Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)[N:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2].[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[S:20][C:21]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=3)=[CH:22][CH:23]=2)[N:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 2-(5-bromothiophen-2-yl)-1-(2,6-dichlorophenyl)-1H-imidazole-4-carboxylic acid ethyl ester (335 mg, 0.75 mmol), 3-methanesulfonyl-phenylboronic acid (180 mg, 0.90 mmol), K2CO3 (0.32 g, 2.3 mmol), Cl2 Pd(dppf)-DCM (30 mg, 5 mol %) and H2O (0.4 mL) in DME (4 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 2 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 30:70 to 80:20) to give the title compound (313 mg, 80%) as a pale yellow solid, which was used in the next step without further purification. 1H-NMR (DCM-d2): δ 8.08 (m, 1H), 7.82 (m, 2H), 7.64 (s, 1H), 7.51-7.62 (m, 4H), 724 (d, 1H), 6.72 (d, 1H), 4.38 (q, 2H), 3.05 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>ClCCl>[Si:20]([O:15][CH2:14][C@@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: OC[C@@H]1COCCN1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1COCCN1Cc1ccccc1
Yield: 95.2 %

Procedure:
(3R)-4-Benzylmorpholine-3-methanol (1.04 g, 5.0 mmol), t-butyldimethylchlorosilane (0.83 g, 5.5 mol), and imidazole (0.41 g, 6.0 mmol) were allowed to react in 5 mL of dichloromethane at room temperature overnight. The reaction product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain (3S)-3-(t-butyldimethylsilyloxy)methyl-4-benzylmorpholine (1.53 g, 95%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)c(F)c1
Temperature: 85 °C

Procedure:
(3-Fluoro-4-hydroxy-phenyl)-acetic acid (20.03 g) was dissolved in ethanol (100 mL), and conc. sulfuric acid (1 mL) was added to the solution. The solution was heated to 85° C. for 16 h. The reaction mixture was allowed to cool and evaporated to dryness in vacuo to yield the crude title compound (24.2 g). An aliquot of the crude product was purified by silica gel chromatography (ethyl acetate:hexanes=3:7) for full characterization of the title compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16]/[C:17](/[C:27]([F:30])([F:29])[F:28])=[CH:18]\[C@@H:19]1[C@H:21]([C:22]([OH:24])=[O:23])[C:20]1([CH3:26])[CH3:25].[CH2:31]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[F:46])[CH2:41]O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:16]/[C:17](/[C:27]([F:28])([F:29])[F:30])=[CH:18]\[C@@H:19]1[C@H:21]([C:22]([O:24][CH2:41][C:40]2[CH:43]=[CH:44][C:45]([F:46])=[C:38]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:39]=2)=[O:23])[C:20]1([CH3:26])[CH3:25]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: OCc1ccc(F)c(Cc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)OCc1ccc(F)c(Cc2ccccc2)c1
Yield: 36.5 %

Procedure:
A solution of dicyclohexylcarbodiimide (0.4 g) in dichloromethane (10 cm3) was added to a stirred mixture of (1RS, cis)-3-(Z-2-chloro,3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid (0.54 g), 3-benzyl-4-fluorobenzyl alcohol (0.43 g), 4-dimethylaminopyridine (0.02 g) and dry dichloromethane (5 cm3), and the resultant mixture stirred at the ambient temperature (ca. 20° C.) for 18 hours. The reaction mixture was then heated to the reflux temperature for 3 hours, and subsequently cooled again. The precipitate which formed was removed by filtration, and the filtrate concentrated by evaporation of the solvent under reduced pressure. The residual oil was purified by column chromatography using a silica column eluted with a mixture of ethyl acetate (1 part by volume) and petroleum ether (boiling range 60°-80° C., 19 parts by volume), to yield 3-benzyl-4-fluorobenzyl (1RS, cis)-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylate (0.32 g).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[C:14]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](F)[CH:26]=3)=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[NH:16][CH:17]=2)[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[C:32]1([C@@H:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.C(=O)([O-])O.[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[C:14]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:40][C@H:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:39])[CH:26]=3)=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[NH:16][CH:17]=2)[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C[C@H](N)c1ccccc1
Reactant: C=CCOC(=O)N1CC=C(c2c[nH]c(-c3ccc(F)cc3)c2-c2ccnc(F)c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCOC(=O)N1CC=C(c2c[nH]c(-c3ccc(F)cc3)c2-c2ccnc(N[C@@H](C)c3ccccc3)c2)CC1
Temperature: 150 °C
Reaction time: 10 h
Yield: 51.6 %

