Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:16][CH3:17])=[S:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:20]([CH:22]=[O:23])=[O:21].NC(N)=S>COCCOC.C(N(CC)CC)C>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([N:13]2[CH:20]([OH:21])[CH:22]([OH:23])[N:16]([CH3:17])[C:14]2=[S:15])[CH:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:8]=1
Reactant: O=CC=O
Reactant: CNC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NC(N)=S
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CN1C(=S)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(O)C1O
Temperature: 20 °C
Reaction time: 12 h

Procedure:
30.0 g of N-(3,5-bis-trifluoromethyl-phenyl)-N'-methyl-thiourea were stirred in 100 ml of 1,2-dimethoxyethane and 10 ml of triethylamine, and then 22 g of a 30% strength aqueous glyoxal solution were added. The thiourea thereupon dissolved, the reaction being exothermic. The solution was stirred for a further 12 hours at 20° C. and was concentrated in vacuo and the residue was stirred with water and a little acetic acid. The reaction product, which had solidified, was filtered off, washed and dried. Yield 32.0 g; melting point: 133°-135° C. after recrystallisation from toluene.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([N:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10]2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccccc2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC)cc2)c1
Yield: 96.7 %

Procedure:
Using ethyl 5-phenyl-1H-pyrrole-3-carboxylate (250 mg), sodium hydride (60% in oil, 60 mg) and 4-methoxybenzenesulfonyl chloride (264 mg), a procedure as in Reference Example 4 was performed to give the title compound as a colorless oil (yield 433 mg, 97%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])=[CH:14][CH2:13]1)=[O:11])C)(C)(C)C.[ClH:35].O1CCOCC1>>[ClH:35].[F:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][CH3:26])=[C:18]([C:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C@H:9]([NH:7][CH3:6])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:13][CH:14]=2)[CH:23]=1
Reactant: COc1ccc(F)cc1C1=CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@H](Cc1ccccc1)C(=O)N1CC=C(c2cc(F)ccc2OC)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
The crude product of (R)-{1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridin-1-yl]-2-oxo-ethyl}-methyl-carbamic acid tert-butyl ester was dissolved in 10 mL 4 M HCl/dioxane solution and the resulting mixture brought to reflux. After overnight stirring, the mixture was cooled to room temperature and the solvent evaporated to provide 0.62 g (65% yield for two steps) of the titled product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(F)cc2)CC1

Procedure:
4-Fluorobenzylamine (2.5 g) and N-tert-butoxycarbonyl-4-piperidone (4 g) were reacted as described in Example 98 (step 2), to give the title product as a yellow oil which crystallised (6.2 g). δH (250 MHz, CDCl3) 1.22-1.37 (2H, m), 1.43 (9H, s), 1.82-1.94 (2H, m), 2.60-2.72 (1H, m), 2.74-2.84 (2H, m), 3.80 (2H, s), 3.94-4.10 (2H, m), 6.97 (2H, m), 7.26-7.31 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH2:17][CH3:18])[N:16]=2)[CH:10]=O)=[CH:4][CH:3]=1.C1(P(=[CH:45][CH:46]=[O:47])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH2:17][CH3:18])[N:16]=2)[CH:10]=[CH:45][CH:46]=[O:47])=[CH:6][CH:7]=1
Reactant: CCn1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 94.8 %

Procedure:
The procedure of Example 50 was repeated using 3.25 g (9.5 mmoles) of 3,3-bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenal and 3.05 g (10.0 mmoles) of triphenylphosphoranylidene acetaldehyde and there was thereby produced 3.3 g (95%) of the title compound; m.p.=117°-120° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[CH3:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)ccc1C(=O)NC(C)(C)C
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (3.5 g, 11 mmol) and N-tert-Butyl-4-chloro-2-methyl-benzamide (7.3 g, 32 mmol) followed by purification using silica gel flash column chromatography gives the title compound.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:31]([C:34]3[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:41][CH:42]=3)(=[O:33])=[O:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol and 4-chlorosulfonyl-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 186-188° C.; MS m/e 559 (M−H)+;
Reaction SMILES: CS(C)=O.[CH2:5]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+].[CH3:29]I>O>[CH2:5]([C:20]1[CH:21]=[C:22]([O:26][CH3:29])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Into a two-liter round bottomed flask was placed dimethyl sulfoxide (500 mL), 3-pentadecyl phenol (100.0 g, 0.33 mol) and sodium hydroxide (73.55 g, 1.31 mol). To this mixture methyl iodide (93.5 g, 0.66 mol) was added drop wise with stirring at room temperature. After the addition, the reaction mixture was stirred for further 6 h. Then the reaction mixture was poured into deionized water (1.5 liters). The organic material was extracted by addition of diethyl ether. The diethyl ether layer was separated, washed with water, dried over anhydrous sodium sulfate, and finally evaporated to afford the crude product as a viscous liquid. This material was purified by silica gel column chromatography using petroleum ether as the eluent to obtain 3-pentadecyl anisole Yield 104.6 g (97%), MP 27-28° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[OH:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][N:26]=[CH:27]2)=[CH:22][CH:21]=1.[H-].[Na+]>CN(C=O)C>[CH:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][C:5]3[N:4]=[N:3][C:2]([O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]=[CH:25][N:26]=[CH:27]5)=[CH:22][CH:21]=4)=[C:7]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:6]=3)[CH:29]=2)[CH:24]=[CH:25][N:26]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4ccncc4c3)nnc2Oc2ccc3ccncc3c2)cc1

