Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 160 °C

Procedure:
A 200-ml flask was charged with 6.96 parts of the 2,5-dianilinoterephthalic acid obtained in Example 29 and 70 parts of sulfuric acid having a concentration of 98%, and while the mixture was stirred, the mixture was maintained at 160° C. for 5 hours. Then, the mixture was cooled to 80° C. or lower, and 50 parts of water was gradually added over 4 hours. Then, the mixture was poured into 500 parts of ice-containing water at one stroke, and the mixture was filtered, washed with water and dried to give 5.83 parts (93.5% of the theoretical yield) of an unsubstituted quinacridone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([Cl:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a suspension of 3-nitrobenzoic acid (934 mg, 5.64 mmol) in benzene (15 mL) was added oxalyl chloride (0.6 mL, 6.77 mmol) and DMF (7 mL), respectively. The resulting mixture was stirred at room temperature until a clear solution was formed. The solvent was removed under reduced pressure and crude acid chloride was used in the next reaction without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([OH:12])(=O)[CH:8]=[CH:9][CH3:10].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[C:13]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][C:16]([C:9]([CH3:10])=[CH:8][CH2:7][OH:12])=[CH:15][CH:14]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CC=CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=CCO)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To an ice cooled slurry of LiAlH4 (4.0 g) in dry ether (400 ml) was added ethyl 3-([1,1′-biphenyl]-but-2-enoate (3e, 11 g) in dry ether (200 ml) dropwise. The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with water (10 ml). A solution of 10% NaOH (5 ml) was added, stirred and then ether layer was decanted. The precipitate was washed with ether and combined ether extracts were concentrated. The crude product was purified by chromatography on silica gel to give 7.2 g (77.4% yield) of 3-([1,1′-biphenyl]-4yl)-2-butenol (4e formula 4, R=Ph), m.p. 112-114° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C(=O)N([Br:27])C(=O)C1>C1COCC1>[CH2:16]([O:15][C:13](=[O:14])[C:7]([Br:27])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:17]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To an ice-cooled solution of diethyl phenylmalonate (3.0 g, 12.7 mmol) in THF (90 mL) was added portionwise sodium hydride (1.015 g, 60% in oil, 25.4 mmol). The mixture was stirred in the ice bath for 30 min and NBS (2.486 g, 14 mmol) was added. The mixture was stirred in the ice bath for 10 min, and then at RT for 20 min. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The residue was dissolved in DCM, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% EtOAc in cyclohexane) affording the title compound as a colourless oil (3.418 g, 85%). 1H NMR (CDCl3, 300 MHz): δ 7.60-7.56 (2H, m), 7.39-7.32 (3H, m), 4.33 (2H, q, J=7.1 Hz), 4.32 (2H, q, J=7.1 Hz), 1.30 (6H, d, J=7.1 Hz).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CCCCCC.CN(C)C=O>[Br:3][C:4]1[N:5]=[C:6]2[CH:12]=[CH:11][N:10]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Sodium hydride (60% in mineral oil, 0.800 g, 20 mmol) was washed with hexane then taken up in 30 mL of N,N-dimethylformamide and cooled to 0-5° C. 2-Bromo-5H-pyrrolo[2,3-b]pyrazine (3.0 g, 15 mmol) was added, then SEMCl (3.5 mL, 20 mmol). The mixture was stirred at room temperature for 3 h, then concentrated. Column chromatography afforded 3.25 g (65%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].O>CN(C)C=O>[Br:1][C:15]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([F:9])[C:16]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(C(F)(F)F)c1F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Br)c(C(F)(F)F)c1F
Yield: 76.2 %

