Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]2)=[C:12]([F:25])[CH:11]=1.CN([CH:29]=[O:30])C>C1COCC1>[Br:9][C:10]1[C:11]([CH:29]=[O:30])=[C:12]([F:25])[C:13]([CH:16]2[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]2)=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: CCCC1CCC(c2ccc(Br)cc2F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC1CCC(c2ccc(Br)c(C=O)c2F)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
Under a nitrogen atmosphere, LDA (11.6 mL, 12.87 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (30 mL) solution of compound (70) (3.5 g, 11.70 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then DMF (1.28 g, 17.55 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 50 mL of 1 N hydrochloric acid aqueous solution, and extracted with 20 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 6-bromo-2-fluoro-3-(4-propylcyclohexyl)benzaldehyde (71) (2.3 g, yield 89.7%) was obtained.
Reaction SMILES: [Li+].[CH3:2][C:3]([O-:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>O1CCCC1>[Cl:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10]([O:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Cl
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
Lithium tert-butylate (2.2 M in tetrahydrofuran, 6.2 mL, 13.6 mmol) was added to a solution of 2-chloro-4-nitrobenzoyl chloride (2.00 g, 9.09 mmol) in tetrahydrofuran (12 mL) at 0° C. The orange solution was kept at 0° C. for 1.5 h, then allowed to reach room temperature over 16 h, then partitioned between 1 M aq. sodium carbonate solution and isopropyl acetate. The organic layer was dried (MgSO4) and evaporated to afford tert-butyl 2-chloro-4-nitro-benzoate (2.05 g, 88%) which was directly used in the next step. Brown oil, MS (EI)=257.1 (M+).
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[NH:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>O>[NH2:1][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: NOS(=O)(=O)O
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1nccn1N
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of hydroxylamine-o-sulfonic acid (26.64 g, 235.8 mmol, 3.0 eq) in H2O (17 mL) at 0° C., ethyl 1H-imidazole-2-carboxylate (C-3) (11.0 g, 78.6 mmol, 1.0 eq) is added and the resulting mixture is stirred at 90° C. for 30 min. The mixture is cooled to RT and K2CO3 (3.6 g, 26.2 mmol, 1.0 eq) is added in portions. The resulting mixture is stirred at RT overnight, filtered and rinsed with H2O (10 mL×3). The filtrate is extracted with ethyl acetate (50 mL×5). The combined organic layer is washed with brine, dried over Na2SO4 and filtered. The filtrate is evaporated in vacuo and the residue is purified by flash column chromatography on silica gel (1% MeOH-DCM) to afford the product, ethyl 1-amino-1H-imidazole-2-carboxylate (C-4) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17]([O:19]C)=O)=[C:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:27]=[C:26]([CH3:28])[O:25][N:24]=1.C(OC(C)C)(C)C.C(O)=O.C(OC(C)C)(C)C.CC(C)=O>>[CH2:1]([N:8]1[S:13](=[O:14])(=[O:15])[N:12]([CH3:16])[C:11]([C:17]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[O:19])=[C:10]([OH:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N)no1
Reactant: COC(=O)C1=C(O)CN(Cc2ccccc2)S(=O)(=O)N1C
Solvent: O=CO
Solvent: CC(C)=O
Solvent: CC(C)OC(C)C
Product: Cc1cc(NC(=O)C2=C(O)CN(Cc3ccccc3)S(=O)(=O)N2C)no1
Yield: 59 %

