Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[N:19]1>>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:22]2[N:18]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(I)ccc(C#N)c1Cl
Reactant: CC1(C)OB(c2ccn(C3CCCCO3)n2)OC1(C)C
Product: Cc1c(-c2ccnn2C2CCCCO2)ccc(C#N)c1Cl
Yield: 68.5 %

Procedure:
The title compound was prepared from 2-chloro-4-iodo-3-methylbenzonitrile (3.52 g, 12.68 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.88 g, 13.95 mmol) using the method of Example 34(a) affording 2.62 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH3:17]>CS(C)=O>[NH2:17][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: N
Reactant: COC(=O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CS(C)=O
Product: COC(=O)/C=C/c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of methyl (2E)-3-(4-chloro-3-nitrophenyl)acrylate (from Step 1, 1 eq) in DMSO (0.4 M) at 140° C., ammonia gas was bubbled through for 6 h. The reaction mixture was cooled to RT, degassed with nitrogen, and poured into ice cold water. The precipitate formed was filtered washed with cold water and dried under vacuo to afford the title compound (89%) as a solid. 1H-NMR (400 MHz; DMSO-d6, 300 K) δ 3.70, (s, 3H), 6.46 (d, J 16, 1H), 7.04 (d, J 8.8, 1H), 7.60 (d, J 16, 1H), 7.82-7.86 (m, 3H), 8.25 (s, 1H); MS (ES−) m/z 221 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[S:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[CH:11]=[C:10]([C:20]([F:23])([F:21])[F:22])[N:9]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(5-Chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example B.3) (0.42 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.334 g, 1.3 mmol) according to the general procedure III. Obtained as an off-white solid (0.22 g), which was subsequently deprotected.
Reaction SMILES: C([O:4][C:5]1[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=1[C:7]([NH:9][C:10]1[CH:22]=[C:21]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])=[O:8])(=O)C>FC(F)(F)C(O)=O>[OH:4][C:5]1[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=1[C:7]([NH:9][C:10]1[CH:22]=[C:21]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1cc(CCc2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2-acetoxybenzamido)-4-phenethylbenzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and 0.50 mL of methanol, 0.50 mL of tetrahydrofuran and 10 mg of potassium carbonate were added to the obtained residue sequentially and stirred at room temperature for 3 hours. After insoluble were removed by filtration, 3.0 mL of 10% citric acid aqueous solution was added and a solid; substance was separated, by filtration to obtain 11 mg of 2-(2-hydroxybenzamido)-4-phenethylbenzoic acid as white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH:7](O)([CH3:9])[CH3:8].CS(O)(=O)=O>>[C:1]([CH2:3][C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: CC(C)O
Agent: CS(=O)(=O)O
Product: CC(C)OC(=O)CC#N
Temperature: 105 °C

