Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=O)=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[NH4+]>C1COCC1>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:22])=[CH:23][CH:24]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide (32.0 mg) obtained in Example 142 in THF (10 ml) were added pyridine (0.032 mL) and trifluoroacetic anhydride (0.028 mL) at 0° C., and the mixture was stirred overnight at room temperature. Pyridine (0.032 mL) and trifluoroacetic anhydride (0.028 mL) were added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give a mixture containing the title compound and the raw material (4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide. To a solution of the obtained 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide in THF were added triethylamine (0.055 mL) and trifluoroacetic anhydride (0.028 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was combined with the mixture containing the title compound, and purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.10 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:68]([O:70][CH:71]([O:74][CH2:75][CH3:76])[CH2:72][NH2:73])[CH3:69]>CN(C=O)C.O>[CH2:68]([O:70][CH:71]([O:74][CH2:75][CH3:76])[CH2:72][NH:73][C:17]([C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:20]=[CH:21][C:22]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=4[F:34])=[O:25])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)[NH:16][CH:15]=1)=[O:18])[CH3:69]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: CCOC(CN)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(CNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (500 mg, 1.08 mmol), HATU (456 mg, 1.20 mmol) and N,N-diisopropylethylamine (278 mg, 2.16 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of aminoacetaldehyde diethyl acetal (173 mg, 1.30 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give N-(2,2-diethoxyethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 550 mg, 88%.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([O:24][CH3:25])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]1([C:29]([Cl:31])=[O:30])[CH2:28][CH2:27]1.C(N(CC)CC)C>CC1C=CC=CC=1>[ClH:31].[CH:26]1([C:29]([N:7]([C:8]2([C:22]([O:24][CH3:25])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(N(C(=O)C2CC2)c2ccccc2)CCN(CCc2ccccc2)CC1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 5.1 parts of methyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate, 1.9 parts of cyclopropanecarbonyl chloride, 2.7 parts of N,N-diethylethanamine and 67.5 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is cooled to room temperature and poured onto water. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica-gel using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the hydrochloride salt in 2,2'-oxybispropane and 2-propanol. The salt is filtered off and crystallized from 4-methyl-2-pentanone, yielding methyl 4-[N-(cyclopropylcarbonyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate hydrochloride; mp. 197.8° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>C(Cl)Cl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1F
Temperature: 100 °C

Procedure:
A solution of methyl 2-bromo-4-nitrobenzoate (5.20 g), 2-fluorophenylboronic acid (3.92 g) and potassium carbonate (4.98 g) in a 10:1 mixture of DME:water (120 ml) was degassed by gently bubbling though nitrogen for 30 minutes. Tetrakis(triphenylphosphine) palladium(0) (2.32 g) was then added and the mixture was degassed for a further 10 minutes before being sealed under nitrogen. The reaction mixture was heated to 100° C. for 14 hours. The solvents were removed under vacuum. The residue obtained was redissolved in DCM and washed with water (2×). The organic phase was passed through a hydrophobic frit and then concentrated to dryness under vacuum. The crude residue was purified by chromatography on silica gel, eluting with petrol containing increasing amounts of ethyl acetate.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:16](C)([C:22](OCC)=O)[C:17]([O:19]CC)=[O:18]>C(O)(=O)C.O>[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH:16]([CH3:22])[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1F
Yield: 77 %

Procedure:
Concentrated sulfuric acid (7.5 mL) was added to compound (4) obtained above (7.09 g, 22.6 mmol) in acetic acid (26 mL) and water (18 mL), and the obtained mixture was heated to reflux for 12 hours. After completion of the reaction, the mixture was cooled and concentrated under reduced pressure, and the residue was extracted with dichloromethane. The extract was washed with saturated saline and water and dried (over sodium sulfate). The solvent was then distilled off under reduced pressure to give 3.72 g (77%) of compound (5) of interest as clear reddish brown oil.
Reaction SMILES: [NH:1]([C:5]1[C:10]([Br:11])=[CH:9][C:8]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17](Cl)=[N:16][N:15]3[CH:21]=2)=[C:7]([O:22][CH3:23])[CH:6]=1)[C:2]([CH3:4])=[O:3].[OH-].[K+].O>CN(C)C=O.[Pd]>[BrH:11].[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][N:15]3[CH:21]=2)=[C:7]([O:22][CH3:23])[CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: COc1cc(NC(C)=O)c(Br)cc1-c1cn2nc(Cl)ccc2n1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Br
Product: COc1cc(NC(C)=O)ccc1-c1cn2ncccc2n1