Procedure:
The synthesis is effected analogously to Example 1 using in each case 1 equivalent of methyl 6-benzyl-5,6-dihydro-4-hydroxy-2-methyl-1,1-dioxo-2H-1,2,6-thiadiazine-3-carboxylate and 3-amino-5-methylisoxazole. Chromatography over silica gel using a mixture of diisopropyl ether/formic acid=100/1 or recrystallisation from a diisopropyl ether/acetone mixture gives the title compound in a yield of 59%.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])=[C:20]([F:38])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=[CH:39][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7](=[O:8])[NH:6][C:4]([C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:5])[S:25][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])=[C:20]([F:38])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCOC(=O)C(C)(SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
2,6-Difluorobenzoylisocyanate (3 g) in a 1:1 (v/v) mixture of toluene and petroleum ether (10 ml) was added to a solution of the compound produced by Example 3 (7.6 g) in the same solvent (15 ml), over 30 minutes at 15°-20° C. The solution was stirred for 6 hours at ambient temperature and the solvent was removed by evaporation. Column chromatography on silica using a 1:1 (v/v) mixture of diethyl ether and petroleum ether yielded the title compound as a gum (9.5 g).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=O)[CH:12]=[C:7]12.O=P(Cl)(Cl)Cl.[CH2:24]([C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH3:25]>ClCCCl>[CH2:24]([C:26]1[N:27]=[CH:28][N:29]([C:13]2[CH:12]=[C:7]3[C:8]4[C:3]([CH2:4][CH2:5][N:6]3[C:16](=[O:17])[CH2:15][N:14]=2)=[C:2]([I:1])[CH:11]=[CH:10][CH:9]=4)[CH:30]=1)[CH3:25]
Reactant: CCc1c[nH]cn1
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Temperature: 100 °C
Yield: 97.6 %

Procedure:
111-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (440 mg, 1.24 mmol) in dry DCE (10 mL) was treated with POCl3 (0.23 mL, 2.49 mmol) and heated to 100° C. for 1 h. The mixture was allowed to cool to RT and then poured onto H2O and extracted with DCM. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (10 mL) and 4-ethyl-1H-imidazole (597 mg, 6.21 mmol) was added. The mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto H2O, extracted with DCM and the combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) to give the title compound (523 mg) as a brown oil. UPLC-MS: MS 433.1 (M+H+); UPLC rt 0.93 min.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:27]([CH3:28])[CH2:26][CH2:25][C@@:15]4([C:16]=2[C:17]=1OC1C=CC=CC=1)[C:10]3=[CH:11][C@@H:12]([CH3:31])[C:13]([O:29][CH3:30])=[CH:14]4.[Na].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:27]([CH3:28])[CH2:26][CH2:25][C@@:15]4([C:16]=2[CH:17]=1)[C:10]3=[CH:11][C@@H:12]([CH3:31])[C:13]([O:29][CH3:30])=[CH:14]4
Reactant: COC1=C[C@]23CCN(C)[C@H](Cc4ccc(OC)c(Oc5ccccc5)c42)C3=C[C@H]1C
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COC1=C[C@]23CCN(C)[C@H](Cc4ccc(OC)cc42)C3=C[C@H]1C
Reaction time: 1 h

Procedure:
To liquid ammonia (500 ml) at -78° was added dropwise a solution of 3 (17.20 g, 43 mmol) in toluene (150 ml). To the stirred biphasic system was added sodium (2.94 g, 0.128 g atoms) and the resulting blue solution stirred at -78° for 1 hr. Excess NH4Cl was added to quench the blue color and the ammonia allowed to evaporate at room temperature. The residual suspension was diluted with 5% NaOH and extracted 3 times with ether. Evaporation of the dried organic phase gave 4 as a tan syrup. NMR (CDCl3): δ7.17-6.53; m(3), aromatic; 5.47, d(1), H8, J7,8 =4 Hz; 5.10, s(1), H5α; 3.78, 3.65, 2.43, singlets; 1.23 d(3), 7--CH3, J=7 Hz.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:23]([NH2:25])[CH3:24]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:25][CH2:23][CH3:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Reactant: CCN
Product: CCNC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C

