Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:41]2[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]=[CH2:36])=[CH:30][CH:29]=2)[C:24]([CH3:37])=[N:23][C:22]=1[CH2:38][CH2:39][CH3:40]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[NH:3][C:4](=[O:7])[O:5][N:48]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]=[CH2:36])=[CH:30][CH:29]=2)[C:24]([CH3:37])=[N:23][C:22]=1[CH2:38][CH2:39][CH3:40]
Reactant: C=COc1ccc(-n2c(C)nc(CCC)c(Cc3ccc(-c4ccccc4C#N)cc3F)c2=O)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=COc1ccc(-n2c(C)nc(CCC)c(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2=O)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.72 g), sodium hydrogen carbonate (1.02 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-({2-methyl-6-oxo-4-propyl-1-[4-(vinyloxy)phenyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.58 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution 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 a colorless amorphous solid (0.44 g, 67%).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[N:23][N:22]=[N:21]1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1-c1ccc([N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
N-Methyl-4-nitro-benzamide (2.25 g, 12.5 mmol, 1 eq.) and PCl5 (2.60 g, 12.5 mmol, 1 eq.) were melted together under house vacuum connected to a NaOH trap behind a safety shield. Melting occurred at 100° C. Heated at 130° C. for 1 hour then purified by kugelrohr distillation at 0.1 mmHg at 130° C. CAUTION: THE EXPLOSIVE PROPERTIES OF THIS COMPOUND ARE UNKNOWN). The iminoyl chloride (12.5 mmol 1 eq.) in DMF 10 ml was added to NaN3 in 10 ml of DMF at 25° C. and stirred overnight. Worked up by adding EtOAc then rinsing 3× with H2O. The organic layer was dried over MgSO4, then stripped to obtain yellow solids which were purified over silica gel in 3:1 hexanes/EtOAc to 100% EtOAc. Obtained 1.21 g of yellow solids as product. NMR (300 MHz, CDCl3) δ 8.46 (d, 2H, J=7 Hz), 8.02 (d, 2H, J=7 Hz), 4.27 (S, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[NH2:4].[Cl:17][C:18]1[C:19]([C:30](=[O:35])[NH:31][CH:32]2[CH2:34][CH2:33]2)=[CH:20][C:21]2[N:25]=[C:24]([C:26](O)=[O:27])[NH:23][C:22]=2[CH:29]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[C:19]([C:30]([NH:31][CH:32]2[CH2:34][CH2:33]2)=[O:35])=[CH:20][C:21]2[N:25]=[C:24]([C:26]([NH:4][CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=3)[C:2]([F:15])([F:16])[F:1])=[O:27])[NH:23][C:22]=2[CH:29]=1
Reactant: O=C(O)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2[nH]1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC(c1cccc(C(F)(F)F)c1)C(F)(F)F)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
2,2,2-Trifluoro-1-[3-(trifluoromethyl)phenyl]ethanamine (0.23 g, 0.82 mmol) was dissolved in N,N-dimethylformamide (4 ml), and 6-chloro-5-(cyclopropylcarbamoyl)-1H-benzimidazole-2-carboxylic acid (0.23 g, 0.82 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (0.31 g, 0.82 mmol) and 4-methylmorpholine (0.25 g, 2.47 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then ethyl acetate was added. The organic phase was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution and dried over sodium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (1/1) and gave 0.24 g (57% of theory) of 6-chloro-N5-cyclopropyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-benzimidazole-2,5-dicarboxamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([OH:23])[CH2:18]1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1>CCO.[Pd].O>[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([O:23][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:18]1
Reactant: CN1CCCC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCCC(Oc2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
KHMDS (1.1 equivalent) was added to a THF solution of 1-methylpiperidin-3-ol (1 equivalent) at 0° C. and stirred until H2 evolution ceased. 1-fluoro-4-nitrobenzene (1 equivalent) was then added and the solution was allowed to warm to room temperature. After 2 hours, water was added and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo to give a bright yellow oil which was directly used in the reduction step. The oil (1 equivalent) and a catalytic amount of 10% Pd/C were suspended in anhydrous EtOH at room temperature. The reaction flask was evacuated and subsequently filled with H2. After stirring for 18 hours, the mixture was filtered through Celite, and the solvent was concentrated in vacuo to yield 4-(1-methyl-3-piperidyloxy)phenylamine. LC/MS (m/z) 207.2 (MH+), Rt 0.47 minutes.