Procedure:
The title compound was prepared analogous to the procedure used to prepare Example 48, using 3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 45(d)), (443 mg, 1.5 mmol), 7-hydroxyisoquinoline (444 mg, 3.1 mmol, Lancaster) and NaH (151 mg, 3.8 mmol, 60% suspension in mineral oil, Aldrich) in DMF (10 mL). Purification by flash silica gel chromatography with 2M NH3 in MeOH/CH2Cl2 (0:1→1:24) as eluant gave the title compound as a tan amorphous solid. Mp: 82–86° C. MS (ESI, pos ion.) m/z: 511 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]1([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:11])=[CH:7][CH:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Ic1ccccc1
Reactant: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A mixture of 1-ethynyl-4-(phenylsulfonyl)benzene (100 mg, 0.4 mmol), iodobenzene (0.05 mL, 0.44 mmol) and triethylamine (1 mL) in toluene (1 mL) was degassed. Copper(I) iodide (3 mg, 0.004 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (3 mg, 0.004 mmol) were added and the reaction stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (35 mg, 28%). δH (500 MHz, d6 DMSO): 7.97 (4H, dd, J=2.6, 8.4 Hz), 7.77-7.69 (3H, m), 7.64-7.56 (4H, m), 7.43-7.41 (3H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>>[CH3:29][N:30]([CH:32]=[C:14]1[CH2:15][CH2:16][N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[C:11]2[CH:21]=[CH:20][CH:19]=[N:18][C:12]=2[C:13]1=[O:17])[CH3:31]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc21
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc2C1=O

Procedure:
As described for Reference Example 221, 5,6,7,8-tetrahydro-5-(4-nitrobenzoyl)-9H-pyrido[3,2-b] azepin-9-one is reacted with tert-butoxybis(dimethylamino)methane to give the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:31]1([O:40][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.NO.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([NH:31][OH:40])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)C(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(NO)C(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of 13 (40 mg, 0.14 mmol), BOP (58 mg, 0.13 mmol), and hydroxylamine hydrochloride (9 mg, 0.13 mmol) in pyridine (5 mL) was added triethylamine (0.055 mL, 0.39 mmol) and the reaction mixture was stirred at room temperature for 2 h. The solvents were removed under vacuum and the crude was dissolved in ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified via HPLC (Gilson) reverse-phase column with a gradient of methanol (20-75%) in water to afford compound 14 as a white solid (20 mg, 48%). 1H NMR (CD3OD-d4) δ (ppm): 7.62-7.57 (m, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.40-7.22 (m, 7H), 7.14 (t, J=8.8 Hz, 2H), 4.82 (s, 1H). LRMS (ESI): (calc.) 321.1 (found) 320.4 (MH)−.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].CN.[CH2:36]([N:38](CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([NH:38][CH3:36])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C(C#N)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Reaction time: 3 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (30 mg, 61 μmol) was dissolved in absolute THF (2 ml), a 2 M solution of methylamine in THF (91 μl, 182 μmol; 3 eq.) and triethylamine (6.1 mg, 61 μmol; 1 eq.) were added at room temperature and the mixture was stirred for 3 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (25 mg, 83% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].[F:15][C:16]([F:24])([F:23])[CH2:17]OS(C)(=O)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([O:14][CH2:17][C:16]([F:24])([F:23])[F:15])=[CH:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Reactant: CS(=O)(=O)OCC(F)(F)F
Product: O=[N+]([O-])c1cccc2cc(OCC(F)(F)F)cnc12
Yield: 18 %

