Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1>C(O)(=O)CC>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[C:14]3[NH:10][C:11]([C:5]([C:4]4[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=4)=[C:11]4[N:10]=[C:14]([C:5]([C:4]5[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=5)=[C:11]5[NH:10][C:14](=[C:5]([C:4]6[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=6)[C:11]6[CH:12]=[CH:13][C:14]=2[N:10]=6)[CH:13]=[CH:12]5)[CH:13]=[CH:12]4)=[CH:12][CH:13]=3)[CH:7]=[CH:8][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: O=Cc1cccc(O)c1
Solvent: CCC(=O)O
Product: Oc1cccc(-c2c3nc(c(-c4cccc(O)c4)c4ccc([nH]4)c(-c4cccc(O)c4)c4nc(c(-c5cccc(O)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 140 °C
Reaction time: 12 h

Procedure:
3-Hydroxybenzaldehyde (0.910 g, 7.45 mmol) is dissolved in propionic acid (50 mL) and heated to 140° C. Pyrrole (0.52 mL, 7.45 mmol) is added in one portion and the mixture heated at reflux for 2 h. Stirring is continued for an additional 12 h at room temperature. Propionic acid is removed in vacuo and the residue dissolved in acetone and purified by chromatography on a column (250 g) of silica which is eluted with toluene containing a continuously increasing proportion of ethyl acetate. The product is eluted with toluene:ethyl acetate (6:1 by vol.). Solvent is removed in vacuo to afford the product as a violet solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:18]([CH2:20][CH2:21][C:22]([OH:24])=O)=[O:19].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH2:44]1[NH:49][CH2:48][CH2:47][N:46]2[CH2:50][CH2:51][CH2:52][C@@H:45]12.C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:18](=[O:19])[CH2:20][CH2:21][C:22]([N:49]2[CH2:48][CH2:47][N:46]3[CH2:50][CH2:51][CH2:52][C@H:45]3[CH2:44]2)=[O:24])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: C1C[C@H]2CNCCN2C1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (479 mg, 2.5 mmol) was added to a solution of 3-(3,4-dimethoxybenzoyl)propionic acid (596 mg, 2.5 mmol) and 3-hydroxy-3H-dihydrobenzo[d][1,2,3]triazin-4-one (408 mg, 2.5 mmol) in a mixture of dichloromethane (10 ml) and N,N-dimethylformamide (10 ml). The reaction mixture was stirred for 25 min at 0° C. A solution of the crude dihydrochloride salt of (S)-octahydro-pyrrolo[1,2-a]pyrazine in N,N-dimethylformamide (4 ml) and ethyldiisopropylamine (3.0 ml, 17.5 mmol) were added successively. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by HPLC on a C18-reversed phase column, using a mixture of 1% trifluoroacetic acid in water and acetonitrile as eluent, to give 148 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)[CH3:2].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.O>[CH2:19]([O:18][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([C:12]([NH:29][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)=[O:14])[CH:15]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:20]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(C(=O)O)c1)OCC
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
0.58 g of 5-(3-ethoxy-2-ethoxy-3-oxopropyl)-2-methoxybenzoic acid and 0.34 g of 4-(trifluoromethyl)benzylamine were dissolved in 7 ml N,N-dimethylformamide, and 0.30 ml diethyl cyanophosphonate and 0.27 ml triethylamine were added thereto under ice-cooling. The reaction mixture was stirred at room temperature for 16 hours, then poured into iced water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and brine in this order, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 0.64 g of ethyl 2-ethoxy-3-(4-methoxy-3-(([4-(trifluoromethyl)benzyl)amino)carbonyl)phenyl)propanoate was obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([OH:13])=O.S(Cl)(Cl)=O.Cl.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]3)=[CH:27][C:22]=2[O:21][CH2:20]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O.C1(C)C=CC=CC=1>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:11]([C@@H:2]4[O:1][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3]4)=[O:13])[CH2:29]3)=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: c1cc2c(cc1C1CCCNC1)OCO2
Reactant: O=C(O)[C@H]1COc2ccccc2O1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C([C@H]1COc2ccccc2O1)N1CCCC(c2ccc3c(c2)OCO3)C1
Temperature: 95 °C
Reaction time: 0.75 h
Yield: 84.9 %

