Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])C.[OH-].[K+]>C(O)C.C(OCC)(=O)C>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:26])=[O:3])=[C:8]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[F:24])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(O)cc1C(=O)NCc1ccc(Br)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)COc1ccc(O)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
A solution of [4-hydroxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (0.773 g, 1.83 mmol)in ethanol (10 mL, 0.18 M) was cooled to 0° C. and treated with aq KOH (5 mL, 1.25 M) and warmed to room temperature. The solution was acidified to pH 1–2, diluted with ethyl acetate and washed with sat'd aq NaCL. The organic layer was dried over Na2SO4, filtered and concentrated to give [4-hydroxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid as a white crystaline solid: mp 244 dec.; 1H NMR (DMSO-d6, 300 MHz) δ 10.14 (br s, 1 H), 8.97 (t, J=5.4 Hz, 1 H), 7.75 (dd, J1=8.4 Hz, J2=0.3 Hz, 1 H), 7.48 (d, J=9.6 Hz, 1 H), 7.37–7.26 (m, 2 H), 6.46 (dd, J1=8.7 Hz, J2=2.1 Hz, 1 H), 6.40 (s, 1 H), 4.77 (s, 2 H), 4.47 (d, J=5.4 Hz, 2 Hz). Anal. calcd for C16H13BrFNO5: C, 48.26; H, 3.29; N, 3.52. Found C, 48.19; H, 3.52; N, 3.32.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[C:13]([NH2:21])[C:14]([NH2:20])=[CH:15][CH:16]=3)[CH2:11]2)=[CH:5][CH:4]=1.[C:24](O)(=[O:28])[C:25](O)=[O:26]>Cl>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[CH:15][C:14]4[NH:20][C:25](=[O:26])[C:24](=[O:28])[NH:21][C:13]=4[C:12]=3[CH2:11]2)=[CH:7][CH:8]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2c(c1N)CN(Cc1ccc(C(F)(F)F)cc1)CC2
Agent: Cl
Product: O=c1[nH]c2ccc3c(c2[nH]c1=O)CN(Cc1ccc(C(F)(F)F)cc1)CC3
Temperature: 25 °C

Procedure:
A solution of the product from Example 16 (0.53 g, 1.32 mmol) in 3N HCl (50 mL) was treated with oxalic acid (0.25 g, 1.98 mmol) and refluxed for four hours. After cooling to room temperature, the precipitate was filtered, suspended in water (70 mL), heated to 80° C. and basifyed to pH 8. The solids were filtered, and dried to give the title compound in two crops [125 mg, mp=293-297° C. (dec.)] and [33 mg, mp=263-266° C. (dec.)] yielding 34%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][CH:17]([CH3:16])[CH2:18][CH2:19]1
Reactant: CC1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(C)CC1

Procedure:
Prepared analogously to Example 1.1 C. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 4-methylpiperidine. Yield: 0.7 g (88.2% of theory); C15H22N2O4 (M=294.35); calc.: molecular ion peak (M+H)+: 295; found: molecular ion peak (M+H)+: 295; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:23])[F:24])=[O:25])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(2-trifluoromethylbenzoyl)piperidine-1-carboxylic acid tert-butyl ester (0.812 g, 2.27 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at ambient temperature overnight., then washed with saturated NaHCO3. The organic phase was separated, dried over MgSO4 and concentrated. The title compound was obtained in 55% yield (0.319 g) and used for next step reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)(C)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (obtained above), 4-amino-3-methoxybenzoic acid (585 mg, 3.5 mmol), isopropanol (10 ml), water (5 mL) and concentrated hydrochloric acid (10 drops) was stirred at 100° C. for 20 h. Solid was filtered to give the product as white solid (396 mg). [M+H] calc'd for C22H26FN5O4, 444; found 444.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[CH3:29])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:10]1[CH:11]=[C:12]([S:15][CH2:16][C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:30])=[O:5]
Reactant: Cc1cc(SCC#Cc2ccc(C(F)(F)F)cc2)ccc1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(SCC#Cc2ccc(C(F)(F)F)cc2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 75 mg (1.7 mmol) of the above prepared {2-methyl-4-[3-(4-trifluoromethyl-phenyl)-prop-2-ynylsulfanyl]-phenoxy}-acetic acid tert-butyl ester in 2 ml dichloromethane was treated at 0° C. with 0.4 ml TFA and stirred at RT for 3 h. The reaction was evaporated, dissolved in toluene and evaporated again (two times). Purification by flash chromatography on SiO2 with a gradient of CH2Cl2/MeOH (98:2 to 9:1) yielded 30 mg of the title compound as white crystals, mp. 130-131° C.
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>>[C:24]1(=[O:33])[N:23]([CH2:22][CH2:21][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[N:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][C:8]4[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=4[C@@H:6]3[CH2:1]2)[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc2c(c1)Cc1cccnc1N1CCNC[C@@H]21
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ncccc3Cc3ccccc3[C@@H]2C1
Yield: 47 %