Procedure:
A mixture of 360 mg (0.85 mmol) of 4-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(2-fluoropyridin-4-yl)-1H-pyrrole [prepared as described in step 73 (ii) above], 3.6 ml (28.3 mmol) of 1(S)-phenylethylamine and 0.36 ml of concentrated hydrochloric acid was stirred at 150° C. for 10 hours. At the end of this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and then this was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to give 229 mg (yield 49%) of the title compound as a brown amorphous solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][CH2:11][CH2:12][N:13]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][CH2:15][C:14]1=[O:26].[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:27]([O:31][C:32](=[O:35])[CH2:33][CH:15]1[CH2:16][CH2:17][CH:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:19][N:13]([CH2:12][CH2:11][O:10][CH3:9])[C:14]1=[O:26])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCCN1CC(c2ccccc2)CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCN1CC(c2ccccc2)CCC(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium diisopropylamide (1.8 M in heptane/tetrahydrofuran/ethylbenzene; 0.58 g, 5.41 mmol) was added to a solution of 1-(2-methoxyethyl)-6-phenylazepan-2-one (1.03 g, 4.16 mmol) in tetrahydrofuran (40 mL) at −78° C. After 2 h, tert-butylbromoacetate was added. After an additional 1.5 h, the reaction was quenched with methanol and allowed to warm to ambient temperature and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave 450 mg (cis isomer) and 350 mg (trans isomer) of the title compound. MS 362 (M+1). cis isomer: 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J=7.6 Hz, 2H), 7.26 (m, 1H), 7.22-7.20 (m, 2H), 4.04 (br d, J=15.2 Hz, 1H), 3.84 (dt, J=13.9, 4.9 Hz, 1H), 3.51 (dd, J=15.4, 3.9 Hz, 1H), 3.40-3.35 (m, 1H), 3.30-3.21 (m, 2H), 3.24 (s, 3H), 3.02-3.00 (m, 1H), 2.84 (dd, J=16.4, 7.6 Hz, 1H), 2.68-2.66 (m, 1H), 2.33 (dd, J=16.4, 6.8 Hz, 1H), 2.11-2.07 (m, 1H), 2.05-1.95 (m, 1H), 1.80-1.76 (m, 2H), 1.46 (s, 9H). trans isomer: 1H NMR (500 MHz, CDCl3) δ 7.32 (t, J=7.3 Hz, 2H), 7.24-7.21 (m, 1H), 7.18 (d, J=7.1 Hz, 2H), 3.96 (dd, J=14.9, 10.0 Hz, 1H), 3.82-3.77 (m, 1H), 3.56-3.46 (m, 2H), 3.43-3.38 (m, 1H), 3.34 (s, 3H), 3.30 (d, J=15.1 Hz, 1H), 3.20-3.15 (m, 1H), 2.85 (dd, J=16.6, 7.8 Hz, 1H), 2.78 (br t, 1H), 2.26 (dd, J=16.6, 6.6 Hz, 1H), 2.10 (br d, J=22.7, 9.3 Hz, 1H), 1.77-1.73 (m, 1H), 1.62-1.59 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)(OCC)=O.[CH3:22][NH:23][C:24](=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:22][N:23]1[C:24](=[O:32])[C:25]2[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:27]=[C:1]1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: CCOC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 16-22 (100 g, 0.32 M), N-methyl anthranilamide (58.7 g, 0.39 M) and p-toluenesulfonic acid (200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (29 g, Y=23%, P=98%).
Reaction SMILES: [C:1]([CH2:6][CH:7]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH:27](=O)[C:28]1[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:30]>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1](=[O:2])/[C:6](/[CH3:7])=[CH:27]/[C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[OH:30])[CH3:5]
Reactant: O=Cc1ccccc1O
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccccc1O
Temperature: 25 °C

Procedure:
To a solution of 75.0 g (carbethoxyethylidene)triphenyl phosphorane in 350 ml of toluene, 23.2 g of salicylaldehyde was dropped in at 20° C. while cooling in an ice-bath. After stirring at room temperature for 90 mn., the reaction mixture was diluted with toluene and washed to neutrality with water.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH:15]=[CH2:16]>CC(C)=O>[CH2:16]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1CCC(O)CC1
Temperature: 5 °C