Procedure:
Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (1.0 g) and 70% aqueous ethylamine solution (0.24 ml), the procedure of Reference Example 8 is repeated to give ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethylaminoacrylate, which is then treated with 60% sodium hydride (0.15 g) as in Reference Example 9 to give ethyl 1-ethyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.6 g), as white crystals, m.p. 157°-159° C.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].O=[C:7]([CH2:29][CH2:30][CH3:31])[CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1)[C:9](OCC)=[O:10]>CO>[CH2:29]([C:7]1[N:5]=[C:3]([SH:4])[N:2]=[C:9]([OH:10])[C:8]=1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:19][CH:20]=1)[CH2:30][CH3:31]
Reactant: NC(N)=S
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: [Na]
Solvent: CO
Product: CCCc1nc(S)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.08 h
Yield: 43.3 %

Procedure:
5.7 g of sodium are dissolved in 150 ml of methanol, and 19 g of thiourea are added to this solution. The mixture is stirred for 5 minutes and 58 g of ethyl 3-oxo-2-[(2'-cyano-4-biphenylyl)methyl]hexanoate, prepared in Example 4, are added. The mixture is then heated to reflux for 10 hours and the methanol is evaporated off under vacuum. The residue is taken up with water and washed with ether, the aqueous phase is neutralised by adding dilute hydrochloric acid and the crystals obtained are filtered off and washed with water and with ether to give 26 g of 6-n-propyl-2-mercapto-4-hydroxy-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine in the form of crystals of melting point 191° C.
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([OH:33])[C:25]=1[CH2:34][CH2:35][CH3:36])[C:9]=2[CH2:37][CH2:38][CH3:39])([O:3][CH2:4][CH3:5])=[O:2].C(O)C>O1CCCC1.[Ni]>[C:1]([CH:6]1[CH2:15][CH:14]([OH:16])[C:13]2[C:8](=[C:9]([CH2:37][CH2:38][CH3:39])[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([OH:33])[C:25]=3[CH2:34][CH2:35][CH3:36])=[CH:11][CH:12]=2)[O:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCc1c(OCCCCCOc2ccc3c(=O)cc(C(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OCC)CC3O)ccc(C(C)=O)c1O
Reaction time: 24 h
Yield: 50 %

Procedure:
The compound of Example 2, 14.3 g (0.027 mole), was dissolved in 150 ml tetrahydrofuran and 150 ml ethyl alcohol and hydrogenated using Raney Nickel (4.2 g) at 2 psi. After 24 hours at room temperature, the catalyst was separated by filtration and the solvent stripped to give crude (14.4 g oil). 2.4 of the crude was chromatographed (50% ethyl acetate-hexane) to give 1.4 g (50% yield based on crude taken) of the title compound as an oil. Calc: C, 68.61; H, 7.80. Found: C, 68.34; H, 7.74.
Reaction SMILES: [CH:1]([CH:3]=O)=O.[N+:5]([C:8]1[C:9]([NH2:15])=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]>CCO>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[N:15]=[CH:1][CH:3]=[N:14]2)([O-:7])=[O:6]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=CC=O
Solvent: CCO
Product: O=[N+]([O-])c1cccc2nccnc12
Temperature: 85 °C
Yield: 97.5 %

Procedure:
Oxaldehyde (40% in water; 1.43 ml, 31.3 mmol) was added to a solution of 3-nitro-o-phenylene-diamine (600 mg, 3.9 mmol) in EtOH (15 ml) and the mixture was heated at 85° C. for 2 h. The solvent was removed in vacuo, the residue was diluted in water and the aqueous phase was extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent to give the title compound (666 mg, 97%).
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[OH-].[Na+:37]>C(#N)C.O>[OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O-:10])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1.[Na+:37]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)[O-])C(C)(C)C3)s2)c1
Temperature: 35 °C

Procedure:
(1S,4R)-4-Hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (9.8 mg, 0.019 mmol) was dissolved in acetonitrile (20 μL) and water (20 μL). Sodium hydroxide (19 μL, 0.019 mmol) was added, and the mixture was heated to 35° C. for 10 min. The mixture was allowed to cool to rt, diluted with water, froze to a solid, and lyophilized to dryness to afford sodium (1S,4R)-4-hydroxy-2,2-dim ethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohexanecarboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:18]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)CCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)CCO)c1
Temperature: 25 °C