Procedure:
A solution of N-bromosuccinimide (24.9 g) in N,N-dimethyl formamide was added to a solution of 2-fluoro-3-trifluoromethylaniline (25 g) in dimethyl formamide. The mixture was stirred for four and a half hours. It was poured into water and the oil was separated. The aqueous layers was extracted with ether and the combined organic layers were washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 4-bromo-2-fluoro-3-trifluoromethylaniline (27.44 g) as an orange oil, b.p. 88°-94° C./4 mbar.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:16][C:17]1[C:23]([OH:24])=[C:22]([F:25])C=C[C:18]=1O>>[Cl:6][CH2:7][C:8]1[C:14]2[C:13](=[C:22]([F:25])[C:23]([OH:24])=[C:17]([F:16])[CH:18]=2)[O:12][C:10](=[O:11])[CH:9]=1
Reactant: Oc1ccc(F)c(O)c1F
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Product: O=c1cc(CCl)c2cc(F)c(O)c(F)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
Sulfuric acid (2 mL) in a flask was cooled to 0° C. After ethyl 4-chloroacetoacetate (0.62 g, 3.8 mmol) was added thereto, 2,4-difluororesorcinol (0.5 g, 3.4 mmol) was added dropwise thereto. The mixture was stirred at room temperature for 2 hours, and the reactant was placed in ice water. The precipitate was filtered, washed with water, and dried by nitrogen gas to obtain the title compound (0.2 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.O=S(Cl)[Cl:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Cl)nc1

Procedure:
Starting from 250 g 6-chloro-nicotinic acid and 850 ml SOCl2, and using the working conditions as in Ex. 1a, there is obtained 243 g 6-chloronicotinoyl chloride, m.p. 49°-51° C.; b.p. 75° C./0,05 mm.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:15])=[CH:8][CH:7]=1>>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])[N:13]1[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 60 °C
Yield: 73 %

Procedure:
Under N2 atmosphere, 11.26 mL chlorosulfonic acid was cooled in an ice bath, and under stirring 10.00 g n-benzylphthalimide was added portionwise over a period of 20 min. The ice bath was removed and the mixture was heated to 60° C. for 30 min. After cooling to room temperature, the mixture was cautiously poured into ice water and extracted twice with chloroform. The combined organic layers were dried over MgSO4 and concentrated to a small volume. The product was obtained by trituration of the concentrate with PA to give 10.44 g (73%) of a white powder. 1H NMR (400 MHz, CDCl3) δ 4.95 (s, 2H), 7.67 (d, J=8.43 Hz, 2H), 7.73-7.78 (m, 2H), 7.85-7.90 (m, 2H), 8.00 (d, J=8.43 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=3)=[CH:11][N:10]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1.O>CN(C)C=O>[C:20]([NH:19][C:15]1[CH:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:40][CH:39]=4)=[O:43])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
40 mg (0,094 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butylpyridin-2-amine were dissolved in 2 ml of dry dimethylformamide and 12 μL (0.094 mmol) of p-trifluoromethylphenylisocyanate were added. The solution was stirred at room temperature for 3 hours. The reaction mixture was then poured into water and the product extracted several times with ethylacetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column eluted with dichloromethane-acetone 9/1, affording 40 mg (70% yield) of the title compound.
Reaction SMILES: O[Li].O.O.C([O:9][C:10]([C:12]1([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]2([C:31]([O:33]CCCC)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])CCC>CCO>[C:31]([C:26]1([CH2:25][CH2:24][CH2:23][CH2:22][C:21](=[O:38])[CH2:20][CH2:19][CH2:18][CH2:17][C:12]2([C:10]([OH:11])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:27][CH2:28][CH2:29][CH2:30]1)([OH:33])=[O:32]
Reactant: CCCCOC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OCCCC)CCCC2)CCCC1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(CCCCC1(C(=O)O)CCCC1)CCCCC1(C(=O)O)CCCC1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
LiOH.H2O (3.21 g, 76.4 mmol) and H2O (40 mL) were added to a solution of butyl 1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate (7.25 g, 15.0 mmol) in EtOH (120 mL) and the resulting mixture was stirred at reflux temperature for 25 h, allowed to cool to rt and concentrated in vacuo to a smaller volume. H2O (100 mL) was added and the resulting mixture was extracted with Et2O (25 mL), acidified with aqueous HCl (6 M, 15 mL) and extracted with Et2O (3×50 mL). The latter organic layers were combined, dried (Na2SO4, to avoid loss of material, a minimal amount of Na2SO4 was used, with the desiccant becoming a white, oily paste. The organic layer was decanted from the desiccant.) and evaporated in vacuo to give 1-[9-(1-carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid (5.46 g, 95% pure by 1H NMR, 94%, mp=99-103° C.) as a white solid. An analytical sample was obtained after recrystallization from iPr2O/heptane. mp=104-106° C. 1H NMR (CDCl3): δ=2.39 (t, J=6.9 Hz, 4H), 2.18-2.10 (m, 4H), 1.69-141 (m, 20H), 1.27-1.14 (m, 4H). 13C NMR (CDCl3): δ=211.1, 184.6 (2×), 53.9 (2×), 42.5 (2×), 39.0 (2×), 35.9 (4×), 25.7 (2×), 24.9 (4×), 24.0 (2×). Anal. calcd for C21H34O5: C, 68.82; H, 9.35. found: C, 68.78; H, 9.47.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-bromobenzoic acid (5 g) and thionyl chloride (15 mL) was stirred at the room temperature for 16 hours, heated to reflux for 6 hours and then stirred at room temperature for 16 hours. At the end of this period, the reaction mixture was diluted with chloroform and evaporated. The residue was treated with toluene, evaporated and the process was repeated three times. The product was obtained as a solid (5.63 g); MS: 221; NMR: 7,5 (m, 2), 7.9-8.1 (m, 2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.O=S(Cl)[Cl:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
A mixture of 4-bromobenzoic acid (8 g, 39.8 mmoL) in SOCl2 (80 mL) was stirred at 80° C. for 4 hours and then concentrated under reduce pressure. The resulting white solid was used directly for next step without further purification (8.5 g, yield 97.3%).
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[O:1]([CH:8]([CH3:12])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(CO)Oc1ccccc1