Procedure:
2 g (5 mmol) of 2-(4-Acetamino-5-bromo-2-methoxy-phenyl)-6-chloro-imidazo[1,2-b]pyridazine are suspended in 100 ml of dimethylformamide, mixed with 0.28 g (5 mmol) of ground potassium hydroxide and hydrogenated for 50 minutes at ambient temperature and in a Parr apparatus with 0.5 g of 20% Pd/C under a hydrogen pressure of 5 bar. Then 25 ml of water are added and the catalyst is filtered off. The mother liquor is concentrated by centrifuging and after stirring with 50 ml of water it is suction filtered, washed with water and dried in a vacuum drying cupboard at 50° C. over phosphorus pentoxide.
Reaction SMILES: C1(S(CC2C(C(O)=O)=C(OCCN(C(OC(C)(C)C)=O)C)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[CH2:37]([N:39]([CH2:42][CH:43]1[CH2:46][CH2:45][N:44]1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[S:53]([CH2:56][C:57]1[C:62]([C:63]([O:65]C)=[O:64])=[C:61]([O:67][CH3:68])[C:60]([C:69]2[CH:73]=[CH:72][O:71][CH:70]=2)=[CH:59][CH:58]=1)(=[O:55])=[O:54])[CH2:40][CH3:41])[CH3:38]>>[CH2:37]([N:39]([CH2:42][CH:43]1[CH2:46][CH2:45][N:44]1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[S:53]([CH2:56][C:57]1[C:62]([C:63]([OH:65])=[O:64])=[C:61]([O:67][CH3:68])[C:60]([C:69]2[CH:73]=[CH:72][O:71][CH:70]=2)=[CH:59][CH:58]=1)(=[O:54])=[O:55])[CH2:40][CH3:41])[CH3:38]
Reactant: CCN(CC)CC1CCN1c1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Agent: CN(CCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O)C(=O)OC(C)(C)C
Product: CCN(CC)CC1CCN1c1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 124, starting from methyl 6-[2-(2-diethylaminomethylazetidin-1-yl)benzenesulphonylmethyl]-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 205) as a white solid
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.C1OC1C>[CH:21]1([CH2:27][CH2:28][NH:29][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCC1CCCCC1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CC1CO1
Solvent: CCO
Product: Nc1nc(NCCC2CCCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-chloroadenosine (15.05 g) and 2-cyclohexylethylamine (31.75 g) is stirred under nitrogen at 140° over 6 hours. The reaction mixture is cooled to room temperature, diluted with ethanol (500 ml), propylene oxide (50 ml) is added and the mixture is stirred at room temperature for 3 hours. The solid is collected by vacuum filtration, washed with ethanol, then ether, and dried at 80°/0.1 mm over 16 hours. The white solid obtained is recrystallized from ethanol to yield 2-(2-cyclohexylethylamino)-adenosine, the compound of example 4q, m.p. 142°-145°, [alpha]D25 -30.5° (c=1, dimethyl sulfoxide).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[CH:2]1([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: BrC1C=CCCCC1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C1=CC(N2CCOCC2)CCCC1
Yield: 50.2 %

