Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[CH:19][C:20]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:21]([CH:31]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1)=[O:23]>COCCOC.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>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][O:32][C:20]2[CH:19]=[CH:18][C:17]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=[O:23])=[CH:39][CH:38]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccnnc1)c1cc(-c2ccncc2)ccc1OCc1ccc(F)cc1
Temperature: 120 °C

Procedure:
4-Pyridinylboronic acid (81 mg, 0.66 mmol), sodium carbonate (1.09 ml, 1.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (37.9 mg, 0.03 mmol) were added to a solution of 5-bromo-2-{([(4-fluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared as described in Example 77; 220 mg, 0.55 mmol) in 1,2-dimethoxyethane (5 ml). The reaction was heated at 120° C. for one hour. The solvent was removed in vacuo, redissolved in 1:1 dimethylsulfoxide/methanol and purified by MDAP to yield the title compound as a white solid. 58 mg.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[C:16](Cl)(=O)C>CO>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([O:11][C:12]([F:14])([F:13])[F:15])[CH:4]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(F)c(OC(F)(F)F)c1
Solvent: CO
Product: COC(=O)c1ccc(F)c(OC(F)(F)F)c1
Yield: 75 %

Procedure:
To a stirred suspension of 21.2 g (96.9 mmol) 4-Fluoro-3-trifluoromethoxy-benzoic acid (JRD-Fluoro) and 161 ml methanol were added 30.4 g (387.6 mmol) acetyl chloride drop wisely at 0° C. The reaction mixture was stirred over night, filtered and concentrated. The residue was diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (hexane:ethylacetate). The desired product 14a was obtained in 75% yield (17.3 g; 72.7 mmol)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([O:11]CC#C)=[O:10])=[CH:7][C:6]=1[F:17])[C:2]#[CH:3].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[F:17])[C:2]#[CH:3]
Reactant: C#CCOC(=O)c1ccc(OCC#C)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCOc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To 50 ml of ethanol were added 10.8 g of 2-propynyl 4-(2-propynyloxy)-3-fluorobenzoate and 30 ml of 15% aqueous sodium hydroxide solution and the mixture obtained was stirred at room temperature for 2 hours. Then, the reaction mixture was added to hydrochloric acid for acidification. Crystals precipitated were collected by filtration and dried to obtain 8.0 g of 4-(2-propynyloxy)-3-fluorobenzoic acid represented by the formula:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[C:8]([CH:14]2[CH2:16][CH2:15]2)[N:7]=1>C(OCC)C>[Cl:5][C:6]1[N:7]=[C:8]([CH:14]2[CH2:15][CH2:16]2)[N:9]=[C:10]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:11]=1[F:12]
Reactant: Fc1c(Cl)nc(C2CC2)nc1Cl
Reactant: NC1CC1
Solvent: CCOCC
Product: Fc1c(Cl)nc(C2CC2)nc1NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Cyclopropylamine (11.4 g, 0.200 mol) is added to 4,6-dichloro-2-cyclopropyl-5-fluoropyrimidine 18 (4.80 g, 23 mmol) and the solution is stirred at room temperature for 1 h. The mixture is diluted with diethylether, washed two times with a saturated sodium bicarbonate solution. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford 6-chloro-N,2-dicyclopropyl-5-fluoro-4-pyrimidinamine 31 as a yellow oil (4.99 g, 95%) which is used in the next step without further purification.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].Cl>CCl>[C:13]([C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH:5]=1)[CH:3]=[O:2])(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(OC)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: CCl
Agent: Cl
Product: O=Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3-dimethoxymethyl-4-nitro-phenyl)-phenyl-methanone (0.0659 mol) and 5N HCl (40 mL) in CH3Cl (80 mL) was stirred at room temperature overnight. Then the mixture was refluxed for 4 h. After cooling, the organic layer was separated. The organic layer was alkalized by adding dropwise NH4OH. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue (14.6 g) was crystallized from diisopropyl ether/EtOAc (50 mL:20 mL). The precipitate was filtered off, washed with diisopropyl ether/EtOAc, diisopropyl ether and dried in vacuo at 50° C. to yield the title compound as a residue.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:1][CH:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])=[CH:17][CH:16]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccc(F)cc2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 4-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(4-fluorophenoxy)ethyl)benzoate (490 mg, 35%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: OCC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of tetrahydropyran-2-methanol (2 g, 17.2 mmol) cooled at 0° C. is added toluene-4-sulfonyl chloride (3.6 g, 18.92 mmol), followed by (2.63 mL , 18.92 mmol) of triethylamine. The mixture is allowed to reach RT and stirred overnight. Then poured into an aqueous saturated solution of NaHCO3. The layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 80:20) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9. MS (LC-MS): 271.1 [M+H]+, tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, flow: 1.5 ml/min): 5.32 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[N:12]=1.[Cl:24]N1C(=O)CCC1=O>CN(C)C=O>[Cl:24][C:10]1[S:9][C:8]([N:3]2[C:2]([CH3:23])([CH3:1])[CH2:6][O:5][C:4]2=[O:7])=[N:12][C:11]=1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(-c2csc(N3C(=O)OCC3(C)C)n2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(N3C(=O)OCC3(C)C)sc2Cl)cc1
Reaction time: 120 h