Reaction SMILES: C[C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=O)=[CH:19][CH:18]=1.[K+].[Br-]>CC(=O)OCC>[CH3:2][C:3]1[C:4](=[O:5])[C:6]2[C:11]([C:12](=[O:13])[C:24]=1[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]([F:28])([F:27])[F:14])=[CH:18][CH:19]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1=C(Cc2ccc(OC(F)(F)F)cc2)C(=O)c2ccccc2C1=O
Yield: 78 %

Procedure:
As starting materials for the coupling reaction menadione and 4-(trifluoromethoxy)phenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:1, UV), 494 mg (1.43 mmol, 78% yield) of P_TM97 were isolated as yellow solid. Melting point: 64-65° C. —1H-NMR (300 MHz, CDCl3): δ=8.03-8.10 (m, 2H), 7.65-7.71 (m, 2H), 7.34 (d, 3J=8.74 Hz, 2H), 7.09 (d, 3J=8.08 Hz, 2H), 4.01 (s, 2H), 2.23 (s, 3H). —13C-NMR (75 MHz, CDCl3): δ=185.17 (Cq), 184.52 (Cq), 147.42 (Cq), 144.72 (Cq), 144.57 (Cq), 136.76 (Cq), 133.57 (CH), 132.07 (Cq), 131.92 (Cq), 129.87 (CH), 126.47 (CH), 126.33 (CH), 121.15 (CH), 120.44 (q, 1JCF=256.91 Hz), 31.78 (CH2), 13.27 (CH3). —EI MS (70 eV, m/z (%)): 346.0 ([M]+, 32), 331.1 (100), 261.1 (8), 175.1 (71), 76.0 (10), 28.0 (49). —IR (KBr): 3077 cm−1 (w), 3047 (w), 3021 (w), 3003 (w), 2963 (w), 2948 (w), 2853 (w), 2143 (w), 2004 (w), 1975 (w), 1901 (w), 1876 (w), 1664 (vs), 1620 (m), 1596 (s), 1508 (s), 1446 (w), 1435 (w), 1378 (m), 1333 (s), 1297 (vs), 1271 (vs), 1217 (vs), 1188 (vs), 1166 (vs), 1111 (m), 1019 (w), 976 (m), 793 (w), 770 (w), 708 (s), 692 (w). —EA: obs. C, 65.78%; H, 3.98%, calcd. C, 65.90%; H, 3.78% for C19H13F3O3.
Reaction SMILES: CN(C)C=O.[CH3:6][C@@:7]1([CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[N:13]=[C:12]2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[CH2:9][O:8]1.[N:29]1([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>C(OCC)(=O)C>[N+:16]([C:14]1[N:13]=[C:12]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[N:11]([CH2:10][C@:7]([OH:8])([CH3:6])[CH2:9][N:32]2[CH2:31][CH2:30][N:29]([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[CH:43][CH:42]=3)=[O:36])[CH2:34][CH2:33]2)[CH:15]=1)([O-:18])=[O:17]
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Sc2ccccc2[N+](=O)[O-])CO1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1ccccc1[N+](=O)[O-]
Yield: 88.9 %

Procedure:
N,N-Dimethylformamide (0.25 ml) solution of (R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(2-nitrophenylthio)imidazole (50 mg) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazin-1-carboxylate (51 mg) was stirred at 60° C. for 1 day. Water and ethyl acetate were added to the reaction mixture, the organic layer was taken by separation. The ethyl acetate layer was washed with water, an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/methanol=30/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-{3-[4-nitro-2-(2-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (86 mg, yield: 87%) as yellow amorphous product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:16]>C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:16]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(N=O)c1
Reaction time: 72 h
Yield: 34 %

Procedure:
To a stirred solution of 3-aminobenzamide (Aldrich Chemical Co.) (0.476 g, 3.50 mmol) in ethyl acetate (50 ml) at ambient temperature was added 1.208 g of 3-chloroperoxybenzoic acid (commercial grade, 50-60% purity, Aldrich), whereupon the solution turned green. After 10 minutes the mixture was extracted with 0.14M aqueous sodium bicarbonate (58 ml), washed with three successive 40-ml portions of water, dried over sodium sulfate, then reduced in volume to 20 mL by rotary evaporation and placed in the freezer (-20° C.), whereupon the product slowly deposited as a light yellow solid daring a period of 72 hours (0.180 g, 34% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([B:29]([OH:31])[OH:30])=[CH:25][CH:24]=1)(O)=[O:21].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:23]3[CH:24]=[CH:25][C:26]([B:29]([OH:31])[OH:30])=[CH:27][CH:28]=3)=[O:21])[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccc(B(O)O)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