Procedure:
The title compound was prepared by the procedure of Preparation 2 in quantitative yield from 2-phenoxypropionic acid (Aldrich Chem. Co.) and lithium aluminum hydride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl[Pd]Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol), K2CO3 (749 mg, 5.43 mmol) ανδ PdCl2 (dppf) (140 mg, 0.18 mmol) were stirred in DMSO (10 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80° C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc, 100:0 to 50:50) afforded the title compound title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.N1C=CC=CC=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O>[CH3:22][C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[O:28])=[CH:30][CH:31]=1)([CH3:20])[CH3:21]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 16.8 g. (0.1 mol) 4-methoxy-2-nitroaniline in 150 ml. anhydrous pyridine are added dropwise, while cooling with ice, 19.7 g. (0.1 mol) 4-tert.-butylbenzoic acid chloride. The reaction mixture is stirred for 1 hour at ambient temperature, poured into 1 liter of cold water and the precipitate obtained is filtered off with suction. There are obtained 32.3 g. (98% of theory) of the title compound in the form of yellow crystals; m.p. 103°-107° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (163 mg, 1.45 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (300 mg, 1.03 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and Cul (15 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 70° C. for 14 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 120 mg, 33%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[C:28]([Si:32]([O:35][CH2:36][CH2:37]I)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29].Cl>C1COCC1.O>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:37][CH2:36][O:35][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiHMDS in THF (72.9 mL of a 1 M solution, 72.9 mmol, 2.2 eq) at −78° C. under Ar was added a solution of (1R,4S)-methyl 4-((t-butoxycarbonyl)amino)cyclopent-2-enecarboxylate (prepared according to the procedure of US 20050101628 A1 (see page 31, column 1, Procedure B, step B)), 8.00 g, 33.2 mmol, 1 eq) in THF (40 mL) dropwise over 1 hr. After stirring for 30 min, a solution of t-butyl(2-iodoethoxy)dimethylsilane (13.29 g, 46.4 mmol, 1.4 eq) in THF (20 mL) was added. The solution was kept at −78° C. for 15 min, then gradually warmed to 0° C. over 2 hrs, and kept at 0° C. for 1 hr. 1 N HCl and water were added, the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated. Purification by chromatography (400 g column) eluting with 5 to 20% EtOAc/heptane afforded the title compound of Step A. 1H NMR (CHLOROFORM-d) δ: 5.76-5.85 (m, 2H), 4.90 (d, J=9.0 Hz, 1H), 4.72-4.82 (m, 1H), 3.69 (s, 3H), 3.57-3.64 (m, 2H), 2.24 (dd, J=13.9, 8.0 Hz, 1H), 2.14 (dd, J=14.1, 3.5 Hz, 2H), 1.71-1.82 (m, 1H), 1.40-1.50 (m, 9H), 0.84-0.90 (m, 9H), 0.03 (s, 6H). ESI-MS (m/z): Calculated for C20H37NO5Si: 422.2 (M+23). found: 422.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: COc1ccc(CC(=O)O)cc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (3-bromo-4-methoxy-phenyl)-acetic acid (5.226 g, 21.32 mmol) in MeOH (52 mL) was added thionyl chloride (3.1 mL, 42.65 mmol), and the reaction was stirred at room temperature for 2 hours. Once no starting material was seen by analytical LCMS, the mixture was concentrated and then diluted with CH2Cl2 and aqueous 1N NaOH. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Na].Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12](OCC)(=[O:19])[CH2:13][C:14](OCC)=[O:15]>C(O)C>[C:4]1([C:3]2[N:11]=[C:14]([OH:15])[CH:13]=[C:12]([OH:19])[N:10]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Oc1cc(O)nc(-c2ccccc2)n1
Yield: 44836.7 %