Procedure:
Methyl 4-[2-(4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzoate, prepared in Example 129, and N-chlorosuccinimide are combined in dimethylformamide (5 mL). The mixture is stirred for 5 days and partitioned between water and ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated onto silica gel. The residue is purified by silica gel Flash Chromatography to give the title compound. The melting point is anticipated to be 152-155° C.
Reaction SMILES: C(O)(=O)C.C[O:6][C:7](=[O:34])[C@@H:8]([NH:15][C:16](=[O:33])[CH:17]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>Cl.O>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH:17]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[C:16]([NH:15][C@@H:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:7]([OH:34])=[O:6])=[O:33])=[CH:24][CH:23]=1)(=[NH:26])[NH2:27]
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N(C)C)C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN(C)C(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
[3-(4-Carbamimidoyl-phenyl)-2-(R,S)-dimethylcarbamoyl-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester acetic acid salt (7 g, 14.7 mmol) was dissolved in a mixture of hydrochloric acid (50 ml) and water (50 ml). After 15 hours stirring at room temperature the mixture was evaporated and after addition of water lyophilized. The residue was purified by chromatography on Sephadex LH20 employing n-butanol (17): glacial acetic acid (1): water (2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water and the aqueous solution was lyophilized. Yield: 4.5 g (76%); MS m/z: 403.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([F:31])=[C:4]([C:23]([F:30])=[C:24]([F:29])[C:25]=1[N+:26]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15]CC2C=CC=CC=2)[CH:7]=1.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:3]([F:31])=[C:4]([C:23]([F:30])=[C:24]([F:29])[C:25]=1[NH2:26])[O:5][C:6]1[CH:7]=[C:8]([OH:15])[C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)c(O)c([N+](=O)[O-])c(F)c2F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2c(F)c(O)c(N)c(F)c2F)cc1O
Reaction time: 72 h

Procedure:
43.6 g of 1-(3-hydroxy-4-nitro-2,5,6-trifluorophenoxy)-3-benzyloxy-4-nitrobenzene prepared as described in Example 13 (0.1 mol) are dissolved in 400 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 4.4 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow solution is evaporated to half in a rotary evaporator an left to stand at room temperature overnight, during which the reaction product precipitates in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at, 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]2[CH2:28][CH3:29])=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:28]([C:18]1[N:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][OH:8])=[CH:16][CH:15]=2)[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:19]=1)[CH3:29]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCO)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-4-phenyl-1H-imidazole (1.84 g, 4.6 mmol) in tetrahydrofuran (25 mL) was added tetrabutylammonium fluoride (1.84 g, 6.9 mmol) at 0° C. After 1 h, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 0:1) to afford 1.44 g (quant) of the title compound as colorless amorphous : MS (ESI) m/z 293 [M+H]+1H-NMR (CDCl3)δ1.26 (3H, t, J=7.5 Hz), 2.72 (2H, q, J=7.5 Hz), 2.95 (2H, t, J=6.6 Hz), 3.93 (2H, t, J=6.6 Hz), 7.22-7.28 (4H, m), 7.34-7.41 (4H, m), 7.79 (2H, d, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]=1Br)=[O:5])[CH3:2].C([Li])(C)(C)C.CN([CH:34]=[O:35])C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]=1[CH:34]=[O:35])=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (I-5d, 4.4 g, 0.01 mmol) in anhydrous THF (100 ml) and under a N2 atmosphere at −78° C. was slowly added tert.-butyl lithium (13 ml of 1.7 M solution in pentane, 0.22 mol). After 1 hour at −78° C., DMF (7.7 ml, 0.1 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2.5 hours, quenched with sat'd aq. NH4Cl (10 ml), allowed to slowly warm to room temperature, and finally poured into sat'd aq. NaCl. The aqueous solution was extracted with Et2O (3×) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified via flash chromatography using a solvent gradient of 1:3 EtOAc/hexanes to 1:1 EtOAc/hexanes to give the desired product I-5e as a pale yellow amorphous glass (2.0 g): +APCI MS (M+1) 389.2; 1H NMR (CD2Cl2) δ 1.41 (3H, t), 4.45 (2H, q), 7.09–7.14 (2H, m), 7.24–7.39 (7H, m), 10.50 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:10][C:11](=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([O:10][C:11](=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1
Reactant: CCN(CC)C(=O)Oc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.7 %