Procedure:
To a solution of 4-tert-butyl-2-(3-hydroxy-1,1-dimethylpropyl)phenol (2 g, 8.5 mmol) and 1.1 mL benzyl bromide in 10 mL of DMF was added 1.75 g of potassium carbonate (K2CO3) and the reaction mixture stirred at room temperature until TLC indicated that the reaction was complete. After stirring overnight, the reaction mixture was diluted with ice and extracted with diethyl ether. The organics were combined, washed four times with water, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on COMBIFLASH® apparatus (0% to 30% ethyl acetate-hexanes) to give 1.7 g of 3-(2-benzyloxy-5-tert-butylphenyl)-3-methylbutan-1-ol as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21](S(C)(=O)=O)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Solvent: C1COCCO1
Product: Fc1cnccc1-c1cc2nc(N3CCOCC3)[nH]c2nc1-c1cccnc1
Yield: 43 %

Procedure:
A solution of 6-(3-fluoropyridin-4-yl)-2-(methylsulfonyl)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridine (0.025 g, 0.068 mmol), morpholine (0.024 mL, 0.268 mmol) in dioxane (0.5 mL) was heated in a sealed tube at 120° C. overnight. The solvent was evaporated and the residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (0.011 g, 44% of yield).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]1[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.O>C(O)(=O)C>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]1[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: FC(F)(F)c1cccc(OC2CCC3(CC2)OCCO3)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(Oc2cccc(C(F)(F)F)c2)CC1

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 2, using 7.6 grams (0.025 mole) of 8-(3-trifluoromethylphenoxy)-1,4-dioxaspiro[4.5]decane and 25 mL of water in 50 mL of acetic acid, yielding 4-(3-trifluoromethylphenoxy)cyclohexanone.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][C@H:19]([C@@H:21]1[C@:39]2([CH3:40])[C@H:24]([C@H:25]3[C@H:36]([CH2:37][CH2:38]2)[C@:34]2([CH3:35])[C:28]([CH2:29][C@H:30]([CH2:32][CH2:33]2)[OH:31])=[CH:27][CH2:26]3)[CH2:23][CH2:22]1)[CH3:20])[CH3:15].[OH:41][C:42]([CH2:45][CH2:46][CH2:47][C@H:48]([C@@H:50]1[C@]2(C)[C@H:53]([C@H:54]3[C@H](CC2)[C@:63]2(C)[C:57]([CH2:58][C@H:59]([CH2:61][CH2:62]2)O)=[CH:56][CH2:55]3)[CH2:52][CH2:51]1)C)(C)C.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+]>>[CH3:63][CH2:62][CH2:61][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]/[CH:54]=[CH:53]\[CH2:52][CH2:51][CH2:50][CH2:48][CH2:47][CH2:46][CH2:45][C:42]([O:31][C@@H:30]1[CH2:29][C:28]2[C@@:34]([CH3:35])([C@@H:36]3[C@@H:25]([CH2:26][CH:27]=2)[C@@H:24]2[CH2:23][CH2:22][C@H:21]([C@@H:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[C@@:39]2([CH3:40])[CH2:38][CH2:37]3)[CH2:33][CH2:32]1)=[O:41]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1