Procedure:
A mixture of 3-bromocycloheptene (1.75 g, 10 mmoles), triethylamine (1.01 g, 10 mmoles), morpholine (0.87 g, 10 mmoles) and chloroform (10 ml) was heated under reflux for 3 hours. After completion of the refluxing, the reaction mixture was after-treated as usual and purified by chromatography to obtain 0.91 g of N-(2-cycloheptenyl)morpholine [Compound (3)].
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].CCOCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:30][CH2:29][C:28]([O:27][CH3:26])=[O:31])=[O:24]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CNC(=O)c1cc2ccccc2n1C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
DMAP (1.222 g, 0.01 mol) and EDAC (2.680 g, 0.014 mol) were added as solids to a solution of 1-methylindole-2-carboxylic acid (1.752 g, 0.01 mol) and glycine methyl ester hydrochloride (1.256 g, 0.01 mol) in methylene chloride (30 mL) and DMF (5 mL) under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and then for 3 hours at room temperature. The reaction mixture was partitioned with ethyl acetate and 5% KHSO4 solution and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) solution and brine, dried over sodium sulfate, and concentrated to give a purple powder as crude product. Trituration of the powder with ether afforded the title product (1.734 mg, 70%). TLC (methanol/methylene chloride 1:9): Rf=0.61; 1H-NMR (CDCl3): δ7.65 (dt, J=8.0, 1.1, 1H), 7.41-7.31 (m, 2H), 7.16 (dd, J=6.6, 1.4, 1H) 6.96 (d, J=0.5, 1H), 6.67 (bs, 1H), 4.25 (d, J=5.2, 2H), 4.05 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2ccc(-c3ccccc3)cc2)CC1
Yield: 54.2 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (249 mg, 0.923 mmol), 1-biphenyl-4-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 16 hours. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound (163 mg, 54.2%) as solid product.
Reaction SMILES: [CH2:1](O)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[OH-:14].[Na+].[K].Br[CH2:18][C:19]1[CH:23]=[CH:22][S:21][CH:20]=1>O1CCCC1.C(Cl)CCC>[CH2:18]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH:2]([OH:14])[CH3:1])[CH2:19][CH2:23][CH3:22].[S:21]1[CH:22]=[CH:23][CH:19]=[CH:20]1
Reactant: BrCc1ccsc1
Reactant: OCCOCCOCCOCCO
Reactant: [OH-]
Agent: [K]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCl
Product: CCCCOCCOCCOCCOC(C)O
Product: c1ccsc1
Yield: 57 %

Procedure:
Butoxyethoxyethoxyethoxyethanol (25.0 g, 0.1 mol) was prepared from tetraethylene glycol, sodium hydroxide and butyl chloride (10:1:1) by a method known in the art and then reacted with potassium metal (3.9 g, 0.1 mol) at room temperature for 1.5 hours in tetrahydrofuran. 3-(Bromomethyl)thiophene (17.7 g, 0.1 mol) was added dropwise, and the mixture stirred under reflux for 24 hours. After cooling and filtration the tetrahydrofuran was removed in vacuo and the residue dissolved in methylene chloride, washed with water and dried with potassium carbonate. The solvent was removed and the crude oil distilled to give 3-butoxyethoxyethoxyethoxyethoxymethyl)thiophene (25.7 g, 57%). B.p. 162°-163° C./0.15 mm Hg. (Found: C, 58.6; H, 8.7; S, 9.5. Calculated for C17H30O5S: C, 58.9; H, 8.7; S, 9.3%); EI m/e Intensity (%): 346 (9, M+), 97 (100, C4H3S.CH2), 57 (75, C4H9); δH(CDCl3): 7.26 (1H, m) 7.20 (1H, m), 7.06 (1H, m), 4.56 (2H, s) 3.65 (16H, m), 3.45 (2H, t), 1.53 (2H, m), 1.34 (2H, m) and 0.91 (3H, t); δC(CDCl3): 13.6, 18.9, 31.4, 68.1, 69.0, 69.8, 70.0, 70.3, 122.5, 125.5, 126.7, 139.1 ppm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([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][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:5].[C:24](O)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[C:24]([O:1][CH2:2][CH2:3][N:4]([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][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:5])(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCCCCN(C)CCO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCN(C)CCOC(=O)CCCCCCCCCCCCCCCCC
Temperature: 180 °C
Yield: 96.5 %