Procedure:
To a solution of diethyl-carbamic acid-3-nitro-phenyl ester (300 mg, 1.26 mmol) in ethyl acetate (5 ml) was added stannous chloride dihydrate (1.08 g, 4.8 mmol) and stirred for 6 hr at room temperature. The reaction mixture was diluted with ethyl acetate and washed with sodium hydroxide solution. The organic layer was separated, washed with brine, dried and concentrated under reduced pressure to give diethyl-carbamic acid 3-aminophenyl ester (120 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:41])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:40])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[C:30]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][C:32](=[O:33])[C:31]=1[CH3:39])\[CH3:27])\[CH3:22].Cl([O-])(=O)=[O:43].[Na+]>C(Cl)(Cl)Cl.O.II>[CH3:39][C:31]1[C:32](=[O:33])[CH2:34][CH2:35][C:36]([CH3:38])([CH3:37])[C:30]=1/[CH:29]=[CH:28]/[C:26](/[CH3:27])=[CH:25]/[CH:24]=[CH:23]/[C:21](/[CH3:22])=[CH:20]/[CH:19]=[CH:18]/[CH:17]=[C:16](\[CH3:40])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:41])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][C:7](=[O:43])[C:2]=1[CH3:1]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: II
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1=O
Temperature: -20 °C
Reaction time: 24 h
Yield: 65.3 %

Procedure:
100 mg of echinenone are dissolved in 10 ml of chloroform under a nitrogen atmosphere and are oxidized with 100 mg of sodium chlorate in 1 ml of water after having added 2 mg of iodine dissolved in 1 ml of chloroform. After stirring for 24 hours at -20° C., 67 mg of canthaxanthin having an all-trans content of 81% are obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][N:7]2[CH2:27][CH2:26][C@@:14]34[C:15]5[C:16]([OH:25])=[C:17]([C:22]([NH2:24])=[O:23])[CH:18]=[CH:19][C:20]=5[CH2:21][C@@H:8]2[C@:9]3([OH:29])[CH2:10][CH2:11][C:12](=O)[CH2:13]4)[CH2:5][CH2:4]1.Cl.[CH3:31]CCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH:3]1([CH2:6][N:7]2[CH2:27][CH2:26][C@@:14]34[C:15]5[C:16]([OH:25])=[C:17]([C:22]([NH2:24])=[O:23])[CH:18]=[CH:19][C:20]=5[CH2:21][C@@H:8]2[C@:9]3([OH:29])[CH2:10][CH2:11][C:12](=[CH2:31])[CH2:13]4)[CH2:5][CH2:4]1
Reactant: CCCCCC
Reactant: NC(=O)c1ccc2c(c1O)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCC(=O)C3
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CS(C)=O
Product: C=C1CC[C@@]2(O)[C@H]3Cc4ccc(C(N)=O)c(O)c4[C@@]2(CCN3CC2CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Sodium hydride (324 mg, 8.1 mmol, 60% dispersion in mineral oil) was washed under an argon atmosphere with hexane. DMSO (5 mL) was added and the mixture heated at 60° C. for 1 hour. Methyltriphenylphosphonium bromide (2.89 g, 8.1 mmol) was added and stirred at the same temperature for 1 hour. A solution of 17-(cyclopropylmethyl)-4,14-dihydroxy-6-oxomorphinan-3-carboxamide [P4] (0.6 g, 1.62 mmol) in DMSO (10 mL) was added and the mixture heated at 65° C. for 42 hours (A further 5 equivalents of Wittig reagent was added after 18 hours). The reaction was allowed to return to room temperature and partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was washed with brine and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave a residue that was stirred with hydrochloric acid (5%) for 30 minutes before washing with ethyl acetate. The aqueous phase was adjusted to pH8 by the addition of 2N sodium hydroxide solution and then extracted with DCM and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave a residue that was purified by prep-HPLC [Xbridge Prep C18 OBD, 30×150 mm, 5 μm; Mobile Phase A: 10 mM NH4HCO3 (pH10), Phase B: MeCN; Flow: 50 ml/min; Column Temperature: 30° C.; Runtime: 25 min.] giving 17-(cyclopropylmethyl)-4,14-dihydroxy-6-methylenemorphinan-3-carboxamide [11] (180 mg, 30% yield); LC/MS (r.t. 13.3 minutes [5 to 95% B]), 369 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>CC(C)=O>[NH:1]1[CH:5]=[C:4]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:3]=[N:2]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2c[nH]nn2)cc1
Reaction time: 7.5 h

