Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:14][N:15]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)=O)C.O>O1CCCC1>[CH2:27]([O:26][C:13]1[C:12]([CH2:10][OH:9])=[CH:16][N:15]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cn(COCc2ccccc2)nc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn(COCc2ccccc2)nc1OCc1ccccc1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a suspension of lithium aluminum hydride (0.13 g) in tetrahydrofuran (5 mL) was added 3-benzyloxy-1-benzyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.65 g) at room temperature, and this mixture was stirred at same temperature for 3 hours. To this reaction mixture was added water, and the insoluble material was removed by filtration. This filtrate was dried over anhydrous magnesium sulfate, and this solvent was removed under reduced pressure to give the title compound (0.57 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N+:35]([O-:37])=[O:36])=[C:30](B(O)O)[CH:31]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N+:35]([O-:37])=[O:36])=[C:28]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:27]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(Cl)ccc1[N+](=O)[O-]
Yield: 7 %

Procedure:
5′-Chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid was prepared in 7% yield (for two steps) from 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6) and 5-chloro-2-nitrophenylboronic acid (available from Combi-Blocks Inc.) using General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode. 1H NMR (300 MHz, DMSO-d6) δ 13.29 (br s, 1H), 8.60 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.29-8.37 (m, 2H), 8.20 (d, J=8.9 Hz, 2H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 7.73-7.82 (m, 2H), 7.60 (d, J=2.3 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][C:10]=2[C:23]([F:26])([F:25])[F:24])=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:33][C@H:30]2[CH2:31][CH2:32][C@H:27]([NH2:34])[CH2:28][CH2:29]2)=[N:6][CH:7]=1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)cnc2C(F)(F)F)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)cnc3C(F)(F)F)c(Cl)cn2)CC1
Temperature: 100 °C

Procedure:
6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine (0.0178 g, 0.046 mmol) was dissolved in anhydrous DMSO (1.0 ml) and charged to a microwave vial. This was treated with trans-cyclohexane-1,4-diamine (0.052 g, 0.456 mmol). The reaction mixture was then heated at 100° C. for 18 hr. The reaction mixture was allowed to cool to ambient temperature. The material was purified by preparative reverse-phase HPLC to give 0.0086 g (32%) of trans-N1-(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)amino-3-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine as the TFA salt. LCMS (m/z): 485.3 (MH+), retention time=0.63 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[CH2:19][CH2:18]2)[N:12]=1)([CH3:10])[CH3:9])(C)(C)C>Cl.CCOCC.CO>[CH:17]1([C:13]2[N:12]=[C:11]([C:8]([NH2:7])([CH3:9])[CH3:10])[CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(C2CC2)n1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(N)c1cccc(C2CC2)n1
Yield: 73.6 %

Procedure:
Dissolve [1-(6-cyclopropyl-pyridin-2-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (1.3 g, 4.7 mmol) in 2 N HCl/Et2O (excess) with a small amount of methanol to effect solution. Stir until the starting material is consumed, monitoring by LC-MS. Evaporate and partition the residue between dichloromethane and aqueous sodium bicarbonate. Extract with dichloromethane, filter and evaporate to give 1-(6-cyclopropyl-pyridin-2-yl)-1-methyl-ethylamine as an orange oil (610 mg, 75%). LC-MS ESI m/z: 177.2 (M+H)+, Tr=1.80 min, method 1.
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][SH:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:32])[C:23]([CH3:31])([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH3:24])=[CH:18][CH:17]=1>CC(N(C)C)=O.C(OCC)(=O)C>[SH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][S:8][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[O:32])[C:23]([CH3:24])([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH3:31])=[CH:20][CH:21]=1
Reactant: SCCCCCCS
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCCCCCS)cc1)N1CCOCC1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
10.0 g (0.066 mol) of 1,6-hexanedithiol are added to a suspension of 3.6 g (0.026 mol) of potassium carbonate in 15 ml of dimethylacetamide. The suspension is heated to 85° C., and a solution of 3.6 g (0.013 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one in 20 ml of dimethylacetamide is added dropwise over 20 min. After stirring for 18 h, the reaction mixture is cooled, diluted with ethyl acetate (60 ml), and filtered. The filtrate is washed with water (3×50 ml), dried over MgSO4, and concentrated i.v. (85° C./5 mm Hg). The resulting oil is purified by flash chromatography on silica gel (hexane/ethyl acetate 85:15) to a pale yellow oil which crystallizes to a colorless solid upon standing. m.p. 61-64° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.35 (t, SH), 1.4-1.8 (m, 8H), 2.53 (q, 2H), 2.57 (t, 4H), 3.00 (t, 2H), 3.69 (t, 4H), 7.24 (d, 2H), 8.50 (d, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[S:19]1[C:20]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:17]=2)=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: c1ccc2sc(-c3ccnc(Nc4ccc5c(c4)OCCO5)c3)cc2c1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401(b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), benzothiophene-2-boronic acid (Frontier Scientific, Inc.) (45 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 361 (M+1). Mp: 154.0-154.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Br:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Br
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Br

Procedure:
using isopropyl 2-bromo-4-fluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2-bromo-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 116°-120° C.,
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:12]=[C:13]([N:23]([CH3:25])[CH3:24])[C:14]([O:21][CH3:22])=[C:15]([C:17](O)([CH3:19])[CH3:18])[CH:16]=1.O>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[C:15]([C:17]([F:7])([CH3:19])[CH3:18])[C:14]([O:21][CH3:22])=[C:13]([N:23]([CH3:25])[CH3:24])[CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1c(N(C)C)cc(Br)cc1C(C)(C)O
Solvent: O
Solvent: ClCCl
Product: COc1c(N(C)C)cc(Br)cc1C(C)(C)F
Yield: 67.5 %

Procedure:
Diethylaminosulfur trifluoride (620 mg) was added to a solution of 2-[5-bromo-3-(dimethylamino)-2-methoxyphenyl]-2-propanol (1 g) in methylene chloride while stirring on ice. After stirring for an additional 30 minutes while cooling on ice, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (680 mg) as an oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11](F)([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.NCC(F)([C:46]([F:49])([F:48])[F:47])C(O)=O>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([C:46]([F:49])([F:48])[F:47])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC(F)(C(=O)O)C(F)(F)F
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(C(F)(F)F)C(=O)N2C

Procedure:
The title compound was synthesized using the analogous procedure to that described in connection with Compound 3 except that 2-(aminomethyl)-2,3,3,3-tetrafluoropropanoic acid was used as the starting material. The final product was purified on reversed phase HPLC as TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.76 (m, 10 H) 1.83-2.09 (m, 4 H) 2.19 (s, 3 H) 2.80 (d, J=11.9 Hz, 2 H) 3.32 (s, 3 H) 3.69-3.81 (m, 1 H) 3.89 (t, 1 H) 3.94 (s, 3 H) 4.15-4.35 (q, 1 H) 4.72 (quin., J=8.1 Hz, 1 H) 7.48 (dd, J=1.77 Hz, 1 H) 7.50 (s, 1 H) 8.00 (s, 1 H) 8.10 (d, J=7.8 Hz, 1 H) 8.26 (d, J=8.3 Hz, 1 H) 8.32 (s, 1 H). [M+H] calc'd for C28H35F4N7O3 594; found 594.
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([N:21]([CH2:36][CH3:37])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)=[O:23])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:36]([N:21]([CH:16]1[CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:38])=[O:5])[CH:20]=[CH:19][C:18]=2[CH2:17]1)[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=1)=[O:23])[CH3:37]
Reactant: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1CCc2cc(SC(C)(C)C(=O)O)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.2 %

Procedure:
To 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester (1.66 g; 3.0 mmol) dissolved in CH2Cl2 (15 mL) is added TFA (15 mL) and the reaction was stirred at RT for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 0.643 g (43%) of 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid as a white solid.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.C([Mg]Cl)(C)C.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].O>O1CCCC1>[CH2:17]([O:16][C:14]([C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: Brc1cscc1Br
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cscc1Br
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 98.5 %

Procedure:
To a 0° C. solution of 3,4-dibromothiophene (1.0 Kg, 4.13 mol) in tetrahydrofuran (7.4 Kg) was added iPrMgCl (2.0 M solution in tetrahydrofuran, 2.58 Kg, 5.17 mol) keeping the temperature below 5° C. The resulting mixture was stirred at 0-5° C. for 5 hours. To the cooled Grignard solution was added ethyl chloroformate (896 g, 5.17 mol) dropwise keeping the temperature below 10° C. The resulting mixture was warmed to room temperature, and stirred for 16 hours. Water (200 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 10 min The majority of the tetrahydrofuran was then removed under vacuum and ethyl acetate (4.5 Kg) was added to the mixture followed by 1N aqueous hydrochloric acid. The layers were separated, and the organic layer was washed with 12% brine (5.0 Kg) The solvent was removed under vacuum to give a yellow oil, which was filtered to remove salts to provide 956 g (98% yield) of 4-bromo-thiophene-3-carboxylic acid ethyl ester, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, 1H, J=3.5 Hz), 7.30 (d, 1H, J=3.6 Hz), 4.34 (q, 2H, J=7.10 Hz), 1.38 (t, 3H, J=7.20 Hz); 13C NMR (400 MHz, CDCl3): δ14.49, 60.95, 110.49, 124.86, 130.93, 133.67, 160.68.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[C:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:2]1.[OH:19]O>CO>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[C:7]2[CH2:12][CH2:11][N+:10]([O-:19])([CH3:13])[CH2:9][CH2:8]2)=[CH:2]1
Reactant: CN1CCC(=C(c2ccsc2)c2ccsc2)CC1
Reactant: OO
Solvent: CO
Product: C[N+]1([O-])CCC(=C(c2ccsc2)c2ccsc2)CC1
Reaction time: 192 h
Yield: 77 %

Procedure:
5.5 grams (0.02 mole) of 4-(di-3-thienyl-methylene)-N-methyl-piperidine were dissolved in 50 ml of methanol and treated with 7.2 grams of 30% hydrogen peroxide dropwise with ice cooling and left at room temperature for 8 days. Excess hydrogen peroxide was destroyed by the addition of Pt-carbon. After the filtering and removal of the solvent at room temperature the amineoxide was crystallized in ethyl acetate. M.P. 92°-96° C.; Yield: 77%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 97 %

Procedure:
To 30 ml of methyl isobutyl ketone were added 3 g of 4-hydroxy-4'-cyanobiphenyl, 21.4 g of 1-bromodecane and 2.5 g of potassium carbonate, and the mixture was reacted under reflux for 30 hours. The reaction mixture was cooled and insoluble substances were removed by filtration. The filtrate was concentrated under a reduced pressure, ethanol was added to the residue and recrystallization was carried out to obtain 5 g of 4-decyloxy-4'-cyanobiphenyl. Thus, 4.1 g of this 4-decyloxy-4'-cyanobiphenyl was dissolved in 25 ml of ethylene glycol, 2.5 ml of 2N sodium hydroxide was added to the solution, and a reaction was carried out under reflux for 4 hours. The reaction liquid was put into dilute hydrochloric acid cooled by ice, and the precipitate was recovered by filtration, washed with water and ethanol, and dried. The dried product was recrystallized from chloroform to obtain 3.0 g of 4'-decyloxybiphenyl-4-carboxylic acid. Then, 20 g of thionyl chloride was dropped into this carboxylic acid and the mixture was reacted under reflux for 2 hours. Unreacted thionyl chloride was removed by distillation under a reduced pressure and 4'-decyloxybiphenyl-4-carboxylic acid chloride was quantitatively recovered.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Br.[CH2:9]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][N:16]1[CH2:17][CH2:18][CH:13]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15]1
Reactant: CCCCC1CCNCC1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCC(=O)OC)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-butyric acid methyl ester (1.35 g, 7.5 mmol) in dry acetonitrile (10 ml) was added 4-butylpiperidine (1.00 g, 7.1 mmol) and K2CO3 (1.10 g, 7.8 mmol). After stirring at rt for 12 h, the reaction mixture was evaporated to dryness followed by addition of water (15 ml). The aqueous phase was extracted with ethyl acetate (3×20 ml) and the combined organic phases were dried (Na2SO4) and concentrated in vacuo to produce 1.71 g of the crude title compound 76. The crude product was purified by flash chromatography (MeOH:ethyl acetate; 2:8) to give the pure title compound. Yield 1.27 g (74%). 1H NMR (CD3OD): δ3.65 (s, 3H), 2.93 (d, 2H), 2.33 (q, 4H), 1.98 (t, 2H), 1.81 (qv, 2H), 1.69 (d, 2H), 1.35-1.18 (m, 9H), 0.90 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.[C:14]([Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34]I)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]1=2)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: CC(C)(C)[Si](OCC(F)CI)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(=O)n(CC(F)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.9 %

Procedure:
6-Methoxypyrido[2,3-b]pyrazin-3(4H)-one (215 mg, 1.213 mmol) and tert-butyl(2-fluoro-3-iodopropoxy)diphenylsilane (805 mg, 1.820 mmol) were dissolved in N,N-dimethylformamide (6 ml). Cesium carbonate (553 mg, 1.698 mmol) was added to the solution and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 399 mg (67%) of the title compound in the form of a light orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C=O)C.O>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=3[CH:13]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CC1=Cc2cc(OCc3ccc(C(F)(F)F)cc3)ccc2OC1
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: A mixture of 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde (2.50 g, 14.2 mmol) and potassium carbonate (3.62 g, 38.4 mmol) in 50 ml of DMF is treated with 4-trifluoromethylbenzyl bromide (3.73 g, 15.6 mmol). The reaction is allowed to proceed overnight at room temperature. The mixture is diluted with water and extracted three times with dichloromethane. The combined organic layers are washed once with water, dried (MgSO4), and evaporated. Purification by silica gel chromatography (20% ethyl acetate/hexane) yields 6-(4-trifluoromethylbenzyloxy)-2H-1-benzopyran-3-carboxaldehyde, m.p. 108°-110° C.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.C(O)=O.Cl>C(N(CC)CC)C>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:21]=[CH:20][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 90 °C

Procedure:
After weighing 14.4 g (0.1 mol) of Meldrum's acid and 16.6 g (0.1 mol) of veratraldehyde to 50 ml of the mixture of formic acid and triethylamine prepared according to Example 1, the reaction mixture was heated to 90° C. during 1 hour and maintained at 90° C. for 2 hours. After cooling down to room temperature 200 ml of ice-water were added to the reaction mixture, the pH value was adjusted to 1 by adding concentrated hydrochloric acid and the mixture was let stand at 5° C. for 16 hours. After filtration the precipitate was washed 3 times on the filter and dried at 40° C. under reduced pressure.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31](F)=[CH:30][C:29]=3N)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrC1C=CC=CC=1[C:44]([F:47])([F:46])[F:45]>>[CH2:2]([O:9][C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:44]([F:47])([F:46])[F:45])[CH2:24][C:23]2=[O:36])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)OCc3ccccc3)CCCCC2)C(O)C1
Agent: Cl
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3C(F)(F)F)CC2=O)CCCCC1)OCc1ccccc1

Procedure:
In accordance with the same procedure as in Example 24, except that 4-[N-[1-[N-(benzyloxycarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol hydrochloride was used instead of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-trifluoromethylbenzene was used instead of 1-bromo-4-fluoro-2-trifluoromethylbenzene in Step 1 of Example 24, 228 mg of the titled compound was prepared.
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=O)=O)=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:12]1([CH2:18][CH:19]2[S:7][CH2:4][CH2:3][CH2:2][O:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=CCc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CC2OCCCS2)cc1

Procedure:
To a solution of the thiol (14.67 g) from step a) in toluene (200 ml) was added p-toluenesulphonic acid (1 g) and phenylacetaldehyde (18.3 ml). The reaction was refluxed using a Dean and Stark apparatus. After the appropriate amount of water had been collected the reaction mixture was cooled, washed with saturated sodium bicarbonate, saturated brine and dried (K2CO3). The crude product was distilled (bp 100°-110°/0.3 mbars) to give a yellow liquid (19.65 g).