Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@@H:8]([CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36])[S:32][CH:33]=1)[C:9](N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)=[O:10])(C)(C)C.[OH2:44].OO.O.[OH-].[Li+]>C1COCC1>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35]([NH:34][C:31]1[S:32][CH:33]=[C:29]([CH2:28][C@H:8]([CH2:7][C:6]([OH:5])=[O:43])[C:9]([OH:10])=[O:44])[N:30]=1)=[O:36]
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1)C(=O)O
Reaction time: 0.08 h

Procedure:
The protected amido acid, 4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5 -methylhexyl]amino}-4-oxo-3-(R)-{{2-[(2,2,2-trichloroethoxy) carbonylamino]-4-thiazolyl}methyl}butanoic acid tert-butyl ester: A solution of the product of section (f) of this example (57.5 mg, 0.10 mmol) in THF (1.5 mL) and H2O (0.5 mL) was cooled to 0°. A 30% aqueous solution of H2O2 (91.3 μL, 0.80 mmol of H2 O2) and lithium hydroxide monohydrate (8.5 mg, 0.20 mmol) were added serially to the cooled solution. The mixture was stirred at 0° for 5 min and then at room temperature for 2.5 h. Excess H2O2 was quenched by the addition of a 1.5M aqueous solution of Na2SO3 (as judged by a KI stick indicator). The resulting mixture was diluted with H2O and washed with CH2Cl2 (3X). The aqueous layer was rendered acidic with 1N aqueous HCl and extracted with EtOAc (3X). The combined EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to dryness to yield the desired monoprotected dicarboxylic acid, i.e. the 4-tert-butyl ester of 2(R)-{{2-[(2,2,2-trichloroethoxy) carbonylamino]-4-thiazolyl}-methyl}-butanedioic acid. The monoprotected dicarboxylic acid was used for the following coupling step without purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OC(C)(C)C)(=O)C>[C:4]([O:11][C:10](=[O:12])[C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])([CH3:9])([CH3:5])[CH3:3]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of D-phenylalanine (1.651 g, 10.0 mmol) in tert-butyl acetate (20 mL) at 0° C., was slowly added HClO4 (0.85 mL, 15 mmol). The reaction mixture was stirred at room temperature for 12 h then washed with H2O (25 mL) and 1.0 M HCl solution (15 mL). The resultant aqueous solution was adjusted to pH 9 by addition of 10% K2CO3 solution, and then extracted with dichloromethane (3×10 mL). The combined organic phases were dried with anhydrous Na2SO4, filtered and concentrated to give an oil. This was purified by flash chromatography on silica gel, using a grading of ethyl acetate/hexane ((1:5) to (2:5)), to give A1 as a colorless oil; (2.020 g, 89.3%). Spectral data were in accordance with those published. [α]D25: −39.5 (c=0.33, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.35-7.29 (m, 2H), 7.27-7.22 (m, 3H), 3.63 (dd, J=6.0, 9.0 Hz, 1H), 3.09-3.02 (m, 1H), 2.89-2.82 (m, 2H), 1.47 (s, 2H), 1.44 (s, 9H); 13C NMR (300 MHz, CDCl3): δ 174.34, 137.57, 129.39, 128.41, 126.65, 81.12, 56.33, 41.29, 28.00; LRMS (ESI): calcd for: C13H19NO2 [M+H]+=222.1, obsd [M+H]+=222.1, [M+Na]+=244.1, obsd [M+Na]+=244.1.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH3:8])[CH:2]=1.[Br:11]Br.CCOCC>O1CCOCC1>[Br:11][CH2:8][C:7]([C:3]1[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: CC(=O)c1cccc(C)c1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-m-tolyl-ethanone (6.0 g, 44.72 mmol) in dioxane (5 ml), bromine (7.14 g, 44.72 mmol) in dioxane (10 ml) and ether (15 ml) was added and stirred at room temperature for 5 hr. The reaction mixture was poured into ice water and the compound was extracted using ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and then evaporated to give crude 2-bromo-1-m-tolyl-ethanone, 7.6 g (80%). The crude compound obtained was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(4-chlorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a light yellow powder (46.5% yield). 1H NMR (500 MHz, CDCl3) δ 8.10, 7.95, 7.75, 7.65, 7.58, 7.35, 7.25, 7.15, 7.00, 4.10, 3.95-3.66, 3.38, 2.90.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:20]=[N:19][N:18]=2)[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[N:30]=[C:31]2[N:38]([CH2:39][CH2:40][CH:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[C:37]([CH3:48])([CH3:47])[C:36](=[O:49])[NH:35][C:32]2=[N:33][CH:34]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:47][C:37]1([CH3:48])[C:36](=[O:49])[NH:35][C:32]2=[N:33][CH:34]=[C:29]([C:7]3[CH:6]=[CH:5][C:4]([C:17]4[N:21]([CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)[CH:20]=[N:19][N:18]=4)=[CH:3][C:2]=3[CH3:1])[N:30]=[C:31]2[N:38]1[CH2:39][CH2:40][CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: CC1(C)C(=O)Nc2ncc(Br)nc2N1CCC1CCOCC1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)N(CCC1CCOCC1)C(C)(C)C(=O)N2
Temperature: 100 °C
Yield: 97 %