5-Chloro-2-(piperazin-1-ylsulphonyl)-1H-indole (5.42 g, 18.1 mmol) was added to a solution of 4-carboxyphenyl boronic acid (3.00 g, 18.1 mmol) N,N-diisopropylethylamine (2.34 g, 18.1 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (5.81 g, 18.1 mmol) in 80 mL N,N-dimethylformamide, the mixture was stirred for 2 hours at room temperature. N,N-Dimethylformamide was removed in vacuo and the crude was purified by flash chromatography three times (dichloromethane/methanol, 100-98/2) to give 4-({4-[(5-chloro-1H-indol-2-yl)sulphonyl]piperazin-1-yl}carbonyl)phenyl boronic acid as a colourless solid (56% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH2:22](O)[CH3:23]>>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:22][CH3:23])=[O:5]
Reactant: CCO
Reactant: Nc1ncccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cccnc1N
Temperature: 120 °C
Yield: 60 %

Procedure:
Absolute ethanol (10 mL) was added to 2-aminonicotinic acid (120, commercially available) (3.9 g, 28 mmol). To the resulting stirred mixture was added H2SO4 (96%, 5 mL). The mixture was heated and refluxed at 120° C. for ~4 h. The suspension was cooled to room temperature, poured over ice (30 g), and neutralized to pH 5 using solid Na2CO3. The aqueous suspension was extracted with EtOAc (3×25 mL). These combined organic extracts were washed with water (3×30 mL), dried (Na2SO4), and rota-evaporated to dryness, leaving the title compound as off-white crystals (2.8 g, 60%); mp 90.5°-92.5° C. (Lit., 94°-95° C., Hirai, E., Chem. Pharm. Bull. 14:861 (1966)). 1H NMR (CDCl3): δ1.38 (t, J=7.2, 3, CH3CH2), 4.34 (q, J=7.2, 2, CH3CH2O), 6.40 (bm, 2, NH2), 6.62 (dd, J1 =4.9, J2 =7.8, 1, H-4), 8.14 (dd, J1 =1.0, J2 =8.4, 1, H-5), 8.21 (dd, J1 =1.2, J2 =3.8, 1, H-6).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Reactant: CCCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.53 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.53 ml (5.0 mmol) of 1-pentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 3 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4). After the solvent was distilled off, the residue was recrystallized from ether to yield 1.11 g (59%, white crystal) of the desired product.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:46]([C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][C:52]=3[OH:58])=[N:47][NH:48][C:49]=2[CH3:50])=[CH:41][CH:40]=1>ClCCl>[Br:1][C:55]1[CH:56]=[C:51]([C:46]2[C:45]([C:42]3[CH:41]=[CH:40][C:39]([O:38][CH3:37])=[CH:44][CH:43]=3)=[C:49]([CH3:50])[NH:48][N:47]=2)[C:52]([OH:58])=[CH:53][C:54]=1[OH:57]
Reactant: COc1ccc(-c2c(-c3ccc(O)cc3O)n[nH]c2C)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3cc(Br)c(O)cc3O)n[nH]c2C)cc1
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
Benzyltrimethylammonium tribromide (4.0 g, 10.2 mmol) was added portion-wise to a suspension of 4-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol (2.95 g, 10 mmol) in dichloromethane (50 ml) and the mixture stirred for ˜90 mins. The mixture washed with water (3×50 ml) and saturated aqueous sodium chloride solution (25 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale yellow solid. Crude product was purified by column chromatography, on silica, eluting with ethyl acetate/hexane (1:2) to give 4-bromo-6-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol (1.75 g)
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][CH2:9][CH:10]([CH3:36])[CH2:11][O:12][C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)(C)(C)C.Cl>O1CCOCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:12][CH2:11][CH:10]([CH3:36])[CH2:9][O:8][CH2:7][C:6]([OH:37])=[O:5])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)COCC(=O)OC(C)(C)C)c23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)COCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dissolve 45 mg (0.09 mmol) (3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-2-methylpropoxy)acetic acid tert.