Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](=[O:51])[NH:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:50])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]4[CH2:45][CH2:44][N:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:42][CH2:41]4)=[CH:35][CH:34]=3)=[CH:27][CH:26]=2)[C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1)=[O:7])(C)(C)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:49][S:46]([N:43]1[CH2:44][CH2:45][N:40]([CH2:39][C:36]2[CH:37]=[CH:38][C:33]([NH:32][C:31]([C:28]3[CH:27]=[CH:26][C:25]([C:16]4[C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=[C:14]([NH:13][C:12]([C@@H:9]5[CH2:10][CH2:11][N:8]5[C:6]([OH:7])=[O:5])=[O:51])[CH:15]=4)=[CH:30][CH:29]=3)=[O:50])=[CH:34][CH:35]=2)[CH2:41][CH2:42]1)(=[O:48])=[O:47]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)[C@@H]5CCN5C(=O)O)ccc4OC(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-{4′-[4-(4-Methanesulfonyl-piperazin-1-ylmethyl)-phenylcarbamoyl]-6-trifluoromethoxy-biphenyl-3-ylcarbamoyl}-azetidine-1-carboxylic acid tert-butyl ester in dioxan (5 ml) was treated with conc. hydrochloric acid (3 ml) and the mixture stirred at room temp for 18 h. The mixture was then carefully basified with solid potassium carbonate and the mixture then was extracted with DCM. The residue was then purified on silica gel. Elution initially with DCM:EtOH:ammonia; 200:8:1 gave a colourless foam (impure). Further purification eluting with DCM:MeOH:AcOH:water; 90:10:1:1 gave a colourless gum (nmr suggests probably acetate salt of desired product). This material was then dissolved in DCM:EtOH:ammonia;25:8:1 and then passed down an SCX cartridge giving the title compound as a colourless solid (14 mg). This material is still not entirely pure as shown by 1H NMR. No further purification of this material was carried out.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as a white solid (276 mg, 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH2:28][CH2:29][C:30](O)=[O:31])[CH:3]=1.[NH2:33][C:34]1[C:39]([NH2:40])=[CH:38][C:37]([I:41])=[CH:36][N:35]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[NH2:33][C:34]1[C:39]([NH:40][C:30](=[O:31])[CH2:29][CH2:28][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:5]=2)=[CH:38][C:37]([I:41])=[CH:36][N:35]=1
Reactant: Cc1cc(CCC(=O)O)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: Nc1cc(I)cnc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: Cc1cc(CCC(=O)Nc2cc(I)cnc2N)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Yield: 54.9 %

Procedure:
1.30 g of 3-[4-methyl-6-(trityl-amino)pyridin-2-yl]-propionic acid and 724 mg of 2,3-diamino-5-iodo-pyridine are dissolved in 37 ml of pyridine and sequentially treated with 1.06 g of O-[(ethoxycarbonyl)canomethylene-amino]-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate and 579 μl of diisopropylethyl amine. The reaction mixture is warmed to 50° C. for 24 h. Thereafter the solvents are evaporated in vacuo. The remaining residue is coevaporated twice with toluene yielding 3.55 g of crude product. Purification by chromatography on LiChroprep® NH2 (25-40 μm, Merck, Darmstadt) (75 g, eluent: toluene/ethyl acetate 1:1) affords 1.08 g of the title compound as an amorphous solid. ESI-MS: 640.0 (MH+). TLC: Rf=0.16 (toluene/ethyl acetate 1:1, LiChroprep® NH2 HPTLC).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc(-c2cccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(-c3ccccc3)s2)CC1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
To a solution of 2-phenylthiophene (1.35 g, 9.1 mmol) in tetrahydrofuran (40 ml) at -40° C. under a nitrogen atmosphere was added a solution of n-butyllithium (1.6M in hexanes, 6 ml, 95 mmol) keeping the temperature below -40° C. The reaction was stirred at -40° C. for 10 minutes, allowed to warm to 0° C. and stirred at 0° C. for 30 minutes. The reaction was cooled to -78° C. and a solution of 1-tert-butoxycarbonyl-4-piperidone (1.8 g, 9.1 mmol) in tetrahydrofuran (20 ml) added, keeping the temperature below -50° C. When addition was complete, the reaction was stirred at -60° C. for 30 minutes and at room temperature for 1 hour. The reaction was cooled to 0° C. and quenched by addition of saturated aqueous ammonium chloride (10 ml), poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo to an oil. Purification by chromatography on silica eluting with ethyl acetate/hexane (1:2) gave the title compound as a foam, (2.5 g, 76%). δH (CDCl3) 1.41 (9H, s, OC(CH3)3), 1.84-1.97 (2H, m, piperidinyl H), 2.36 (1H, t, J 9.0 Hz, piperidinyl H), 3.20-3.28 (2H, m, piperidinyl H), 3.64 (1H, t, J 8.9 Hz, piperidinyl H), 3.82 (2H, m, piperidinyl H), 6.86-6.91 (1H, m, ArH), 7.09 (1H, m, ArH), 7.09 (1H, d, J 5.3 Hz, ArH), 7.16-7.33 (3H, m, ArH), 7.46-7.51 (2H, m, ArH).
Reaction SMILES: OC(CC(=N)O)C(=N)O.[CH2:10]([O:12][C:13]([NH:15][C@@H:16]([C:24]([OH:26])=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH3:11].[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30].C(N(CC)CC)C>N1C=CC=CC=1>[CH2:10]([O:12][C:13]([NH:15][C@@H:16]([C:24]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH3:11]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCOC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: N=C(O)CC(O)C(=N)O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.34 g (10 mmol) of ethoxycarbonyl-3-phenyl-D-alanine hydroxysuccinimidate (Synthesis 1, Step B) is dissolved in 15 ml of pyridine and 1.15 g (10 mmol) of L-proline and 1.4 ml (10 mmol) of triethylamine are added. The reaction mixture is stirred at room temperature for 10 hours, then evaporated at a pressure of 2.0-2.5 kPa. The residue is distributed between 30 ml 5% NaHCO3 solution and 10 ml of diethyl ether. The aqueous phase is washed with 3×5 ml of diethyl ether, the pooled organic washings are extracted with 5 ml 5% NaHCO3-solution. The bicarbonate phases are pooled, acidified with 1M KHSO4 solution to pH3 and extracted with 3×10 ml of ethyl acetate. The pooled organic extracts are dried over anhydrous sodium sulphate and evaporated at a pressure of 2.0-2.5 kPa. The oily residue is crystallised with diethyl ether, the crystals are filtered, washed with diethyl ether and dried in a vacuum desiccator.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12]O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:38]I>C1(C)C=CC=CC=1>[I:38][CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: OCCC1CCC2(CC1)OCCO2
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: ICCC1CCC2(CC1)OCCO2
Temperature: 3 °C
Yield: 93.9 %