Procedure:
More specifically, cultured J774 cells were plated on a 24 F culture plate containing a serum-free RPMI 1640 medium so as to account for 1×10-6 cells/well. Added to the cells were [14C]oleic acid, delipidized BAS (bovine serum albumin), reconstituted ribosome (0.3 M glucose solution containing cholesterol and phosphatidylcholine at a weight ratio of 2:1) and 25-hydroxycholesterol to culture the cells for 4 hours at 37° C. under 5% CO2. After the culturing, the cultured cells were disrupted with a 1% SDS (sodium dodecyl sulfate) solution, and the lipid in the disrupted solution was extracted with hexane. The extract was dried to solid under reduced pressure. After the resultant residue was then developed (developing solvent: diethyl ether/hexane/acetic acid=80/20/1) by TLC (thin-layer chromatography), the amount of cholesteryl oleate formed was determined by an imaging plate.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1>S(=O)(=O)(O)O>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N+:1]([O-:4])=[O:2])[CH:10]=[N:9][CH:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cncc2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2cncc(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium nitrate (5.34 g; 0.052 mol) was added to 20 ml of concentrated sulfuric acid and slowly dissolved by careful heating. The resulting solution was added dropwise to a solution of 4-bromoisoquinoline (10 g; 0.048 mol) dissolved in 40 ml of the same acid at 0° C. After removal of the cooling bath, the solution was stirred for one hour at room temperature. The reaction mixture was then poured onto crushed ice (400 g) and made basic with ammonium hydroxide. The resulting yellow precipitate was collected by filtration and the filtrate was extracted with diethyl ether (3×500 ml), dried (Na2SO4), and concentrated to give a yellow solid that was combined with the initial precipitate. Recrystallization from methanol gave 12.1 g (89%) of slightly yellow crystals: mp 172-174° C.; 1H NMR: (300 MHz, CDCl3): 9.27 (s, 1H); 8.87 (s, 1H); 8.21 (dd, 1H, J=6.6, 1.2 Hz); 7.96 (dd, 1H, J=6.6, 1.2 Hz); 7.73 (t, 1H, J=7.5 Hz). CIMS m/z: 253 (M+H+, 100%); 255 (M+H++2, 100%). Anal. Calc'd for C9H5BrN2O2: C, 42.72; H, 1.99; N, 11.07. Found: C, 42.59; H, 1.76; N, 10.87.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=[O:16].O>CN(C=O)C>[O:16]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[CH2:14][N:6]1[C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: Oc1nc2c(s1)CCCC2
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)Cn2c3c(sc2=O)CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of 2-hydroxy-4,5,6,7-tetrahydrobenzothiazole (335 mg, 2.16 mmol) in DMF (3 mL) was added NaH (101 mg, 2.52 mmol). After stirring 10 minutes at room temperature, a solution of 2-bromo-4′-methylacetophenone (668 mg, 2.82 mmol) in DMF (5 mL) was added and the mixture was stirred overnight. Water was added and the mixture was extracted with EtOAc, dried over MgSO4 and the solvent was evaporated. The oil recovered was purified by flash chromatography on silicagel (CH2Cl2) to give 29 as a solid in 65% yield: mp 108-110° C.; 1H-NMR (DMSO-d6) 1.73 (s, 4H), 2.19 (s, 2H) 2.40 (m, 5H), 5.23 (s, 2H), 7.39 (d, 2H), 7.95 (d, 2H); Anal. (C16H17NO2S) C, H, N.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[Br-].[K+].[CH2:20](Cl)[CH:21]=[CH2:22].Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O.C1(C)C=CC=CC=1>[CH2:22]([C:11]1[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]([OH:17])=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1)[CH:21]=[CH2:20]
Reactant: C=CCCl
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
80 g (2 mols) of powdered sodium hydroxide are added, at about 35° C. under a stream of nitrogen gas, to a mixture of 412 g (2 mols) of 2,6-di-tert.-butylphenol, 67.5 g (0.128 mol) of tricaprylmethylammonium chloride, 15 g (0.126 mol) of potassium bromide and 400 ml of toluene, and the mixture is heated to 50° C. in the course of 15 minutes. 199 g (2.6 mols) of allyl chloride are added dropwise to the suspension in the course of 30 minutes. The suspension is stirred for 4 hours at 48° to 53° C. 400 ml of water and 5 ml of 36 percent by volume aqueous hydrochloric acid are added with stirring, and the aqueous phase is then separated off. The organic phase is dried over anhydrous sodium sulfate and freed from toluene in vacuo at 10 to 150 mm Hg. The 4-allyl-2,6 -di-tert.-butylphenol obtained in this way in a very high yield can be used without further purification as a lubricant additive.