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-1,2,3,4,10,14b-hexahydropyrazino [2,1-a]pyrido[2,3-c][2]benzoazepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a yield of 47%.
Reaction SMILES: [CH3:1][C:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[O:12][P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1([C:8]([P:13](=[O:12])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: COP(c1ccccc1)c1ccccc1
Product: CC1(C(=O)P(=O)(c2ccccc2)c2ccccc2)CCCCC1

Procedure:
Using a method similar to that described for compound XI, 80 parts of 1-methyl-1-cyclohexanecarboxylic acid chloride and 108 parts of methoxydiphenylphosphine, in the absence of a solvent, give 100 parts of 1-methyl-cyclohexanoyldiphenylphosphine oxide as an oily crude product, which is purified by chromatography over silica gel (using toluene as the migrating agent).
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH3:20])=[CH2:3].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH:2]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:5]1[CH3:20])([CH3:3])[CH3:1]
Reactant: C=C(C)n1c(C)c(-c2ccc(F)cc2)c2cccnc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(-c2ccc(F)cc2)c2cccnc2n1C(C)C
Reaction time: 16 h

Procedure:
Into a parr vessel are placed 330 mg of the olefinic product of Step 4, above, 20 ml of 100% ethanol and 100 mg of 5% palladium on carbon. Hydrogen gas is added at 40 to 50 psi and held at R.T. for about 16 hrs. Ethyl acetate is then added, the mixture filtered through Celite® and then evaporated to dryness to give the title product of this step as a slightly yellowish gum, which solidified on standing to a light cream solid (mp 57°-68°).
Reaction SMILES: [C:1](=[O:12])([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:2][CH2:3]Cl.[I-:13].[Na+]>CC(C)=O>[C:1](=[O:12])([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:2][CH2:3][I:13]
Reactant: [I-]
Reactant: O=C(OCCl)OC1CCCCC1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCI)OC1CCCCC1

Procedure:
A solution of 0.78 g of chloromethyl cyclohexyl carbonate and 1.0 g of sodium iodide in 15 ml of acetone is stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue is extracted with ether and the solvent is distilled off under reduced pressure to give the title compound as pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[OH:18][C:19]1[CH:34]=[CH:33][C:22]([CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)C(=Cc1ccc(O)cc1)C(=O)OC
Reactant: ClCc1ccc(-c2nc3ccccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(=Cc1ccc(OCc2ccc(-c3nc4ccccc4o3)cc2)cc1)C(=O)OC
Temperature: 0 °C
Yield: 41 %

Procedure:
A mixture of 0.1 mole 2-(4-chloromethylphenyl)benzoxazole (C) and 0.1 mole dimethyl 4-hydroxybenzylidenemalonate (D) in 300 ml. 2-butanone containing 100 g. potassium carbonate was refluxed for 18 hours and poured onto 1,000 g. ice/water. Filtration, washing with water and recrystallization from methyl cellosolve/isopropyl alcohol gave a 41% yield of the light tan crystalline product II. ##STR5##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:11][C@H:12]([CH3:17])[CH2:13][OH:25])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Solvent: CN(C)C=O
Product: C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and R-(−)-2-amino-1-propanol employing methods similar to those described in Example 2 and using N,N-dimethylformamide as the reaction solvent. The product was obtained as an off-white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.72 (1H, br s), 10.70 (1H, br s), 10.04 (1H, br s), 8.17 (0.23H, s), 8.14 (0.77H, s), 7.34-7.22 (3H, m), 7.14-7.08 (2H, m), 4.79-4.77 (1H, m), 3.98 (2H, s), 3.97-3.92 (1H, m), 3.29-3.21 (1H, m), 1.13 (1.65H, d, J=6.6 Hz),1.08 (1.35H, d, J=6.6 Hz); HRMS calcd for C19H18FN3O4+H+: 372.1354. Found 372.1361.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[CH2:22][O:21][C:20](=[O:24])[N:19]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(O)C>[CH2:25]([N:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:23]=2[CH2:22][O:21][C:20]1=[O:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: O=C1OCc2c(N3CCNCC3)cccc2N1Cc1ccccc1
Temperature: 100 °C