Procedure:
3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (1 equiv), 6-bromo-3,3-dimethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.1 equiv), 1 M sodium carbonate in water (3 equiv), 1,4-dioxane and isopropanol were combined and the system was purged with nitrogen. The resulting mixture was stirred vigorously and heated at 100° C. for 1.5 h. The resulting mixture was cooled to room temperature, diluted with methanol and the volatiles removed under reduced pressure. The residue was partitioned between dichloromethane and water, shaken and the layers separated. The water layer was extracted with dichloromethane. The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (20-100% ethyl acetate in hexane followed by 0-10% methanol in dichloromethane) to give the desired product in 97% yield. MS (ESI) m/z 532.7 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:15][CH2:16][CH3:17])=[C:6]([C:10]([CH3:14])=[C:11]([Cl:13])[CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:25]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:29]2C=CC=C[C:28]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)C.C1COCC1>CN(C)C=O.O>[C:1]([C:4]1[C:5]([O:15][CH2:16][CH3:17])=[C:6]([C:10]([CH3:14])=[C:11]([Cl:13])[CH:12]=1)[C:7]([NH:25][CH2:29][CH3:28])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)=O)c1OCC
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
To a solution of 3-acetyl-5-chloro-2-ethoxy-6-methylbenzoic acid (0.26 g, 1.0 mmol) in N,N-dimethylformamide (5 mL)was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.67 g, 1.5 mmol). After stirring for 10 min, N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) and 2.0 M ethylamine in THF (2.5 mL, 5.1 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction solution was diluted with water, and extracted with dichloromethane. The combined organic layers were concentrated and purified on silica gel column (eluting with 0% to 50% EtOAc in hexanes) to give the desired product (0.2 g, 70%). LCMS calculated for C14H19ClNO3 (M+H)+: m/z=284.1; Found: 284.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH3:20])[N:3]=1.[Cl:21][C:22]1[C:23]([N:30]2[CH2:35][CH2:34][NH:33][C@H:32]([CH3:36])[CH2:31]2)=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:21][C:22]1[C:23]([N:30]2[CH2:35][CH2:34][N:33]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[N:5]=[C:4]([N:15]4[CH2:19][CH2:18][CH2:17][CH:16]4[CH3:20])[N:3]=3)[CH:32]([CH3:36])[CH2:31]2)=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: COc1ccc(Cl)c(N2CCN[C@H](C)C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)C(C)C2)n1

Procedure:
Heat a mixture of 4-chloro-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (440 mg, 1.51 mmol), 1-(3-chloro-6-methoxy-pyridin-2-yl)-3-(R)-methyl-piperazine (400 mg, 1.66 mmol), and K2CO3 (230 mg, 1.66 mmol) in DMA at 120° C. for 16 hours. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 10% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound. 1H NMR (300 MHz, CDCl3): δ1.36 (m, 6H, 2×CH3); 1.70 (m, 1H, CH2CH2); 1.93 (m, 1H, CH2CH2); 2.06 (m, 2H, CH2CH2); 3.05 (m, 2H); 3.38 (m, 1H); 3.70 (m, 2H); 3.88 (s, 3H, OCH3); 3.90 (m, 2H); 4.35 (m, 2H); 4.70 (m, 1H); 6.232 (s, 1H); 6.30 (d, 1H, J=8.4 Hz); 7.12 (m, 2H); 7.46 (d, J=9.0 Hz, 1H); 8.00 (m, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]>>[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([Cl:3])=[O:17])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCC(CC(=O)O)CC1
Product: CC(=O)N1CCC(CC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To 240 parts of thionyl chloride are added portionwise 25 parts of 1-acetyl-4-piperidineacetic acid and the whole is stirred overnight at room temperature. The reaction mixture is evaporated, yielding 26.5 parts (95%) of 1-acetyl-4-piperidineacetyl chloride as an oily residue.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][C:12]2[CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH2:2])[CH:5]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate hydrochloride (1.23 g, 2.95 mmol) was added LiAlH4 (5.90 mL, 1N in THF, 5.90 mmol) and the reaction was stirred at room temperature until the was complete per monitoring with LC-MS. The reaction mixture was diluted with Et2O (50 mL) and quenched with Na2CO3 (saturated aqueous), filtered, concentrated and purified with Combiflash chromatograph to afford 0.59 g (68%) of the title compound. LC-MS m/z 295 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]([O:25]CC)=[O:24]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: O=S(=O)(O)O
Product: Nc1c(C(=O)O)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 85.8 %