Procedure:
8 g of 1,2,3-triazole, 10.67 g of potassium carbonate and 750 mg of potassium iodide are added in succession to a solution of 15.13 g of 4-bromomethylbenzonitrile in 375 ml of acetone. The reaction mixture is then stirred at 55° for 7.5 hours, and is then cooled and concentrated. The residue is dissolved in CH2Cl2 and washed in succession with water and brine. After drying over sodium sulfate, the solution is concentrated and the resulting crude product is purified by column chromatography (SiO2, toluene/ethyl acetate 3:19) to yield the precursor (1), IR (CH2Cl2): 2230, 1615, 1225, 1075 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1.[C:23](Cl)(=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>>[C:23]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1)(=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1

Procedure:
Preparation analogously to Example 37 from 9-amino-5-oxo-6-benzyl-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline and isovaleric acid chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1.[CH:26](=O)[CH3:27].Cl.[BH4-].[Na+]>CO.O>[ClH:22].[CH2:26]([NH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1)[CH3:27]
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Reactant: CC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.5 g of 1-(4-amino-2-chlorobenzoyl)-4-[2-(4-chlorophenyl)ethyl]-piperazine (see Example 7) are dissolved together with 0.26 g of acetaldehyde and 0.8 ml of 5N alcoholic hydrochloric acid in 15 ml of methanol. 0.41 g of 85% NaBH4 is added thereto and the reaction solution is stirred at room temperature for 24 hours. Water is added to the reaction solution, which is then decanted off and taken up in methylene chloride, dried and concentrated by evaporation. The oily material is chromatographed on silica gel and converted into the hydrochloride, yielding 1-[4-(N-ethylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine hydrochloride having a melting point of 230°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[N:9][CH:10]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N(C(C)C)CC)(C)C.ClC(OC(C)C)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cn3)cc2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cn3)cc2)CC1
Yield: 94.3 %

Procedure:
The title compound (53 mg, 91%) was prepared as an off-white solid from 1,1-dimethylethyl 4-[({4-[5-(methylsulfonyl)-2-pyridinyl]phenyl}oxy)methyl]-1-piperidinecarboxylate (Example 78, 60 mg, 0.13 mmol) and TFA (0.25 mL) in CH2Cl2 (4 mL) then diisopropylethylamine (1.5 ml) and isopropyl chloroformate (1.0M in toluene, 0.16 mL, 0.16 mmol) in a manner similar to Example 74. 1H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 8.21 (d, 1H, J=8.3 Hz), 8.04 (d, 2H, J=8.8 Hz), 7.84 (d, 1H, J=8.3 Hz), 7.00 (d, 2H, J=8.6 Hz), 4.92 (septet, 1H, J=6.3 Hz), 4.21 (bs, 2H), 3.88 (d, 2H, J=6.4 Hz), 3.13 (s, 3H), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 433 (M+H).