Procedure:
A mixture of (R)-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid (167 mg, 0.93 mmol), thionyl chloride (338 μl, 551 mg, 4.63 mmol) and dry toluene was heated at 95° C. for 1.5 h and then evaporated to dryness. Toluene was added and the evaporation was repeated. The evaporation residue was dissolved in DCM (2 ml) and added slowly to a cold solution (0° C.) of 3-benzo[1,3]dioxol-5-yl-piperidine HCl (224 mg, 0.93 mmol) and DIPEA (0.324 ml, 240 mg, 1.85 mmol) in DCM (5 ml). The reaction mixture was stirred for 1 h 45 min at RT. Water was added, layers were separated and the organic phase was washed twice with 1 M HCl and sat. NaHCO3. The organic phase was dried (Na2SO4), filtered and evaporated to give 290 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].[Si]([O:38][C@H:39]1[CH2:44][CH2:43][C@H:42]([N:45]2[C:49]([CH3:50])=[C:48](I)[C:47]([CH3:52])=[N:46]2)[CH2:41][CH2:40]1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+].Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:48]3[C:47]([CH3:52])=[N:46][N:45]([C@H:42]4[CH2:43][CH2:44][C@H:39]([OH:38])[CH2:40][CH2:41]4)[C:49]=3[CH3:50])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: Cc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c(C)c1I
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c(C)nn([C@H]4CC[C@H](O)CC4)c3C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (30.0 mg, 0.0696 mmol), 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4-iodo-3,5-dimethyl-1H-pyrazole (60.5 mg, 0.139 mmol), Pd(PPh3)4 (4.02 mg, 0.00348 mmol), NaHCO3 (17.6 mg, 0.209 mmol) and 4:1 dioxane:water was heated to 80° C. overnight. 2 M of HCl in H2O (0.5 mL, 1 mmol) was added, and the solution was stirred at rt for 1 h. The material was concentrated in vacuo, redissolved in MeOH (1 mL) and passed through a syringe filter pad for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.42-1.57 (m, 2H), 1.80 (d, J=7.1 Hz, 3H), 1.87-2.02 (m, 3H), 2.03 (s, 3H), 2.04-2.12 (m, 3H), 2.14 (s, 3H), 3.64 (br. s., 3H), 3.66-3.72 (m, 1H), 4.11 (tt, J=11.5, 3.9 Hz, 1H), 5.04-5.14 (m, 1H), 6.89 (dd, J=9.2, 4.2 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.28 (s, 1H), 7.35 (d, J=1.3 Hz, 1H), 7.95 (br. s., 1H). MS (ES+): m/z=497.21/499.21 (100/50) [MH+]. HPLC: tR=1.40 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][C:7](=[N:9][OH:10])[NH2:8].[CH:15](OCC)(OCC)OCC>B(F)(F)F.CCOCC>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][C:7]1[N:8]=[CH:15][O:10][N:9]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1c(Cl)cccc1OCC(N)=NO
Agent: FB(F)F
Solvent: CCOCC
Product: Cc1c(Cl)cccc1OCc1ncon1
Yield: 57.4 %

Procedure:
7.0 g (32.6 mmol) of 3-chloro-2-methyl-phenoxy-acetamide oxime are introduced into 70 ml of triethyl orthoformate, and 5 drops of boron trifluoride etherate are added at room temperature. The mixture is subsequently stirred at reflux temperature until the reaction is complete (approximately 1 hour) and the entire batch is concentrated in vacuo. The residue is taken up in 100 ml of methylene chloride and washed in succession with 100 ml of 2N hydrochloric acid, saturated sodium carbonate solution and water. The organic phase is dried over sodium sulphate and the solvent is subsequently distilled off. The oily residue which remains is distilled using a bulb tube. 4.2 g (57.4% of theory) of 3-(3-chloro-2-methyl-phenoxymethyl)-1,2,4-oxadiazole are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O.O>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:27])[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Reactant: O=C(O)C1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)C3CC3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
A solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) in DMF (0.2 mL) was added to a solution containing cyclopropanecarboxylic acid (24.8 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uranium tetrafluoroborate (101.7 mg, 0.32 mmol), N,N-diisopropyl ethyl amine (247 μL, 1.44 mmol) in DMF (0.3 mL) and the resulting mixture stirred at room temperature overnight and then heated at 110° C. for 2.5 h. The resulting mixture was then poured into a mixture of brine: water (1:1) and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulphate and evaporated to leave a brown solid. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (12.4 mg, 12%) which was obtained as an off-white solid. MS: m/e 359.0 [M+H]+.
Reaction SMILES: [CH2:1]=[CH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[CH2:10][C:11](=[O:12])[CH2:2][CH2:1]2
Reactant: C=C
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cc(Br)ccc2C1
Temperature: -10 °C

Procedure:
To a two-liter round bottom flask equipped with a gas inlet tube connected to an external tank of ethylene, an addition funnel containing a solution of the crude 4-bromophenylacetyl chloride described above in methylene chloride (75 ml), a thermometer, a gas inlet adapter connected to a bubbler and a positive nitrogen flow, and a heavy-duty magnetic stirrer was added dry methylene chloride (1000 ml) and aluminum chloride (56 g, 0.42 mole). The stirred suspension was cooled to −10° C. using an ice/salt bath, and ethylene was introduced through the gas inlet tube, which was positioned just above the vortex. Dropwise addition of the phenylacetyl chloride solution was started at a moderate rate, and adjusted periodically so that the reaction temperature stayed below 0° C. Ethylene flow was continued for 30 minutes after addition of the acid chloride solution was complete, and then reaction mixture was poured over 2000 ml of ice, stirred vigorously for a few minutes, and left to sit until the ice melted. The methylene chloride layer was separated and the aqueous layer was extracted three times with methylene chloride (100 ml each). Combined methylene chloride layers were filtered through a short silica gel plug and then evaporated under reduced pressure to leave an amber-colored oil, which was purified using silica gel column chromatrography, eluting with ethyl acetate:hexane (35:65) to give 6-bromo-2-tetralone as an amber crystalline solid. (25 g, 95%).
Reaction SMILES: [Na].[SH:2][C:3]1[S:7][S:6][C:5](=[S:8])[C:4]=1[C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)C>[CH2:24]([S:2][C:3]1[S:7][S:6][C:5](=[S:8])[C:4]=1[C:9]1[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)c1cc(-c2c(S)ssc2=S)cc(C(C)(C)C)c1O
Reactant: CCCCCCBr
Agent: [Na]
Solvent: CCO
Product: CCCCCCSc1ssc(=S)c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 50 °C

Procedure:
0.92 parts of sodium was dissolved in 80 parts of ethanol and to this was added 14.8 parts of 5-mercapto-4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione, as prepared in example 11 dissolved in 200 parts ethanol. The mixture was then warmed to 50°C and a solution of 6.6 parts n-hexyl bromide in 50 parts ethanol was added dropwise. The mixture was refluxed for 5 hours, the ethanol evaporated, and the residue extracted with diethyl ether. Evaporation of the ether solution gave a crystalline residue which was crystallised from ether to give 12 parts of 5-n-hexylthio 4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione, m.p. 110°.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12]([CH3:18])([C:15]([OH:17])=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([C:15]([C:12]3([CH3:18])[CH2:11][CH2:10][N:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[N:8]=4)[CH2:14][CH2:13]3)=[O:17])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Reactant: CCc1nccc(N2CCC(C)(C(=O)O)CC2)n1
Product: CCc1nccc(N2CCC(C)(C(=O)N3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)n1

Procedure:
In a similar process as described in Example 39 using 1-(2-ethylpyrimidin-4-yl)-4-methyl-piperidine-4-carboxylic acid and 1-(4-bromophenylsulphonyl)-piperazine the following was produced 1-(4-bromophenylsulphonyl)-4-[1-(2-ethylpyrimidin-4-yl)-4-methyl-piperidin-4-ylcarbonyl]piperazine.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:26][CH2:25]C2[C:19](=CC=CC=2)[CH2:18]1.Cl.CC1N(C2N=CC=CN=2)N=CC=1/C=C/CN1CCC2C(=CC=CC=2)C1.Cl.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[N:62]1CCNCC1>>[ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[F:55])[CH2:25][CH2:26]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1c(C(=O)CCN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: Cc1c(/C=C/CN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: Cl
Product: Cc1c(/C=C/CN2CCN(c3ccccc3F)CC2)cnn1-c1ncccn1

Procedure:
The procedures of Example 6 (1) and (2) were repeated but substituting the 1,2,3,4-tetrahydroisoquinoline hydrochloride employed in Example 6 (1) by 1-(2-fluorophenyl)piperazine hydrochloride. After the completion of the post treatment, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[N:22][C:17]2=[N:16][CH:15]=1)CCC>>[CH3:8][C:4]1[N:3]=[C:2]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[N:22][C:17]3=[N:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: Cc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 36.5 %

Procedure:
2-Bromo-6-methylpyridine (367 mg, 2.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-(6-methylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (142 mg) as a white solid: δH (400 MHz, DMSO) 2.62 (3H, s), 7.26 (1H, d, J 7.4), 7.70 (1H, d, J 7.4), 7.86 (1H, t, J 7.8), 7.94 (1H, s), 8.83 (1H, s), 10.55 (1H, d, J 7.8); m/z (ES+) 279 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][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][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Cl.Cl[CH2:40][C:41]1[CH:50]=[CH:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=1.C(=O)([O-])[O-].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:12]=[C:13]([O:36][CH2:40][C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=2)[CH:14]=[C:15]([O:17][CH2:18][CH2:19][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][CH3:35])[CH:16]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccc3ccccc3n2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 78 %

Procedure:
A mixture of 1.5 g (2.9 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 0.935 g (4.35 mmol) of 2-(chloromethyl)quinoline hydrochloride (Lancaster Organic Research Chemicals), 2.0 g (14.5 mmol) ofpotassium carbonate and 0.435 g (2.9 mmol) of sodium iodide in 100 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 24 hours. The solvents were removed at reduced pressure and the residue was treated with water and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was purified by HPLC using 30% ethyl acetate-hexane followed by recrystallization from hexane to give 1.5g (78% yield, mp 76°-79°) of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycine methyl ester.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[OH:27][C@@H:28]([C@H:32]([OH:36])[C:33]([OH:35])=[O:34])[C:29]([OH:31])=[O:30]>CO>[OH:27][C@@H:28]([C@H:32]([OH:36])[C:33]([OH:35])=[O:34])[C:29]([OH:31])=[O:30].[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CO
Product: C[C@@H](N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine (CB58) (0.60 g, 1.7 mmol) in methanol (10 mL) was added (2S,3S)-2,3-dihydroxysuccinic acid (0.25 g, 1.7 mmol). The resultant solid was filtered and air dried overnight: mp 182-185° C. The solid was redissolved in methanol (10 mL) and heated to reflux (˜65° C.). The solution was cooled to room temperature and let stand overnight. The white solid that formed was filtered and air-dried to give the title compound as a white solid (0.40 g, 46%): mp 191-194° C.; 1H NMR (400 MHz, CDOD3) d 9.16 (s, 1H), 8.15 (d, J=8.2 Hz, 2H), 8.02 (d, J=9.1 Hz, 2H), 7.50 (dd, J=9.2, 1.0 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.40 (s, 2H), 3.59 (dt, J=8.1, 6.2 Hz, 1H), 3.07 (dd, J=13.6, 6.1 Hz, 1H), 2.88 (dd, J=13.6, 8.3 Hz, 1H), 1.29 (d, J=6.5 Hz, 3H) (OH and NH2 not observed).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:19]([C@H:20]([CH3:23])[CH2:21][OH:22])[CH2:18][CH:17]=4)[C:11]1([CH3:34])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>CC(C)=O>[C:1]([O:9][C@H:10]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:19]([C@@H:20]([CH:21]=[O:22])[CH3:23])[CH2:18][CH:17]=4)[C:11]1([CH3:33])[CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Product: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
—Tetrapropylammonium perruthenate (0.180 g) was added to a solution of (3β,5α,20S)-4,4,20-trimethylpregna-8,14-diene-3,21-diol 3-benzoate (WO09852965; 4.62 g) and 4-methylmorpholine N-oxide (3.50 g) in acetone (80 ml). After 30 min. stirring at room temperature the reaction mixture was filtered over dicalite and silica. The filtrate was concentrated under reduced pressure, to give (3β,5α,20S)-3-(benzoyloxy)-4,4-dimethylpregna-8,14-diene-20-carboxaldehyde (4.28 g) which was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15]C(=O)OCC1C=CC=CC=1.[H][H]>[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH2:15]
Reactant: [H][H]
Reactant: O=C(Nc1cc(OC2CCCC2)c(Cl)cc1F)OCc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Yield: 99.6 %

Procedure:
Benzyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (2.00 g, 5.51 mmol) synthesized as described above, 5% Pd/C (100 mg) as a catalyst, and toluene (15 ml) as a solvent were charged into a 50 cc round-bottom flask, and the inside of the flask was replaced sufficiently with a hydrogen gas. Then, in a hydrogen gas atmosphere, the mixture was thoroughly stirred for 8 hours at 50° C. After completion of the reaction, the catalyst was separated by filtration, the resulting filtrate was dried with anhydrous magnesium sulfate. After separating the drying agent by filtration, the solvent was distilled off under reduced pressure from the filtrate to obtain quantitatively 2-fluoro-4-chloro-5cyclopentyloxyaniline (1.26 g) as a pale brown oily substance. The spectral data and the like are shown in Reference Example 1.