Procedure:
4-(1-Benzyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (33 mg, 0.08 mmol) was dissolved in 4 ml ethanol. To this solution was added 2 M ethanolic hydrochloric acid solution (1 ml). The reaction mixture was heated at 100° C. for 20 minutes, at which time a crystalline solid formed. The solution was allowed to cool to room temperature and 13 mg of 1-Benzyl-5-piperazin-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one hydrochloride salt was collected a light yellow powder. MS: 324 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8]>C(O)C>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CCOC(C)([O-])[O-]
Reactant: CC(C)=CCO
Solvent: CCO
Product: C=CC(C)(C)CC(=O)OCC
Yield: 51.7 %

Procedure:
A mixture of 4.3 g of 3-methyl-2-buten-1-ol and 8.1 g of ethyl orthoacetate was heated with stirring. The temperature was increased slowly from room temperature to 165° over 2hours, during which 2.21 g of ethanol was collected. The temperature was maintained at 165° for 26 hours, during which time an additional 1.52 g of ethanol was collected. The reaction mixture was then allowed to cool and diluted with diethyl ether. The ether solution was washed successively with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The washed solution was dried over magnesium sulfate and distilled to give 4.03 g (52% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 80°-85°/52 mm.
Reaction SMILES: [C:1](O)(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC.C([Li])CCC.[C:28]([O:49][CH2:50][CH3:51])(=[O:48])[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].CI>>[CH3:1][CH:29]([CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:28]([O:49][CH2:50][CH3:51])=[O:48]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OCC
Agent: [Li]CCCC
Solvent: CI
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCC(C)C(=O)OCC

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: [N:1]1([CH2:14][CH2:15][NH:16]C(=O)C)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.O.[OH-].[K+].Cl>C(O)CO>[NH2:16][CH2:15][CH2:14][N:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(=O)NCCn1ccc2c1-c1ccccc1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: NCCn1ccc2c1-c1ccccc1CC2
Temperature: 120 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
N-[2-(4,5-Dihydro-1H-benzo[g]indol-1-yl)ethyl]acetamide (5.0 g) was suspended in 60 ml of ethylene glycol and 25 ml of water under argon and treated with 5.0 g of powdered potassium hydroxide. The mixture was stirred at 120° C. for 18 hours, subsequently cooled and treated with 150 ml of 2N hydrochloric acid while cooling. The solution was washed with 200 ml of methylene chloride, the organic phase was extracted three times with 100 ml of 2N hydrochloric acid each time, the aqueous phases were combined and made strongly alkaline with 28% sodium hydroxide solution while cooling with ice. The aqueous solution was extracted once with 200 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 4.0 g of brown oil, was chromatographed on 250 g of silica gel with methylene chloride/methanol mixtures (99:1 to 19:1) as the eluent. There were obtained 3.7 g (88%) of 1-(2-aminoethyl)-4,5-dihydro-1H-benzo[g]indole which was processed without further purification.
Reaction SMILES: [I:1][CH:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH3:11]O>S(=O)(=O)(O)O>[CH3:11][O:9][C:8](=[O:10])[CH:4]1[CH2:3][CH:2]([I:1])[CH2:7][CH2:6][NH:5]1
Reactant: CO
Reactant: O=C(O)C1CC(I)CCN1
Agent: O=S(=O)(O)O
Product: COC(=O)C1CC(I)CCN1
Yield: 86 %

Procedure:
To a solution of 13a prepared in general method Q (5 g, 13.26 mmol) in methanol (500 mL) was added a few drops of conc. sulfuric acid. The reaction mixture was refluxed overnight. The solvent was evaporated and the residue was purified by chromatography to give 4-iodopipecolinic acid methyl ester 14a as a yellow solid (3.0 g, 86%): 1H NMR (300 MHz, CDCl3) δ 8.49 (d, J=1.5, 1), 8.37 (d, J=5.4, 1), 7.85 (dd, J=1.6, 5.2, 1), 4.00 (s, 3); MS (ESPOS): 264.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]([CH:11]([N:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N+:33]([O-])=O)[C:25]1=[O:36])[CH2:12][CH2:13][C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:10])C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:33][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH2:32][N:24]([CH:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:25]2=[O:36]
Reactant: O=C(CCC(C(=O)OCc1ccccc1)N1Cc2c(cccc2[N+](=O)[O-])C1=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1CN(C(CCC(=O)O)C(=O)O)C2=O
Yield: 81.4 %