Procedure:
A four-neck flask provided with a stirrer, a thermometer and a dehydrating tube was charged with 200 g of the N-(2-hydroxyethyl)-N-methyloctadecylamine and 174 g of octadecanoic acid. The mixture was heated to 180° C. and maintained at this temperature for 12 hours while distilling off the water thus formed. Thus 350 g of N-(2-octadecanoyloxyethyl)-N-methyloctadecylamine was obtained. Based on the NMR and IR spectra, it was confirmed that this product had the following structure. This compound will be referred to as the enhancer 25 hereinafter. ##STR31##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][Cl:41].O>CN(C)C=O>[Cl:41][CH2:40][CH2:39][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:23]([C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: ClCCBr
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(O)cc3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCCl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-(4-hydroxy-phenyl)-methanone (compound 188) (128 mg) was dissolved in N,N-dimethylformamide to prepare a solution. Potassium carbonate (215 mg) and 1-bromo-2-chloroethane (134 mg) were then added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (99 mg, yield 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl[C:14]([N:18](C)[CH3:19])=C(C)C.C(N(CC)CC)C.CNC.C1COCC1>C(Cl)Cl.Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:18]([CH3:19])[CH3:14])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: CC(C)=C(Cl)N(C)C
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(F)c(F)cc1Cl
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 2-chloro-4,5-difluorobenzoic acid (385 mg, 2.0 mmol) in DCM (5 mL) was treated with (1-chloro-2-methylprop-1-en-1-yl)dimethylamine (293 mg, 2.2 mmol) and stirred under argon for 1 hour. The mixture was then treated with triethylamine (0.56 mL, 4.0 mmol) and a 2M solution of dimethylamine in THF (1.2 mL, 2.4 mmol), and stirred for 18 hours. The mixture was diluted with DCM (5 mL) and 2M hydrochloric acid (4 mL) and separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (425 mg). The residue was used without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1
Reactant: CCOC(=O)Cc1cccc(I)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2Cl)c1
Yield: 49.6 %

Procedure:
Ethyl 3-iodophenylacetate (2.90 g), 2-chloro-4-(trifluoromethyl)phenyl boronic acid (3.3 g), 2M aqueous sodium carbonate solution (5 mL), dioxane (10 mL) and dichloro-bis(triphenylphosphine)palladium(II) (350 mg) were heated at 80° C. for 30 min with stirring. The reaction mixture was then cooled, poured into water, extracted with ethyl acetate, and the organic layer was separated and concentrated under vacuum in the presence of Celite® to a solid residue. This solid residue was purifed by medium pressure liquid chromatography on silica gel eluting with a gradient of ethyl acetate in hexanes to yield 1.7 g of the title compound. 1H NMR (CDCl3) δ 7.14 (s, 1H), 7.56 (d, 1H) 7.30-7.45 (m, 5H), 4.77 (q, 2H), 3.67 (s, 2H), 1.26 (t, 3H).
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=1.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.C([BH3-])#N.[Na+]>CO>[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH:20]3[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)[CH:10]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Brc1cnn(C2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Brc1cnn(C2CCN(C3CC3)CC2)c1
Temperature: 60 °C

Procedure:
Acetic acid (1.258 ml, 21.98 mmol) is added dropwise, under stirring at RT, to a solution of 4-(4-Bromo-pyrazol-1-yl)-piperidine (as obtained in preparation 89, 1.686 g, 7.327 mmol) and [(1-ethoxy-1-cyclopropyl)oxy]trimethylsilane (2.210 ml, 10.99 mmol) in MeOH (20 ml). Sodium cyanoborohydride (775 mg, 11.7) is then added in one portion at RT. The mixture is then heated at 60° C. for 3 h. After cooling, the reaction mixture is concentrated in vacuo and the residue dissolved in EtOAc and diluted with saturated NaHCO3. After separation, the aqueous phase is re-extracted 3× with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is used without further purification in the next step, and afford the title compound as colorless solid, Rt=0.618 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 270 (M+1, 79Br)+