Procedure:
Fourth Step: 150.0 g of the compound (13), 274.3 g of triphenylphosphine (Ph3P), 71.3 g of imidazole and 900 mL of toluene were added to a reactor under nitrogen atmosphere, and stirred at 3° C. 255.5 g of iodine was added thereto by dividing into 10 portions at a temperature range of from 3 to 10° C., followed by further stirring at 0° C. for 3 hours. After confirming that the reaction had been completed by GC analysis, a yellow solid thus deposited was filtered off. The filtrate was concentrated, and 400 mL of heptane was added to the resulting residue, followed by filtering off a pale yellow solid thus deposited. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography using toluene as eluent, and the solvent was removed by distillation under reduced pressure to obtain 223.9 g of 8-(2-iodoethyl)-1,4-dioxaspiro[4,5]decane (14) as a colorless transparent liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].C(N(CC)CC)C>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)OCC(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 110.5 g of o-nitrobenzenesulfonyl chloride and 50.0 g of 2,2,2-trifluoroethanol in 600 ml of diethyl ether was added 52.0 g of triethylamine at 5°-15° over a 45 minute period. The reaction mixture was stirred at 25° for 1 hour then washed with water, dried over MgSO4, and stripped in vacuo to give 2,2,2-trifluoroethyl 2-nitrobenzenesulfonate as an oil weighing 110.3 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH3:28])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.[H][H]>CO.[Pt]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: CC#Cc1ccc(NC(=O)c2cccnc2NCc2ccc(OC)nc2)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CCCc1ccc(NC(=O)c2cccnc2NCc2ccc(OC)nc2)cc1C(F)(F)F

Procedure:
A solution of 2-[(6-methoxypyrid-3-yl)methylamino]-N-[4-propynyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (Example 30; 1.87 g, 4.25 mmol) in methanol (100 mL) is hydrogenated at atmospheric pressure over 5% platinum on carbon (0.4 g) at 22° C. The calculated amount of hydrogen is taken up in 13 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from dichloromethane—hexane to give the title compound as a colourless crystalline solid, m.p. 51-61° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])#[C:28][CH2:29][CH2:30][CH3:31].C(NCC)C>[Cu]I.CN(C)C=O>[F:18][C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH:8]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:4]3[CH:3]=[C:2]([C:31]#[C:30][CH2:29][CH2:28][CH2:27][N:32]4[C:33](=[O:42])[C:34]5[C:35](=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:36]4=[O:37])[CH:7]=[CH:6][CH:5]=3)=[N:10][C:11]=2[CH:17]=1
Reactant: CCCC#CN1C(=O)c2ccccc2C1=O
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3cc(F)ccc3[nH]2)CC1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CN1CCC(OC(c2cccc(C#CCCCN3C(=O)c4ccccc4C3=O)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A screw-capped tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole (example 437D, 418 mg), PEPPSi-sono catalyst (19 mg), copper (I) iodide (38 mg), N-pentynylphthalimide (428 mg), diethylamine (880 μL) and N,N-dimethylformamide (1.5 mL). The tube is evacuated, filled with argon and sealed. The reaction mixture is stirred at 80° C. overnight. As the reaction is not completed, PEPPSi-sono catalyst (10 mg) and N-pentynylphthalimide (214 mg) are added, and the reaction mixture is heated at 80° C. for 24 h. The mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol from 98/2/to 90/10) to give 2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione. 1H NMR: 9.65 (sl, 1H), 7.84-7.65 (m, 4H), 7.54 (s, 1H), 7.48-6.95 (m, 4H), 5.84 (s, 1H), 3.90 (t, 2H, J=6.9 Hz), 3.65-3.50 (m, 1H), 2.85-2.70 (m, 2H), 2.52 (t, 2H, J=7.0 Hz), 2.32 (s, 3H), 2.28-1.50 (m, 8H).
Reaction SMILES: [CH2:1]([F:12])[O:2][CH:3]([C:8](F)([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].C(OCOCC)C>>[F:5][C:4]([F:6])([F:7])[C:3]([O:2][CH2:1][F:12])=[C:8]([F:9])[F:10]
Reactant: FCOC(C(F)(F)F)C(F)(F)F
Solvent: CCOCOCC
Product: FCOC(=C(F)F)C(F)(F)F

Procedure:
30 grams of sevoflurane (0.15 mols) was cooled to about −36.2° C. under nitrogen. Approximately 10 mL of a 3.0 M solution of CH3Li/CH2(OC2H5)2 (0.03 mols of the base) was added over 29 minutes while maintaining a temperature between about −37.5° C. and about −30.5° C. After addition of the methyl lithium was complete, the addition funnel was washed with a few mL of diethoxymethane. The reaction mixture was then stirred for approximately 20 minutes at a temperature between about −39° C. and about −35° C. A vacuum (0.3 mmHg) applied to the reaction mixture for approximately 1 hour, 46 minutes while the reaction mixture was held at a temperature between about −38.5° C. and about 10.7° C. afforded approximately 30.0 grams of a crude liquid product. GC analysis of this liquid showed it contained 22.8% compound A, 47.1% unreacted sevoflurane, and 29.7% diethoxymethane.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC([N:7]2[C:20]3[C:15](=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=3)=CC=1.[C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:39]=[CH:38][C:37]([N:40](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:17]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:19][C:20]([N:40]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][C:50]4[N:7]([C:8]5[CH:9]=[CH:10][C:11]([C:8]6[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=6)=[CH:12][CH:13]=5)[C:20]5[C:15](=[CH:16][C:17]([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=6)=[CH:18][CH:19]=5)[CH2:14][C:49]=4[CH:48]=3)=[CH:43][CH:42]=2)[C:37]2[CH:36]=[CH:35][C:34]([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)=[CH:39][CH:38]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccc2c(c1)Cc1cc(-c3ccccc3)ccc1N2c1ccc(-c2ccccc2)cc1
Reactant: CC1(C)OB(c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccc5c(c4)Cc4cc(-c6ccccc6)ccc4N5c4ccc(-c5ccccc5)cc4)cc3)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
10-(biphenyl-4-yl)-2-bromo-7-phenyl-9,10-dihydroacridine (14 g, 28.6 mmol) was dissolved in toluene (500 mL) under a nitrogen atmosphere. Then, N-(biphenyl-4-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)biphenyl-4-amine (15 g, 28.6 mmol) was added thereto. To the resultant mixture solution, tetrakis triphenyl phosphine palladium (1.32 g, 1.14 mmol) and potassium carbonate (9.9 g, 71.5 mmol) were added. Then, distilled water (70 mL) was added thereto, followed by reflux-stirring for 4 hours. The resultant solution was cooled to about 60° C., and purified by silica gel. Then, a toluene layer was extracted. The extracted organic solvent was concentrated and removed, and methanol was added to produce a solid. Through filtration, a yellowish brown solid was obtained. It was purified through silica gel column chromatography (methylene chloride/n-hexane (1/10)) to obtain N-(biphenyl-4-yl)-N-(4-(10-(biphenyl-4-yl)-7-phenyl-9,10-dihydroacridin-2-yl)phenyl)biphenyl-4-amine as a Cpd 14 compound (15 g, yield 65%, pale yellow solid).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([O:22]C)[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CCCCCCC.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(OC)cc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 5 (1.0 g, 2.5 mmol) in dichloromethane (15 mL) cooled at 0° C. was added a solution of boron tribromide in heptane (1.0 M, 5.0 mL, 5.0 mmol). The reaction was stirred at 25° C. for 30 min and then poured into aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[CH3:27][C:22]1([CH3:28])[C:23](=[O:24])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[O:10]1
Reactant: CC(C)(Br)C(=O)C#N
Reactant: CSc1ccc(C(=O)Cc2cccc(F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a stirred solution of 2-(3-fluorophenyl)-1-{4-(methylthio)phenyl}-ethan-1-one (100 g) in 1 L dry THF, was added portion-wise 26 g of 95 % sodium hydride at 0° C. The reaction solution was stirred at the same temperature for 1 hour. Then 69 g of α-bromo-isobutyryl cyanide diluted in 25 ml dry THF was added dropwise to the stirred solution at 0° C. The reaction mixture was stirred overnight while allowing to warm gradually to room temperature. The solution was concentrated in vacuo, to which was added 50 ml water. The aqueous solution was extracted with ethylacetate (1 L). The organic layer was concentrated in vacuo and purified by column chromatography (hexane/ethylacetate=6:1) to give 102 g of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylthio)phenyl}-3(2H)-furanone. mp: 106° C. NMR: δ1.55 (s, 6H), 2.50 (s. 3H), 6.97-7.11 (m, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.26-7.36 (m, 1H), 7.55 (d, J=9.0 Hz, 2H).
Reaction SMILES: [N:1]1[C:13]2[N:4]([C:5](=[O:14])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[NH:3][C:2]=1[C:15]([O:17]CC1C=CC=CC=1)=[O:16].[H][H]>CO.[Pd]>[N:1]1[C:13]2[N:4]([C:5](=[O:14])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[NH:3][C:2]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(OCc1ccccc1)c1nc2c3ccccc3nc(=O)n2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1nc2c3ccccc3nc(=O)n2[nH]1

Procedure:
5 g (15.6 mmoles) of benzyl 1,2,4-triazolo[1,5-c]quinazolin-5-one-2-carboxylate were dissolved in 250 ml of methanol, 1 g of 5% strength Pd/C was added, and the mixture was then stirred under atmospheric pressure in a hydrogenation apparatus until the absorption of hydrogen was complete. The precipitate was filtered off under suction and dissolved in 50 ml of hot dimethylformamide, the solution was filtered and the solvent was distilled off. The residue was digested with methanol and dried.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10](Br)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:14]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:12][CH:11]=2)=[CH:27][N:26]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]
Reactant: Brc1cnc(-c2ccccc2)nc1
Reactant: CCCCCCCCC=COc1ccc(B(O)O)cn1
Product: C=CCCCCCCCCOc1ccc(-c2cnc(-c3ccccc3)nc2)cn1

Procedure:
The synthesis was carried out analogously to Example 27 from 2-phenyl-5-bromopyrimidine and 2-decenyloxypyridine-5-boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1([CH2:8][CH2:9][CH2:10]Br)[CH2:7][CH2:6]1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1([CH2:8][CH2:9][CH2:10][N:13]=[N+:14]=[N-:15])[CH2:7][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CC1(CCCBr)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1(CCCN=[N+]=[N-])CC1

Procedure:
680 mg (2.89 mmol) of methyl[1-(3-bromopropyl)cyclopropyl]acetate and 1128 mg (17.35 mmol) of sodium azide in 5 ml of DMF were stirred at 60° C. for 2 h. The reaction mixture was then concentrated under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 389 mg (1.97 mmol, 68% of theory) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=1>C(O)C>[CH3:1][C:2]1[S:3][C:4]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=1
Reactant: CCCCCc1nc(C)sc1Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CCCCCc1nc(C)sc1Cc1ccc(N)cc1
Yield: 91.1 %

Procedure:
1.7 g of 2-methyl-5-(4-nitrobenzyl)-4-pentylthiazole (5.6 mmol) in 100 ml of ethanol are hydrogenated according to Example 25 to give 1.4 g of 2-methyl-5-(4-aminobenzyl)-4-pentylthiazole in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:30]C#N)[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([C:30]2[O:21][N:20]=[C:17]3[CH:16]=[CH:15][C:14]([C:13]4[N:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[N:10]=[CH:11][CH:12]=4)=[CH:19][C:18]=23)[CH:27]=[CH:28][CH:29]=1
Reactant: N#CCc1cccc(F)c1
Reactant: COc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: COc1ccc(-n2nccc2-c2ccc3noc(-c4cccc(F)c4)c3c2)cc1

Procedure:
The title compound, light green solid (81 mg, 62%), MS (ISP) m/z=386.2 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 1 from 1-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate G) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.