Procedure:
A mixture of 1-(4-nitro-1-oxoisoindolin-2-yl)propane-1,3-dicarboxylic acid dibenzyl ester (2.6 g, 5.3 mmol), 10%Pd/C (0.26 g) and methanol (50 mL) is hydrogenated at 50 psi of hydrogen for 6 hours. The mixture is filtered through celite and the celite pad is washed with methanol (50 mL). The filtrate is concentrated in vacuo to give 1-(4-amino-1-oxoisoindolin-2-yl)propane-1,3-dicarboxylic acid (1.2 g, 81%); mp 183-185° C.; 1H NMR (DMSO-d6) δ7.17 (t, J=7.6 Hz, 1H), 6.89 (d, J=7.3 Hz, 1H), 6.79 (d, J=7.8 Hz, 1H), 5.50 (b, 2H), 4.82-4.77 (m, 1H), 4.23 (s, 2H), 2.31-1.98 (m, 4H); 13C NMR (DMSO-d6) δ173.46, 172.28, 168.98, 143.58, 132.21, 128.73, 125.65, 116.24, 110.34, 52.83, 45.19, 30.32, 24.42; Anal. Calcd. For C13H14N2O5; C, 56.11; H, 5.07; N, 10.07. Found: C, 55.95; H, 5.37; N, 9.73.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH:11]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[N:10]=[C:6]2[C:5]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:49])[CH2:44][CH2:43]3)=[N:40][CH:41]=2)O1>>[C:18]([O:17][C:15]([N:13]1[CH2:14][CH:11]([C:9]2[N:10]=[C:6]3[C:5]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:4][CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][C:39]([N:42]5[CH2:47][CH2:46][N:45]([C:48]([O:50][CH2:51][C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)=[O:49])[CH2:44][CH2:43]5)=[N:40][CH:41]=4)[N:7]3[CH:8]=2)[CH2:12]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC1(C)OB(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC(c2cn3c(Br)cnc(N4CCOCC4)c3n2)C1
Product: CC(C)(C)OC(=O)N1CC(c2cn3c(-c4ccc(N5CCN(C(=O)OCc6ccccc6)CC5)nc4)cnc(N4CCOCC4)c3n2)C1

Procedure:
Compound 29b was subjected to Suzuki coupling reaction conditions with benzyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate using the methods described in Example 1, Step G to obtain compound 29c. Mass Spectrum (LCMS, ESI pos.) Calcd. for C35H42N8O5: 655.3 (M+H). Found 655.3.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>>[F:14][C:2]([F:1])([F:13])[C:3]1[N:4]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c[nH]c(C(F)(F)F)n1
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c(C(F)(F)F)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(b) starting from ethyl 2-(trifluoromethyl)-1H-imidazole-4-carboxylate (9.5 mmol, 2 g) and SEM-Cl (11.5 mmol, 2.1 ml). Yield 1.9 g. 1H-NMR (400 MHz; CDCl3): δ −0.01 (s, 9H), 0.91 (t, 2H), 1.40 (t, 3H), 3.54 (t, 2H), 4.40 (q, 2H), 5.43 (s, 2H), 7.85 (s, 1H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Br)[CH:29]=[CH2:30]>>[CH2:30]([N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21])[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Product: C=CCn1c(=O)n(O)c(=O)c2oc3ccccc3c21

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with allyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 4.92-4.94 (m, 2H); 5.09-5.18 (m, 2H); 6.03-6.16 (m, 1H); 7.45 (dd, J=8 Hz, 1H); 7.65 (dd, J=8 Hz, 1H); 7.81 (d, J=8 Hz, 1H); 7.98 (d, J=8 Hz, 1H); Ret. time=1.94 min., m/z=259.0.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:13]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C@@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)[N:36]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCOCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 32) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as an off-white solid as a mixture of diastereomers (0.60 g, 53%); ES+-HRMS m/e calcd for C27H31N5O6F2 [M+H+] 560.2315 found 560.2319. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.29 (m, 2H), 1.25 (s, 3H), 1.30, 1.31 (2×s, 3H), 1.35-1.59 (m, 3H), 1.84-1.94 (m, 1H), 2.15-2.26 (m, 1H), 3.09-3.27 (m, 2H), 3.70-3.85 (m, 3H), 3.97-4.18 (m, 3H), 4.31-4.40 (m, 1H), 5.54 (dd, J=11.1, 4.0 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.34-7.43 (m, 2H), 7.43-7.53 (m, 1H), 7.60 (br s, 1H), 8.29 (d, J=2.7 Hz, 1H), 10.86, 10.87 (2×s, 1H).