=CC=1.CO>[CH2:1]([N:8]1[C:11](=[O:19])[C:12]2[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:14][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)c1ccccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccccc2c(=O)n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of benzyl isocyanate (13.3 g, 0.10 mol) in xylene (40 ml) is metered, at room temperature, into a solution of methyl anthranilate (15.1 g, 0.10 mol) in xylene (80 ml). After the addition has ended, the batch is stirred at 110° C. for 2 hours. 1.80 ml of a 30% solution of methanolic sodium methylate (0.010 ml) are metered in, and the mixture is stirred at 90° C. for a further 2 hours, during which process methanol is distilled off. 0.9 ml of 85% formic acid (0.020 mol) is subsequently added and the mixture is stirred at 90° C. for a further hour. After cooling, the product is filtered off with suction, washed with 3×25 ml of xylene, 3×25 ml of ethanol and 3×25 ml of water, and dried. 22.2 g of 3-(benzyl)-2,4(1H,3H)-quinazolinedione (yield: 88.0% of theory) of melting point 231° to 232° C. (lit. 227° to 228° C.) are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[N:9]=3)=[CH:6][CH:7]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)cc1OC
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.3 g, 0.9 mmol), 3,4-Dimethoxyphenylboronic acid (0.276 g, 1.5 mmol), Na2CO3 (2 M, 2.5 mL), and Pd(PPh3)2Cl2 (87 mg, 0.7 mmol) in toluene/ethanol (1:1, 6 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give 6-(3′,4′-Dimethoxy-biphenyl-4-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 68% yield.