Procedure:
To ethanol (200 mL) was added sodium (7.9 g, 34 mmol). After dissolution, benzamidine hydrochloride (20.0 g, 0.128 mmol) and diethyl malonate (20 mL, 132 mmol) were added. The reaction was heated for 4 hours and the solvent was removed in vacuo. Hydrochloric acid was added and a precipitate formed. The solid was collected and dried in a vacuum oven to give 10.8 g (45%) of 2-phenyl-4,6-dihydroxypyrimidine.
Reaction SMILES: [O-]CC.[Na+].Cl.[C:6]([NH2:14])(=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15](OCC)(=[O:22])[CH2:16][C:17](OCC)=[O:18]>C(O)C>[OH:18][C:17]1[CH:16]=[C:15]([OH:22])[N:14]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:13]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)nc(-c2ccccc2)n1
Yield: 83.8 %

Procedure:
Using a 20% solution of sodium ethoxide in ethanol (150 g), benzamidine hydrochloride (34.5 g), diethyl malonate (32 g) and ethanol (500 ml), the same procedures as Reference Example 11-(1) are repeated to give crude 4,6-dihydroxy-2-phenylpyrimidine (31.5 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=O)=O.[Mg+2].CCN(CC)CC>>[CH2:12]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO4 (1.33 g) in 1,2-dicholoroethane (300 mL) and Et3N (3.1 mL, 22.3 mmol) at RT was added NaHB(AcO)3. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated aqueous NaHCO3 (200 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10%) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23%). Mass calculated for C14H22N2O2=250.34; found: [M+H]+=251.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>COCCO>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: COCCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(F)ccc12
Reaction time: 1 h
Yield: 65.7 %

Procedure:
2-Amino-4-fluorobenzoic acid (15 g, 96 mmol) was dissolved in 2-methoxyethanol (97 ml). Formamidine acetate (20.13 g, 193.4 mmol) was added and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated and the residue stirred in aqueous ammonium hydroxide (0.01 N, 250 ml) for 1 hour. The suspension was filtered, washed with water and dried over phosphorus pentoxide to yield 7-fluoroquinazolin-4(3H)-one as an off-white solid (10.35 g, 65% yield):