-butyl ester (Enantiomer 2) in 0.5 ml dioxan, add 0.2 ml 4 N hydrogen chloride in dioxan and stir for 48 h at RT. Then add a further 0.4 ml 4 N hydrogen chloride in dioxan to the reaction mixture and stir again for 16 h at RT. After concentrating the reaction solution by evaporation under vacuum, purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 21 mg (53% of theor.) of the desired product is obtained as Enantiomer 2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:51][C:52](OC(C)=O)=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:52](=[O:53])[CH3:51])[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution containing 35 (228 mg, 0.4 mmol), DIPEA (104 mg, 0.8 mmol) and DMAP (cat) in DCM (5 mL) was cooled to 0° C., followed by the addition of Ac2O (50 mg, 0.48 mmol). After 1 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with saturated aqueous NaHCO3, 1N HCl, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford crude 38 which was used without further purification. Mass spectrum, m/z [615.1] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH3:26][N:27]1[CH:34]=[N:33][C:29]([CH2:30][CH2:31][NH2:32])=[CH:28]1.C(N(CC)C(C)C)(C)C.[I-].[K+]>C(O)CCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:32][CH2:31][CH2:30][C:29]2[N:33]=[CH:34][N:27]([CH3:26])[CH:28]=2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: Cn1cnc(CCN)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cnc(CCNCCNc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)c1
Yield: 16.2 %

Procedure:
Prepared as in Example 32 using 2-chloro-5-[(2-chloroethyl)amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 29c, 0.200 g), 1-methylhistamine (0.400 g), N,N-diisopropylethylamine (1 ml), potassium iodide (0.080 g) and n-butanol (4 ml) to give the title compound as a gum (0.040 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:12]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:12]
Reactant: II
Reactant: COC(=O)c1ccc(N)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-aminobenzoate (30.23 g, 200 mmol) was added to a mixture of iodine (60.91 g, 240 mmol) and silver sulfate (81.07 g, 260 mmol) in 1 L of ethanol at room temperature. The mixture was stirred at room temperature for 18 hours, filtered over Celite and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (230-400 mesh) and eluted with 1% ethyl acetate in hexane to give 35 g (63%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11](=[O:18])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])N.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:14]([O:13][C:11](=[O:18])[NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:6][CH:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
As shown in scheme 5, tyramine is protected as the t-butyl carbamate 22 and then reacted with 4-fluoronitrobenzene with cesium carbonate in DMF to yield the corresponding biarylether, {2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (19). Compound 19 is reduced by catalytic hydrogenation with palladium on carbon at the nitro group to afford the amine 23. Compound 23 is then N-acylated with acetyl chloride to afford the N-acyl compound 25. The t-Boc protecting group is removed from compound 25 using TFA in dichloromethane and the resulting amine 26 is reacted with various aldehydes under reductive amination conditions to afford compound 27.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][NH:24][CH2:23][CH2:22]2)=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([CH2:2][CH:3]1[O:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4]1)[CH2:23][CH2:22]2)=[O:16]
Reactant: BrCC1COc2ccccc2O1
Reactant: COC(=O)c1cccc2c1CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2c1CN(CC1COc3ccccc3O1)CC2
Temperature: 140 °C

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (0.2 g, 0.88 mmol) and 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (0.14 g, 0.88 mmol) in DMF (10 ml) was added K2CO3 (0.61 g, 4.41 mmol). The reaction mixture was heated under microwaves at 140° C. for 10 min. Water was then added and the mixture extracted with DCM (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 95:5).