Procedure:
3.05 G (0.007 mol) of 5-amino-4-ethoxycarbonyl-3-trifluoromethyl-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole in 14 ml of concentrated sulphuric acid are heated at 75° C. for 5 hours. After the mixture has been cooled to room temperature, it is diluted with ice-water and filtered with suction. 2.45 g (86% of theory) of 5-amino-4-hydroxycarbonyl-3-trifluoromethyl-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole of melting point 191° C.-195° C. (decomposition) are obtained.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[CH2:32][CH2:31][C:7]2[N:8]([CH2:16][CH:17]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C:19]([O:21]CC)=O)[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1>O>[CH3:3][N:4]1[CH2:32][CH2:31][C:7]2[N:8]([CH2:16][CH:17]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C:19]([NH:2][CH3:1])=[O:21])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: CN
Reactant: CCOC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Solvent: O
Product: CNC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
Methylamine (1 mL) was added to ethyl 4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate (50 mg, 0.122 mmol) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to RT, diluted with water (5 mL) and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel chromatography (100-200 mesh) eluting with 0-7% MeOH-DCM as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[O:15]1[CH2:14][CH:13]1[CH2:11][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: ClCC1CO1
Reactant: Oc1ccc2[nH]ccc2c1
Product: c1cc2cc(OCC3CO3)ccc2[nH]1

Procedure:
The title compound was prepared from 5-hydroxyindole and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:13])(O)[CH3:11])=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])OCC[O:17]1.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O.C(O)CCC>[Br:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:13][CH:10]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:11][O:17]1
Reactant: Cc1ccc(CCC(C)(O)O)cc1
Reactant: Clc1ccc(C2(CBr)OCCO2)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(CCC2COC(CBr)(c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
A mixture of 14.4 parts of 1-[2-(4-methylphenyl)ethyl]-ethanediol, 15.6 parts of 2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane, 5-parts of 4-methylbenzenesulfonic acid, 225 parts of methylbenzene and 40 parts of butanol is stirred and refluxed for 3 days with water-separator. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane. The solution is stirred for 30 minutes with silica gel. The latter is filtered off and the filtrate is evaporated, yielding 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-[2-(4-methylphenyl)ethyl]-1,3-dioxolane as a residue.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:5]([N+:23]([O-])=O)=[C:4]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:3]=1>C(O)C.[Pt]>[NH2:23][C:5]1[C:4]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Agent: [Pt]
Solvent: CCO
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCNC(=O)OC(C)(C)C)c1C
Yield: 78.4 %

Procedure:
A solution of of tert-butyl 2-{2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]ethoxy}ethylcarbamate (15.34 g, 34.35 mmol) in absolute ethanol (500 mL) was combined with 5% platinum on carbon (12.02 g) in a Parr vessel and placed under hydrogen pressure overnight. The reaction mixture was filtered through a layer of Celite® filter aid. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (250 g of silica gel eluting with 1/1 ethyl acetate/hexanes) to provide 11.21 g of tert-butyl 2-{2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethoxy}ethylcarbamate.
Reaction SMILES: [NH2:1][C:2](=[S:14])[C:3]1[CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[S:6][C:7]=1[O:8][CH3:9].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>>[CH3:9][O:8][C:7]1[S:6][C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[C:2]1[S:14][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:1]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1cc(C(N)=S)c(OC)s1
Product: COC(=O)c1cc(-c2nc(-c3ccccc3)cs2)c(OC)s1
Yield: 9.8 %