Procedure:
To a 500 mL 3-necked round-bottomed flask, was added 24.0 g of 4-hydroxypiperidine dissolved in 140 mL of acetone. To this mixture was added 40.9 g of powdered anhydrous potassium carbonate. The reaction mixture was cooled to 5° C. with an ice bath. While stirring, 28.7 9 of allyl bromide in 60 mL acetone was added slowly to the reaction mixture. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The solid residue was removed by filtration, and acetone was removed from the filtrate using a rotary evaporator yielding 25.0 g of N-allyl(4-hydroxy)piperidine as viscous liquid. To a 500 mL 3-necked round-bottomed flask was added 20 g of N-allyl(4-hydroxy)piperidine dissolved in 75 mL diethyl ether. After cooling to 5° C. with an ice bath, 21.4 g of allyl bromide dissolved in 30 mL of diethyl ether was added slowly. After completion of addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed with diethyl ether (2×1.5 L). The washed solid was recrystallized from acetonitrile. After removal of acetonitrile by filtration, the residue was dried under vacuum yielding 22 9 of N,N-diallyl(4-hydroxy)piperidinium bromide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[C:17]1([NH:23][C:24]([C:26]2[O:27][C:28](Br)=[CH:29][CH:30]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:28]3[O:27][C:26]([C:24]([NH:23][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:25])=[CH:30][CH:29]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccccc1)c1ccc(Br)o1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Solvent: O
Product: Cc1cccc(C#CC=C2CCN(c3ccc(C(=O)Nc4ccccc4)o3)CC2)n1
Yield: 19.3 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (100 mg, 0.47 mmol) and N-phenyl-5-bromofuran-2-carboxamide (125 mg, 0.47 mmol) was stirred at 120° C. for 8 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography eluting with Petroleum Ether-EtOAc 7:3, affording the title product (36 mg) as a brown solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>C(#N)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[I:1])=[CH:18][CH:17]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Nc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1ccc(CNc2ccccc2I)cc1

Procedure:
To a solution of 2-iodoaniline (280 mg, 1.82 mmol) in acetonitrile (6 mL) was added K2CO3 (212 mg, 1.54 mmol) and 4-chlorobenzyl bromide (276 mg, 1.34 mmol). After refluxing overnight under a nitrogen atmosphere, the reaction mixture was diluted with ethyl acetate and filtered. The solvent was removed under reduced pressure and the crude product was used in next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.C([Mg]Cl)(C)C.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:22](=[O:34])[C:21]2=[O:35].[Cl-].[NH4+]>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:22](=[O:34])[C:21]2([OH:35])[C:9]1[C:8]([OH:11])=[CH:7][C:3]2[O:4][CH2:5][CH2:6][O:1][C:2]=2[CH:10]=1
Reactant: O=C1C(=O)N(Cc2ccccn2)c2ccc(Br)cc21
Reactant: Oc1ccc2c(c1)OCCO2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C1N(Cc2ccccn2)c2ccc(Br)cc2C1(O)c1cc2c(cc1O)OCCO2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 101.1 %

Procedure:
To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (2.55 g, 16.8 mmol) in anhydrous dichloromethane (100 mL) at 0° C. added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 10.0 mL, 19.9 mmol). The solution was stirred at 0° C. for 20 min and 5-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione (4.85 g, 15.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 h, saturated aqueous ammonium chloride (25 mL) was added and the mixture was concentrated in vacuo. The residue was triturated with ethyl acetate (250 mL) and the solid collected by filtration to afford 5-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (7.26 g, 98%) as a beige solid: 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.71 (d, J=4.9 Hz, 1H), 8.06 (dd, J=7.80 Hz, 1H), 7.63-7.55 (m, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.35 (dd, J=8.3, 2.0 Hz, 1H), 7.20 (s, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.16 (s, 2H), 5.09 (ABq, 2H), 4.20-4.10 (m, 4H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:20])([F:19])[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:8]([F:11])([F:10])[F:9]>>[F:5][C:6]([F:19])([F:20])[C:7]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([N+:1]([O-:4])=[O:2])[CH:18]=1)([OH:12])[C:8]([F:9])([F:11])[F:10]
Reactant: OC(c1ccccc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Fuming nitric acid (90%, 5 mL) was added drop wise to 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanol (4.2 mL, 25 mmol) in concentrated suifliic acid (15 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and at room temperature for 2 hours. Then it was poured into ice water. The solid was fitered, washed with sodium bicarbonate solution, water, and hexane, and dried to give 6.2 g of 1-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-3-nitrobenzene. 1H NMR (CDCl3): δ 8.66 (s, 1H), 8.38 (d, J=8 Hz, 1H), 8.06 (d, J=8 Hz, 1H), 7.69 (t, J=8 Hz, 1H), 3.66 (bs, 1H). MS (EI) m/z 289 (M+).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24]C=C(O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[Cl:46][C:47]1[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[C:48]=1[CH2:49][N:50]1[CH2:55][CH2:54][N:53](CCCN)[CH2:52][CH2:51]1>>[Cl:46][C:47]1[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[C:48]=1[CH2:49][N:50]1[CH2:51][CH2:52][N:53]([CH2:24][CH2:25][CH2:20][NH:19][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:10][CH2:1][O:2][C:3]=4[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)[CH2:54][CH2:55]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: NCCCN1CCN(Cc2c(F)cccc2Cl)CC1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(NCCCN2CCN(Cc3c(F)cccc3Cl)CC2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-[4-(2-chloro-6-fluorobenzyl)piperazino]propylamine were reacted to yield N2-[3-[4-(2-chloro-6-fluorobenzyl)piperazino]propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=3.0 Hz), 7.37 (d, 1H, J=2.4 Hz), 7.19-7.15 (m, 2H), 7.00-6.93 (m, 2H), 6.81 (d, 1H, J=8.7 Hz), 6.56 (d, 1H, J=2.7 Hz), 5.48 (bs, 1H), 4.27-4.21 (m, 4H), 3.70 (d, 2H, J=1.8 Hz), 3.36 (q, 2H, J=6.3 Hz), 2.68-2.35 (m, 10H), 1.75 (q, 2H, J=6.3 Hz); 19F NMR (CDCl3): −31693, −48483; LCMS: ret. time: 18.20 min.; purity: 97%; MS (m/e): 532 (MH+).
Reaction SMILES: [I-].[Li+].[CH3:3][C:4]([CH3:27])([CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:5]([O:7]C)=[O:6]>N1C(C)=CC(C)=CC=1C>[CH3:3][C:4]([CH3:27])([CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:5]([OH:7])=[O:6]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCC(C)(C)C(=O)OC
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCC(C)(C)C(=O)O

Procedure:
The instant compounds having the 5, 8, 11 and 14 double bonds are prepared preferably by alkylating the appropriate alkyl ester of arachidonic acid with an alkyl iodide in the presence of a base, such as a secondary amine, and n-alkyl lithium, i.e. n-butyl lithium. Typically, ethyl arachidonate is added to n-isopropylcyclohexylamine containing n-butyl lithium at a low temperature, e.g. -78°C., and then methyl iodide is added to yield ethyl 2-methylarachidonate. That same procedure then is repeated with ethyl 2-methylarachidonate in place of ethyl arachidonate to yield ethyl 2,2-dimethylarachidonate. The ester moiety can be cleaved with lithium iodide in an aromatic amine, e.g. collidine, to yield the corresponding acid. For example, methyl 2,2-dimethylarachidonate, when treated with lithium iodide in collidine, affords 2,2-dimethyl arachidonic acid.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:23])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:8][N:9]=1)[C:5]#[N:6].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:23][C:3]1[C:2]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[N:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:4]=1[C:5]#[N:6]
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cnc(Cl)c1Cl
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ncc(-c3ccc(Oc4ccccc4)cc3)c(C#N)c2Cl)cc1
Temperature: 150 °C
Yield: 55.2 %

Procedure:
A mixture of 2,3-dichloro-5-(4-phenoxyphenyl)isonicotinonitrile (109 mg, 0.319 mmol), 4-methoxyphenylboronic acid (58.3 mg, 0.383 mmol), potassium phosphate (136 mg, 0.639 mmol) and palladium tetrakis(triphenylphosphine) (18.46 mg, 0.016 mmol) was pumped and backfilled with nitrogen 3 times. N,N-Dimethylacetamide (2 mL) was added. The mixture was again pumped and backfilled with nitrogen 3 times. The reaction tube was sealed and heated to 150° C. under microwave for 30 min. The mixture was diluted with ethyl acetate (30 mL), washed with 1:1 mixture of brine and water (15 mL), brine (15 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 5-30% ethyl acetate in hexanes, gave 3-chloro-2-(4-methoxyphenyl)-5-(4-phenoxyphenyl)isonicotinonitrile (72.7 mg, 52% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.75 (1H, s), 7.74-7.83 (2H, m), 7.56-7.64 (2H, m), 7.37-7.47 (2H, m), 7.21 (1H, t, J=7.42 Hz), 7.09-7.18 (4H, m), 7.00-7.09 (2H, m), 3.90 (3H, s); MS (ES+) m/z: 413 (M+H); LC retention time: 4.810 min (analytical HPLC Method A).