Procedure:
Cyanoacetic acid (85.5 g; 1.0 mol), isopropanol (80 g; 1.33 mol) and methanesulfonic acid (1.00 g; 0.01 mol) were introduced into a 500 ml flask. The mixture was slowly heated to a maximum of 105° C. while collecting distillates at 77-80° C. Additional isopropanol (220 g; 3.67 mol) was added to maintain the flask at 105-110° C. and the collection of distillates was continued at 77-80° C. After distilling off the unreacted isopropanol, the isopropyl cyanoacetate (bp 100° C./20 mm Hg) was collected as a clear liquid. The yield was 120 g (94.5% of theoretical and its purity was >99% (GC assay).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.N>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12]([C:24]3[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[CH:22][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1c(Br)cnn(-c2ccc(F)c(Cl)c2)c1=O
Reactant: CSc1ccc(B(O)O)cc1
Agent: N
Product: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound is prepared according to the method of Example 6 starting with 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone and substituting 4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 3.2 g, 63%). 1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H), 4.13 (s, 3H), 7.25 (t, J=9 Hz, 1H), 7.35 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.55–7.64 (m, 1H), 7.78 (dd, J=9 Hz, 3 Hz, 1H), 7.93 (s, 2H). MS (DCI/NH3) m/z 377 (M+H)+, 394 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1[CH:23]=[C:22]2[CH:24]=[CH:25][C:26]([C:28](O)=[O:29])=[N:27][C:21]2=[CH:20][CH:19]=1>>[N:27]1[C:21]2[C:22](=[CH:23][CH:18]=[CH:19][CH:20]=2)[CH:24]=[CH:25][C:26]=1[C:28]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:29]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc5ccccc5n4)cc23)CC1
Yield: 91.6 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.0 mg (0.10 mMol) 2-quinaldic acid, 17.6 mg (92%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC(C)=O.[CH2:38]([OH:41])[CH:39]=[CH2:40]>CN(C)C=O.C(N(C(C)C)C(C)C)C>[NH2:8][C:6]1[CH:7]=[C:2]([CH2:40][CH2:39][CH:38]=[O:41])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C=CCO
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: Nc1cc(CCC=O)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
A solution of bromoarene 2 (1.544 g, 7.11 mmol) (or any haloarene of choice); tri-o-tolyl-phosphine (280 mg; 0.9 mmol) and trkdibenzylidene acetone)dipalladium(0) (280 mg; 0.3 mmol) in N,N-dimethylformamide (6 mL) and ethyl diisopropyl amine (3 mL) was treated with prop-2-en-1-ol (3 mL, 40 mmol) (or any alken-1-ol of choice, 6 eq.) and the solution was stirred at 120° C. for 3 h under nitrogen. The reaction mixture was concentrated under high vacuum and the residue was purified by flash chromatography (eluent 5% MeOH in dichloromethane) to afford the aldehyde 80 (253 mg, 18% yield).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Br:11].[F:13][C:14]([Si](C)(C)C)([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CO>[Br:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:3](=[O:12])[C:14]([F:16])([F:15])[F:13]
Reactant: COC(=O)c1ccc(Cl)cc1Br
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
2-Bromo-4-chloro-benzoic acid methyl ester (12.4 g, 50 mmol) in toluene (200 ml) was cooled to −70° C., and trifluoromethyl trimethyl silane (13 ml, 70 mmol) was added. Tetrabutylamonium fluoride (1M, 2.5 ml) was added dropwise, and the mixture was allowed to warm to room temperature over 4 h, after which it was stirred for 10 h at room temperature. The reaction mixture was concentrated to give the crude [1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-1-methoxy-ethoxy]-rimethyl-silane. The crude intermediate was dissolved in methanol (100 ml) and 6N HCl (100 ml) was added. The mixture was kept at 45-50° C. for 12 h. Methanol was removed, and the crude was extracted with dichloromethane (200 ml). The combined DCM layer was washed with water (50 ml), NaHCO3 (50 ml), brine (50 ml), and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography, using 1-2% ethyl acetate in hexane as solvent, to afford 1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (10 g, 70%). 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.50 (d,1H), 7.65(d,1H), 7.80(s,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]=O)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:42][C:39]3[CH:38]=[CH:37][C:36]([C:33]([CH3:35])([CH3:34])[C:32]([OH:44])=[O:31])=[CH:41][CH:40]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(C)(C)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CC(C)(C(=O)O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-(4-formyl-phenyl)-2-methyl-propionic acid methyl ester according to the procedure of Example 66. MS m/z 569; MS m/z 567.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].CN(C=O)C.N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: Oc1c(F)cccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1Br
Temperature: 60 °C
Yield: 82.6 %

Procedure:
A 500-mL three-neck, round bottomed flask, equipped with a stir bar, temperature probe and nitrogen inlet, was charged with 2-bromo-6-fluorophenol (25 g, 130.9 mmol, 1.00 eq), DMF (252 mL, 0.52 M), imidazole (12.3 g, 181 mmol, 1.38 eq) and tertbutyldimethylsilyl chloride (19.7 g, 131 mmol, 1.00 eq). The mixture was heated at 60° Celsius for 3 hours. The reaction was cooled to room temperature and diluted with water. The aqueous phase was extracted with ethyl acetate and the resultant organic solution washed with water and brine and dried over sodium sulfate. The organic phase was concentrated to dryness and purified using FCC to provide (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane as a colorless oil (33 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH2:25].Cl>C(O)(C)C>[ClH:1].[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccncc1
Yield: 51.9 %

Procedure:
A stirred solution of 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (35 mg, 0.1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (15 mg, 0.1 mmol) in a mixture of ethereal hydrogen chloride (2 ml) and isopropanol (5 ml) was heated at reflux for 4 hours. The precipitated product was collected by filtration, washed with acetone and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline hydrochloride (23 mg, 47%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16](CC2C=CC(OC)=CC=2)[N:15]=1)=[O:13])[CH3:2].C(Cl)Cl.CO>C(O)(C(F)(F)F)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[NH:16][N:15]=1)=[O:13])[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(Cc2ccc(OC)cc2)c2c1CCCc1cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc1-2
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(CC)c1NC(=O)c1n[nH]c2c1CCCc1cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc1-2
Temperature: 70 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
N-(2,6-diethylphenyl)-1-(4-methoxybenzyl)-9-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxamide (0.905, 1.29 mmol) was dissolved in TFA. The mixture was stirred for 2 hours at 70° C. The organic solvent was evaporated to dryness and the residue was dissolved in DCM (50 mL) and washed with NaHCO3. The organic layer was dried over anhydrous NaSO4 and the solvent evaporated to dryness. The crude solid was purified by flash chromatography on silica gel eluant: DCM/MeOH:95/5) to afford 0.628 mg (84% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:13])[C:10]([OH:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:13])[C:10]([O:12][CH3:19])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)[C@H](O)c1cc(Cl)cc(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)c1cc(Cl)cc(Cl)c1

Procedure:
A solution of (R)-2-(3,5-dichlorophenyl)-2-hydroxyethanoic acid (19.10 g) in methanol (200 mL) containing concentrated sulfuric acid (1 mL) was stirred at reflux under nitrogen for 16.5 h. The solution was then concentrated under vacuum, and the resulting oil was dissolved in ethyl acetate (200 mL). This solution was washed with saturated aqueous sodium bicarbonate solution, followed by saturated aqueous sodium chloride solution (10 mL). After drying (magnesium sulfate), the ethyl acetate was removed, and the yellow oil was recrystallized from hexane (70 mL) to afford the title compound as a colorless crystalline solid (10.68 g). The mother liquor afforded additional product (3.61 g) upon concentration.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[F:17][C:18]1[CH:19]=[C:20]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[C:22]([F:24])[CH:23]=1.C(O)(=O)C.ClC(Cl)C.C([BH3-])#N>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]2[CH2:26][CH2:27][N:28]([CH2:1][C:3]3[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]4[C:12]=3[CH:11]=[CH:10][CH:9]=[CH:8]4)[CH2:29][CH2:30]2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: Fc1cc(F)cc(C2CCNCC2)c1
Reactant: O=Cc1cc(C(=O)O)c(=O)n2ccccc12
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=C(O)c1cc(CN2CCC(c3cc(F)cc(F)c3)CC2)c2ccccn2c1=O
Temperature: 120 °C

Procedure:
In a 2-5 mL Emrys™ process vial, a mixture of the 1-formyl-4-oxo-4H-quinolizine-3-carboxylic acid (35 mg, 0.16 mmol), 4-(3,5-difluorophenyl)piperidine (45.4 mg, 0.23 mmol), glacial acetic acid (0.055 mL, 0.97 mmol) and 0.80 mL of dichloroethane was stirred vigorously. To the stirring mixture was added resin-bound MP-cyanoborohydride (20.3 mg, 0.32 mmol). The mixture was heated via Emrys Optimizer™ microwave to 120° C. for 30 minutes. The reaction was filtered, providing material, which was purified by reverse phase HPLC to yield the title compound that gave a high resolution mass spectrum (ES+) m/z of 399.1512 calculated for M+H+ [C22H20F2N2O3: 399.1515].
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:22])[C@@H:9]1[CH2:13][C:12](=O)[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:6])([CH3:5])[CH3:4].[CH2:23]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:3]([O:7][C:8](=[O:22])[C@@H:9]1[CH2:13][C:12](=[CH2:23])[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:6])([CH3:5])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=C1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
To an oven-dried 2-necked round-bottomed flask was added sodium hydride (80% oil dispersion) (497 mg, 16.56 mmol) followed by dry tetrahydrofuran (42 mL) and methyltriphenyl-phosphonium bromide (5.92 g, 16.56 mmol). The suspension was stirred for 4 hours at 50° C., at which time a solution of 1-(tert-butyloxycarbonyl)-4-oxo-L-proline tert-butyl ester (1.18 g, 4.14 mmol) in THF (10 mL) was added dropwise with stirring over 30 minutes. The reaction mixture was stirred for 2 hours at 50° C., cooled, filtered, and evaporated. The residue was taken up in ethyl acetate (100 mL), washed with N hydrochloric acid (2×), water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The crude product was subjected to flash silica gel chromatography eluting with 15% diethyl ether/hexane. The title compound was obtained as a colorless oil; yield 519 mg (43%). 400 MHz 1HNMR (CDCl3): δ1.42-1.47 (3s, 18H); 2.54 (m, 1H); 2.92 (m, 1H); 4.03 (m, 2H); 4.23-4.38 (m, 1H); 4.98 (m, 2H).
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][CH:11]=[CH:12][CH:5]2[C:4]1=[O:13].[CH2:14](Cl)[CH3:15]>C(OC)(C)(C)C>[CH2:14]([O:2][N:3]1[C:4](=[O:13])[CH:5]2[CH2:12][CH2:11][CH:10]=[CH:9][CH:6]2[C:7]1=[O:8])[CH3:15]
Reactant: CCCl
Reactant: O=C1C2C=CCCC2C(=O)N1O
Agent: [Na]
Solvent: COC(C)(C)C
Product: CCON1C(=O)C2C=CCCC2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
In an autoclave 60 g of a 20 wt % solution of the sodium salt of N-hydroxytetrahydrophthalimide (0.063 mol), 20 ml of methyl tert-butyl ether and 5.0 g of ethyl chloride were mixed together. The mixture was heated to 100° C. After reaching this temperature the mixture was stirred for a further 5 hours while the temperature was maintained at 100° C. After 5 hours' reaction the excess ethyl chloride was blown out and the reaction mixture was discharged. The reaction mixture was composed of two liquid layers which were separated. The ether layer was analysed by gas chromatography. A yield of 81% of N-ethoxytetrahydrophthalimide (0.051 mol) was found.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[F:12])C=C.Cl.CN(C)[C:16]1[CH:21]=CC=C[CH:17]=1>>[CH2:21]([C:10]1[C:9]([F:11])=[CH:8][CH:7]=[C:6]([F:12])[C:5]=1[OH:4])[CH:16]=[CH2:17]
Reactant: C=CCOc1cc(F)ccc1F
Reactant: CN(C)c1ccccc1
Agent: Cl
Product: C=CCc1c(F)ccc(F)c1O
Temperature: 170 °C
Reaction time: 5 h