Procedure:
A solution of 400 mg (1.73 mmol) of methyl 4-(aminothioxomethyl)-5-methoxythiophene-2-carboxylate was reacted with 345 mg (1.73 mmol) of 2-bromoacetophenone (Aldrich, Milwaukee, Wis., USA) in a manner similar to Example 8, step (a) to give methyl 5-methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (56 mg, 10%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.22 (s, 1H), 8.14 (s, 1H), 8.05 (m, 2H), 7.47 (m, 2H), 7.36 (m, 1H), 4.26 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1([CH2:6]O)[CH2:5][CH2:4]1.CCN(CC)CC.CS(Cl)(=O)=O.[Br-:22].[Na+]>CN(C=O)C.O.CCCCC>[Br:22][CH2:6][C:3]1([C:2]([F:9])([F:8])[F:1])[CH2:5][CH2:4]1
Reactant: OCC1(C(F)(F)F)CC1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)C1(CBr)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a solution of (1-trifluoromethyl-cyclopropyl)-methanol (1.2 g, 8.57 mmol) and Et3N (1.04 g, 10.28 mmol) in dry DMF (10 mL) at −10° C. was added methanesulfonyl chloride (981 mg, 8.57 mmol) over 20 minutes, while retaining the inner temperature at 0° C. After the addition was complete, the resulting solution was stirred at 0° C. for 30 minutes, the resulting mixture was filtered and washed with DMF (3 mL). To the combined filtrates was added sodium bromide (3.7 g, 36 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was cooled in ice, followed by addition of pentane (20 mL) and water (15 mL) while retaining the mixture at 0° C., prior to liquid separation. The organic phase was dried over Na2SO4 and filtered. The filtrate was distilled to remove the most of pentane to give 1-bromomethyl-1-trifluoromethyl-cyclopropane (0.9 g crude), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]2(O)[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)[CH:3]=1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:15]2[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:17][CH:16]=2)[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(C/C=C/c2ccc(Cl)cc2)CC1
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Cl)cc1C1=CCN(C/C=C/c2ccc(Cl)cc2)CC1

Procedure:
A suspension of N-(4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-4-hydroxy-piperidin-4-yl}-phenyl)-2,2-dimethyl-propionamide (1.00 g) in 3NH2SO4 (7.5 ml) and DMSO (3 ml) was heated to reflux temperature for 48 hours. Then, water was added and the mixture extracted three times with CH2Cl2, the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (CH2Cl2:MeOH 95:5) to afford 4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-phenylamine (0.205 g; viscous oil; Retention Time HPLC 2.15 min; MS (ES+) 359 (M+H+) and 4-(2-amino-5-chloro-phenyl)-1-[(E)-3-(4-chloro-phenyl)-allyl]-piperidin-4-ol (0.182 g; M.p. 168-170° C.; Retention Time HPLC 1.95 min; MS (ES+) 377 (M+H+).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=CC(S(OCC(C)CC)(=O)=O)=[CH:3][CH:2]=1.[C:17]1([CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1)[OH:18].[OH-].[Na+]>O.C(O)CCC>[CH3:6][CH:1]([CH2:2][CH3:3])[CH2:16][O:18][C:17]1[CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCC(C)COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCC(C)COc1ccc(O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a n-butanol suspension containing 37 mmol (9.0 g) of 2-methylbutyl p-toluenesulfonate prepared by tosylating S-(-)-2-methylbutanol and 74 mmol (8.2 g) of hydroquinone, added dropwise was a solution of 50 mmol (2.1 g) of sodium hydroxide dissolved in a solvent mixture comprising 3 ml of water and 10 ml of n-butanol, and the obtained mixture was then stirred for 8 hours at 120° C. After addition of water, the reaction solution was extracted with ether, and the extracted solution was dried and concentrated. The resulting concentrate was purified by column chromatography to obtain 4.8 g of the objective ether compound (Yield: 72%).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]3[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=3)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:56]([OH:68])(=O)/[CH:57]=[CH:58]/[C:59]1[CH:66]=[CH:65][C:63]([OH:64])=[C:61]([OH:62])[CH:60]=1>>[C:56]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]1[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=1)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:68])/[CH:57]=[CH:58]/[C:59]1[CH:66]=[CH:65][C:63]([OH:64])=[C:61]([OH:62])[CH:60]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
N-[Nα-(9-fluorenylmethoxycarbonyl)-Nγ-trityl-L-asparagyl]dopamine (1.0 g, 1.5 mmol) was deprotected according to the indications of general procedure G. The intermediate was coupled with caffeic acid (348 mg, 2.2 mmol) following general procedure D. The crude material was purified by flash chromatography using a solvent gradient from 30% to 70% EtOAc/CHCl3 containing 1% AcOH. The final product was obtained as yellow powder (400 mg, 44%).