Procedure:
In a manner analogous to that described in Example 30 a) the alkylation of the 8-nitro-quinolin-3-ol (CAS25369-37-3) with methanesulfonic acid 2,2,2-trifluoro-ethyl ester yielded the title compound as a yellow solid (yield 18%); (calculated) C11H7F3N2O3 [272.2]; (found) [M+H]+=273.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:16]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:15]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])[CH:14]=2)[CH:4]=1.[BH4-].[Na+].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:16]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:15]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])[CH:14]=2)[CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(COc2cc(OC)ccc2C=O)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(COc2cc(OC)ccc2CO)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
4-Methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzaldehyde (93.5 g, 89.2 mmol) was dissolved in THF-methanol (1870 ml+94 ml), and sodium borohydride (4.05 g, 107 mmol) was added at 0° C. After stirring at room temperature for 1.5 hr, 0.2N hydrochloric acid (100 ml) was added at 0° C. to quench the reaction. The solvent was evaporated to about half, and dissolved in chloroform (2400 ml). The mixture was washed twice with 0.1N hydrochloric acid (1200 ml), once with 5% aqueous sodium hydrogen carbonate solution (1200 ml), and once with 20% brine (1200 ml). The solvent was evaporated, and the residue was precipitated with methanol (900 ml) and washed with acetonitrile to give 4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzyl alcohol (92.4 g, 88.0 mmol, 97% yield vs 3,4,5-tris(octadecyloxy)benzyl alcohol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:15])[CH2:13]O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:23]>CCCCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:15])[CH2:13][Br:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)CO
Reactant: BrP(Br)Br
Solvent: CCCCC
Solvent: c1ccncc1
Product: CC(=Cc1ccc(C(C)(C)C)cc1)CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
73.2 g of 3-(p-tert.butyl-phenyl)-2-methyl-allyl alcohol nd 8.6 ml of pyridine in 700 ml of n-pentane are cooled down to -5° C. At this temperature there are added dropwise while stirring over a period of 2 hours 15.2 ml of phosphorus tribromide in 700 ml of n-pentane and the mixture is stirred at room temperature for 3 hours. The mixture is poured on to 500 g of ice and stirred up for 30 minutes. The pentane phase is separated and the aqueous phase is back-extracted with n-pentane. The combined n-pentane phases are washed neutral with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The 3-(p-tert.butyl-phenyl)-2-methyl-allyl bromide, distilled in a high vacuum, boils at 123° C./0.01 Torr.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C1(C)C=CC=CC=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[O:30][CH2:29][CH2:28][O:27]1>O.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[O:27][CH2:28][CH2:29][O:30]1
Reactant: Brc1ccccc1C1OCCO1
Reactant: COc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ccccc2C2OCCO2)c1
Temperature: 80 °C
Yield: 87 %

Procedure:
Potassium hydroxide pellets (35.2 g; 0.63 mol) were dissolved in water (50 ml) and 3-methoxyphenol (78 g; 0.63 mol) was added together with toluene (250 ml). The mixture was heated to and maintained at reflux temperature until water ceased to distil over (a total of 65 ml of water was collected). The mixture was cooled to 80° C. and 2-(2-bromophenyl)-1,3,-dioxolane (120 g; 0.524 mol), DMF (200 ml) and cuprous chloride (0.2 g) were added. The mixture was slowly heated to 150°-155° C. and toluene was distilled off. The mixture was maintained at 150°-155° C. for 6 hours then cooled to 25° C. and water (500 ml) was added. The mixture was filtered and the residue was washed with ether (200 ml). The filtrate was extracted with ether (3×150 ml). The combined ether extracts were washed with 2N sodium hydroxide solution (2× 150 ml), water (4×150 ml) and saturated brine (1×200 ml). After drying and filtration the ether solution on evaporation gave 2-[2-(3-methoxyphenoxy)phenyl]-1,3-dioxolane (124.1 g, 87.1% yield) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH2:20][CH:21]=[CH2:22])[C:12]([OH:19])=[C:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:23].[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>C(#N)C>[CH2:24]([NH:28][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH2:20][CH:21]=[CH2:22])[C:12]([OH:19])=[C:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCBr
Solvent: CC#N
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCNCCCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
1-(4-Bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone (1.9 g) prepared in Example 43 was dissolved in acetonitrile (50 ml), then n-butylamine (2 ml) was added and stirred at 80° C. for 4 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with an aqueous solution saturated with sodium bicarbonate, next with water, then concentrated under reduced pressure. Thus obtained oily residual product was dissolved in ethanol, acidified by adding oxalic acid, then concentrated to dryness, and recrystallized from acetone, there was obtained of 1-(4-n-butylaminobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.oxalate in 35% yield.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[CH3:28][C:29]1([CH3:38])[CH2:34][NH:33][C@H:32]([C:35]([OH:37])=[O:36])[CH2:31][O:30]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:33]2[CH2:34][C:29]([CH3:28])([CH3:38])[O:30][CH2:31][C@H:32]2[C:35]([OH:37])=[O:36])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: CC1(C)CN[C@H](C(=O)O)CO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CC(C)(C)OC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 58.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.26 g, 0.51 mmol) was reacted with (S)-6,6-dimethylmorpholine-3-carboxylic acid hydrochloride (0.1 g, 0.51 mmol) according to the procedure described in Example 1, Step C to give the title compound as a yellow solid (0.16 g, 59%). The compound was characterized by the following spectroscopic data: