Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(OCC)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[CH:15][NH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1c(CCc2ccc3nc(N)sc3c2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: COc1ccccc1
Product: Cc1[nH]cnc1CCc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.2 %

Procedure:
A mixture of 2-amino-6-[2-(5-methyl-1-tritylimidazol-4-yl)ethyl]benzothiazole (1.4 g) in anisole (1.4 ml) and trifluoroacetic acid (6.0 ml) was stirred for 5 hours at ambient temperature. To the reaction mixture was added a diethyl ether, and precipitate was collected by filtration. To the precipitate was added a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by a column chromatography on alumina eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-amino-6-[2-(5-methylimidazol-4-yl)ethyl]benzothiazole (0.24 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:35])[N:8]([CH2:31][C:32]([OH:34])=O)[C:9](=[O:30])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][C:27](=[O:29])[O:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:35])[N:8]([CH2:31][C:32]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:34])[C:9](=[O:30])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][C:27](=[O:29])[O:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1COCCN1
Reactant: CCCCc1nc(C)n(CC(=O)O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(=O)N2CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.2 %

Procedure:
A mixture of [4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]acetic acid (0.12 g), morpholine (0.033 g), 1-hydroxybenzotriazole (0.035 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.05 g) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with diluted hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.080 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([NH2:7])=O>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:13])([F:14])[F:15])[C:5]#[N:7]
Reactant: NC(=O)c1ccc(OC(F)(F)F)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(OC(F)(F)F)c(Cl)c1
Yield: 85 %

Procedure:
750 ml of SOCl2 were added to 239.5 g (1 mole) of 3-chloro-4-trifluoromethoxy-benzamide and the mixture was slowly heated (according to the evolution of gas) to 85° C. The mixture was then fractionally distilled and 189 g of product having a boiling point at 13 mbar of 96° C. and a melting point of 38° to 40° C. were obtained. This corresponds to a yield of 85% of theory.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:23][CH2:22][N:21]([C@@:24]4([CH3:36])[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:13]=2)=[CH:4][N:3]=1.[ClH:37].O1CCOCC1>CO.C1(C)C=CC=CC=1>[ClH:37].[CH3:20][C@H:15]1[CH2:16][O:17][CH2:18][CH2:19][N:14]1[C:12]1[N:13]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=2)[C:9]2[CH2:23][CH2:22][N:21]([C@@:24]3([CH3:36])[CH2:28][CH2:27][NH:26][CH2:25]3)[C:10]=2[N:11]=1
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCNC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a flask containing tert-butyl(3S)-3-{4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-3-methylpyrrolidine-1-carboxylate (3290 mg, 6.625 mmol) in 31 mL MeOH was added 4 N HCl in dioxane (33 mL, 132 mmol) dropwise at 0° C. and the mixture was stirred at room temperature for 2 h. The mixture was diluted with toluene and concentrated. Additional toluene was added and the solution was concentrated to give the title compound (3.73 g, >99%) as a yellow foam. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (br s, 2 H), 8.69 (s, 2 H), 7.33-7.11 (m, 2H), 4.63-4.52 (m, 1 H), 4.20 (d, J=11.5 Hz, 1 H), 4.03-3.89 (m, 2 H), 3.83-3.18 (m, 10 H), 3.14-3.03 (m, 2 H), 2.71-2.55 (m, 1 H), 2.20-2.04 (m, 1 H), 1.48 (s, 3 H), 1.28 (d, J=6.7 Hz, 3 H). m/z (APCI+) for C20H28N8O 397.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6](S(C)(=O)=O)[N:7]=1.[NH2:30][C:31]1[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=1>O1CCOCC1>[CH2:38]([O:37][C:35]([C:34]1[CH:40]=[CH:41][C:31]([NH:30][C:6]2[N:7]=[C:2]([CH3:1])[C:3]3[CH:15]=[CH:14][C:13](=[O:16])[N:12]([C:17]4[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:28][CH:29]=4)[C:4]=3[N:5]=2)=[CH:32][CH:33]=1)=[O:36])[CH3:39]
Reactant: Cc1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(Nc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)OC(C)(C)C)cc4)c3n2)cc1
Reaction time: 14 h
Yield: 63.3 %

Procedure:
A solution of compound 2 (0.5 g; 1.2 mmol) and ethyl p-aminobenzoate (1 g; 6 mmol) in 10 mL of dioxane was refluxed under stirring for 14 h. The reaction mixture was concentrated, purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=1/1 to 1/2) to yield compound 3 (0.38 g; 63%).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5][OH:6].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.C(Cl)Cl>[Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][C:5]([OH:13])=[O:6]
Reactant: CC(C)=O
Reactant: OCCC(F)(Cl)C(F)(F)Br
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(O)CC(F)(Cl)C(F)(F)Br
Temperature: 0 °C
Yield: 85 %

Procedure:
A solution of 4-bromo-3-chloro-3,4,4-trifluorobutanol (IX) (2.41 g, 10 mmol) in acetone (35 mL) was treated with Jones reagent (7.5 mL) in 10 min with stirring and cooling (ice-water bath). The mixture was then stirred at room temperature for 30 min and 0.5 mL of i-propanol was then added. The precipitated salts were removed by filtration, washed with acetone. The residue obtained after concentration of the filtrate was dissolved in methylene chloride (100 mL), washed with 1N HCl (50 mL), brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 2.17 g (85%) of 4-bromo-3-chloro-3,4,4-trifluorobutanoic acid (VIII) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[N:9]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:8]=1)=[O:6]
Reactant: BrCc1ccncc1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCCO4)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccncc3)c3cc4c(cc3c2=O)OCCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 58 mg (0.17 mmol) of 8-(3,4-dimethyl-benzoyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-g]quinolin-9-one, 18 mg of 60% sodium hydride, 57 mg of 4-bromomethylpyridine hydrobromide and 1.2 mL of N,N-dimethylformamide. Yield: 52 mg of a white solid: LC-MSD, m/z for C26H22N2O4 [M+H]+=427.5; HPLC retention time: 1.4 min.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.[NH:21]1[CH:25]=[CH:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>ClCCl.[Cu]I.CS(C)=O>[C:4]1([N:5]2[C:6]3[CH:11]=[C:10]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)[CH:9]=[CH:8][C:7]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:13][CH:14]=[CH:2][CH:3]=1
Reactant: c1cn[nH]c1
Reactant: Brc1ccc2c3ccccc3n(-c3ccccc3)c2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: c1ccc(-n2c3ccccc3c3ccc(-n4cccn4)cc32)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
A pressure vessel was charged with 2-bromo-9-phenyl-9H-carbazole (10 mmol), pyrazole (20 mmol), potassium carbonate (20 mmol), L-proline (2 mmol), copper(I) iodide (1 mmol), and dimethyl sulfoxide (25 mL). After three cycles of evacuation and backfilling with nitrogen, the vessel was sealed and stirred at 90° C. for three days. After cooling, the reaction mixture was diluted with dichloromethane (200 mL), washed four times with water (200 mL), and dried over magnesium sulfate. After removing the solvent under reduced pressure, the crude product was chromatographed over silica with hexane as the eluent, giving 9-phenyl-2-(1H-pyrazol-1-yl)-9H-carbazole in 45% yield.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=1)[CH3:9])(C)(C)C.B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:7][C@H:8]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: COc1cccc([C@H](C)NC(=O)OC(C)(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: C[C@H](N)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-[1-(3-Methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (50.2 g, 210 mmol) in CH2Cl2 (500 mL) was cooled to −78° C. Boron tribromide (450 mL, 1.0M in CH2Cl2) was added slowly and the resulting mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was again cooled to 0° C. and methanol (500 mL) was added slowly. The solvent was removed in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with 5% MeOH in EtOAc to give the title product in quantitative yield.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:33])([F:32])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.C(=O)(O)[O-].[Na+]>ClCCl>[N:19]1([C:16]2[CH:17]=[CH:18][C:13]3[N:14]([C:10]([C:9]([F:8])([F:32])[F:33])=[N:11][N:12]=3)[N:15]=2)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Trifluoroacetic acid (25 mL, 324.49 mmol) was added to a mixture of tert-butyl 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carboxylate (6.7 g, 17.99 mmol) and dichloromethane (100 mL) at ambient temperature and the resulting solution was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated to give an involatile residue that was treated with saturated aqueous sodium bicarbonate solution (100 mL) and then extracted with dichloromethane (4×200 mL). The organic phases were combined and dried over Na2SO4, filtered, and evaporated to give 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.78 g, 98%) as a white solid that was used without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[OH:24]O>>[OH:1][CH:2]([CH2:16][S:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2
Reactant: OO
Reactant: O=C1CCc2c(cccc2OCC(O)CSc2ccccc2)N1
Product: O=C1CCc2c(cccc2OCC(O)CS(=O)c2ccccc2)N1

Procedure:
Prepared analogous to Example 2 from 5-(2-hydroxy-3-phenylmercapto-propoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(F)F
Reactant: O=C(O)Cc1ccccn1
Product: COc1ccc(N2CCN(C(=O)Cc3ccccn3)[C@@H](Cc3ccccc3)C2)cc1OC(F)F

Procedure:
Prepared by the method outlined for Example 189 using pyridin-2-yl-acetic acid and (S)3-benzyl-1-(3-difluoromethoxy-4-methoxy-phenyl)-piperazine (Example 69, Compound 157) as starting materials. Product as an oil. LC/MS (Method B) 2.56 min, [M+1]+ 468. Potency class ND.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:15][O:16][CH:17]([O:21][CH3:22])N(C)C>>[CH3:15][O:16][CH:17]([O:21][CH3:22])[CH:10]1[CH2:9][CH:8]([CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:14][CH2:13][CH2:12][NH:11]1
Reactant: COC(OC)N(C)C
Reactant: c1cn(CCC2CCCNCC2)cn1
Product: COC(OC)C1CC(CCn2ccnc2)CCCN1
Temperature: 100 °C

Procedure:
A mixture of hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine (6.0 g, 0.031 M) and dimethylformamide dimethylacetal (33 ml) was heated at 100° C. for 4 hrs. The reaction was stripped to dryness to give hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine carboxaldehyde dimethylacetal. The solution of the hexahydroazepine carboxaldehyde dimethylacetal in methylene chloride (40 ml) was added to the mixture of 6-aminopenicillanic acid (5.7 g, 0.026 M) and diisopropylethylamine (3.15 ml) in methylene chloride (150 ml) at 0° C. and stirred at 0° C. for 1 hr, room temperature for 3 hrs. The solvent was removed and water (100 ml) was added. After being washed with ether, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[4-[hexahydro[2-(1H-imidazol-1 -yl)ethyl]-1H-azepin-1-yl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.2 molar hydrochloride hydrate (diastereomers) (4.0 g, 32% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17].[CH2:23]([NH:26][C:27]#[N:28])[CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[N:28][C:15]([CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])=[N:14]1
Reactant: CC(C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Reactant: CCCNC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNc1nc(C(C)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 2 h
Yield: 700.8 %

Procedure:
7.8 g (0.02 mol) of 2-trifluoromethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.9 g (0.002 mol) of propyl cyanamide were dissolved in 50 ml of tetrahydrofuran, and 2.6 g (0.026 mol) of triethylamine was dropwise added thereto under stirring and cooling with ice. After completion of the dropwise addition, the stirring was continued at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, hexane was distilled off under reduced pressure. Further, the residue was subjected to distillation under reduced pressure. The fraction having a boiling point of 110°-120° C./0.1-0.2 mmHg was subjected to recrystallization from hexane to obtain 6.1 g (yield: 70%) of the desired compound having a melting point of from 73° to 74.5° C. as white prismatic crystals.
Reaction SMILES: C(OC(=O)[NH:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[C:20]([Si:17]([CH3:19])([CH3:18])[O:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([NH2:7])[CH2:9][CH2:10]1)([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)(C)OC(=O)NN1CCC(CCO[Si](C)(C)C(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OCCC1CCN(N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
{4-[2-(t-Butyl-dimethyl-silanyloxy)-ethyl]-piperidin-1-yl}-carbamic acid t-butyl ester (168 mg, 468 μmol) was at 0° C. combined with dichloromethane (2 mL) and trifluoroacetic acid (2 mL) to give a light yellow solution. The reaction mixture was stirred for 2 h at 0° C. and subsequently concentrated in vacuo to give the title compound as yellow oil, which was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=[C:14]([O:15]C)[C:7]=2[N:6]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[CH:12][CH:13]=[C:14]([OH:15])[C:7]=2[N:6]=1
Reactant: CCC(CC)c1ccc(OC)c2nc(Oc3ccc(Cl)cc3Br)n(C)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(CC)c1ccc(O)c2nc(Oc3ccc(Cl)cc3Br)n(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 2-(2-bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole (80 mg, 0.18 mmol) in dichloromethane (2 mL) was added dropwise a dichloromethane solution (1M, 2 mL) of boron tribromide at 0° C., and stirred at room temperature for 1 h. The reaction mixture was cooled at 0° C., quenched with water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with isopropyl ether and hexane (1:1) to give the title compound (67 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH3:21]>CC(=O)CC>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1ccc([N+](=O)[O-])c(C)c1
Reaction time: 0.08 h
Yield: 193.6 %

Procedure:
Compound 403 (1.5 g, 9.8 mmol) was dissolved in 2-butanone (40 mL). Potassium carbonate (3.4 g, 24.5 mmol) was added and the solution heated at reflux. After 5 min, 1-bromopropane (18 μL, 5 mmol, 2 mL) was added drop-wise and the reaction mixture continued to stir for 18 h. The solvent was evaporated in vacuo and the crude residue was partitioned between EtOAc (150 mL) and saturated NaHCO3 (150 mL). The organic layer was separated, washed with brine (100 mL) and dried over Na2SO4. The resulting oil was purified by column chromatography (0% to 20% EtOAc/hexanes) to yield a yellow oil (1.89 g, 99%): TLC Rf 0.70 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (d, 1H, J=8.76 Hz), 6.79-6.77 (m, 2H), 3.99-3.97 (t, 2H, J=6.54 Hz), 2.63 (s, 3H), 1.85-1.82 (sex, 2H, J=7.44 Hz), 1.06-1.04 (t, 3H, J=7.44 Hz). 13C NMR (150 MHz, CDCl3) δ 162.9, 142.2, 137.3, 127.8, 118.1, 112.4, 70.3, 22.60, 21.98, 10.6. Elemental analysis calculated for C10H13NO3.0.03 hexanes: C, 61.81; H, 6.84; N, 7.08. Found: C, 62.20; H, 6.78; N, 7.23.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCCC1=O.C[O-].[Na+].[CH2:22](Cl)[CH:23]=[C:24]([CH2:26][CH2:27][CH:28]=[C:29]([CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH3:30])[CH3:25]>CO.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][CH:23]=[C:24]([CH2:26][CH2:27][CH:28]=[C:29]([CH2:31][CH2:32][CH:33]=[C:34]([CH3:35])[CH3:36])[CH3:30])[CH3:25])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[O-]
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CO
Product: COC(=O)c1ccc(OCC=C(C)CCC=C(C)CCC=C(C)C)cc1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
After removal of the methanol by distillation from a mixture of 20.0 g (131 mmol) 4-hydroxybenzoic acid methyl ester, 200 ml N-methylpyrrolidone, and 25.9 g (144 mmol) 30% sodium methylate solution in methanol, 1.1 g tetrabutylammonium iodide and 38.0 g (158 mmol) farnesyl chloride were added. This was followed by heating with stirring for 7 hours at 160° C. After cooling to room temperature, the solution was filtered off from the sodium chloride formed, evaporated under reduced pressure to dryness, the evaporation residue was taken up in methylene chloride, washed with water, dried with sodium sulfate, distilled under reduced pressure after concentration by evaporation and the fraction boiling at 190° to 202° C. under 0.015 mbar pressure was chromatographed on silica gel (Merck) (eluent: methylene chloride/toluene =7:3). 19.2 g (41% of the theoretical) of 4-farnesyloxybenzoic acid methyl ester was obtained in the form of a colorless oil having a refractive index at 20° C. of 1.5293.
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=CC=2)CC1.[CH3:25][C:26]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([CH3:29])[CH2:27][CH3:28].FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][C:26]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=2)=[CH:32][CH:31]=1)([CH3:29])[CH2:27][CH3:28]
Reactant: CCC(C)(C)c1ccc(C=O)cc1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Yield: 94 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1,1-dimethylpropyl)-benzaldehyde (prepared as described in example S103) (88 mg, 0.50 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (94 mg, 0.50 mmol) and sodium borohydride (28 mg, 0.75 mmol). The desired product (163 mg, 94%) was isolated without further purification as a colorless oil. MS (ISP) 350.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([OH:19])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C1(C)C=CC=CC=1>[CH2:24]([N:26]([CH2:27][CH3:28])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:19])[CH3:25]
Reactant: CCNCC
Reactant: O=C(O)c1nc(-c2ccccc2)c2ccccc2n1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1nc(-c2ccccc2)c2ccccc2n1

Procedure:
Operations are carried out as for Example 19, starting from 2.5 g of 4-phenyl quinazoline 2-carboxylic acid, 10 ml of thionyl chloride 25 ml of toluene and 25 ml of diethylamine. 1.27 g of N,N-diethyl 4-phenyl quinazoline 2-carboxamide, melting at 101° C., is obtained.