Procedure:
The 2,5-difluorophenol allyl ether (13 g) was dissolved in N,N-dimethylaniline (90 ml) and the resulting solution was stirred under a nitrogen gas stream at 170° C. for 5 hr. Then the liquid reaction mixture was poured into a 10% aqueous solution of hydrogen chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: 7% ethyl acetate/n-hexane) to give 2-allyl-3,6-difluorophenol (7.8 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([C:15]([O:17]CC)=O)[C:4]=1[CH3:20].BrN1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([OH:55])=[O:54])=[CH:48][CH:47]=1.C(N(CC)CC)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[CH2:20][N:45]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]([OH:55])=[O:54])=[CH:50][CH:51]=3)[C:15](=[O:17])[C:5]=2[C:6]([O:13][CH3:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=12
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCOC(=O)c1c(C)c(OC)c2ccccc2c1OC
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c2c(c(OC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.9 %

Procedure:
To a solution of ethyl 1,4-dimethoxy-2-methylnaphthalene-3-carboxylate (73 mg, 0.266 mmol) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (47 mg, 0.266 mmol) and dibenzylperoxide (5 mg). The mixture was heated at reflux under nitrogen for 45 min, illuminating with a 200 W lamp. The reaction was cooled to room temperature, 4-aminophenyl acetic acid (40 mg, 0.266 mmol), triethylamine (74 μl, 0.53 mmol) and DMF (5 ml) added and the reaction stirred for 48 h. Acetic acid (glacial, 1 ml) was added to the reaction and the mixture refluxed for 3 h under nitrogen. Sodium metabisulphite solution (1 ml) was added and the reaction evaporated to dryness under vacuum. The product was partially purified by SPE (NH2, 10 g) eluting with methanol then 5% acetic acid in methanol. The fractions containing product were passed through a silica plug washing with 5% acetic acid in methanol. After evaporation of the solvents under vacuum, the residue was columned on a silica gel flash column eluting with a gradient (1:1 ethyl acetate/cyclohexane to 5% methanol, 1% acetic acid in 1:1 ethyl acetate/cyclohexane) to give [4-(4,9-dimethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetic acid (15 mg, 15%).
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI.CCOC(C)=O>CN(C=O)C>[C:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]([CH3:14])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)=O)[nH]n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(C)=O)nn1C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of ethyl 5-acetyl-1H-pyrazole-3-carboxylate (0.050 g, 0.274 mmol) in DMF (3 mL), Cs2CO3 (0.134 g, 0.412 mmol) and methyl iodide (0.022 mL, 0.357 mmol) were added. The reaction was continued at r.t. overnight then AcOEt (20 mL) was added and the organic phase washed with water (20 mL). The aqueous fraction was extracted with AcOEt (20 mL). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (eluant: AcOEt/hexane 2/8) provided 37 mg (68% yield) of ethyl 3-acetyl-1-methyl-1H-pyrazole-5-carboxylate.