Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[C:3]=1[F:13].[CH3:14][N:15](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(OCC)(=O)C>CC(N(C)C)=O.[Pd].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:13][C:3]1[C:4]([O:11][CH3:12])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:14]#[N:15]
Reactant: COc1c([N+](=O)[O-])ccc(Br)c1F
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1c([N+](=O)[O-])ccc(C#N)c1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 433.4 %

Procedure:
A mixture of 1-Bromo-2-fluoro-3-methoxy-4-nitrobenzene (250 mg, 1 mmol) and zinc cyanide (70 mg, 0.6 mmol) were stirred in DMA (5 mL) and purged with nitrogen. The palladium catalyst, Pd2(dba)3 (92 mg, 0.1 mmol), and the ligand, Davephos (79 mg, 0.2 mmol), were added and the reaction mixture was stirred at 90° C. overnight. It was then cooled to rt., diluted to ethyl acetate, washed with brine. Organic dried, concentrated and purified by flash column (EtOAc/Hexane=1:20) to give 170 mg product (87%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.15 (s, 3H) 7.42 (dd, J=9.0, 6.2 Hz, 1H) 7.65 (dd, J=9.0, 1.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C>[Cl:31][C:27]1[CH:28]=[C:29]([CH3:30])[C:21]2[N:20]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:23](=[O:24])[C:22]=2[CH:26]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a solution of 3.1 g of 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride in 100 ml of acetonitrile, 1.9 g of 2-amino-5-chloro-3-methylbenzoic acid was added. The mixture was stirred at room temperature for 10 minutes and then, 1.0 g of triethylamine was added thereto. The mixture was stirred at room temperature for 20 minutes and then, 2.0 g of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 1.2 g of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were poured into the residue to separate layers. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressured. The resulting residue was subjected to silica gel column chromatography to obtain 4.2 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][C:2]([OH:41])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C@@H:12]([S:32][CH2:33][C:34]1([CH2:37][C:38]([O-:40])=[O:39])[CH2:36][CH2:35]1)[C:13]1[CH:14]=[CH:15][CH:16]=[C:17](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[N:30]=2)[CH:18]=1)[CH3:3].[Na+].ClC1C=C2C(C=CC(C=CC3C=C([C@@H](OS(C)(=O)=O)CCC4C=CC=CC=4C(OC4CCCCO4)(C)C)C=CC=3)=N2)=CC=1.C(SCC1(CC(OC)=O)CC1)(=O)C>NN.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C.O1C=CC=CC1>[CH3:3][C:2]([OH:41])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C@@H:12]([S:32][CH2:33][C:34]1([CH2:37][C:38]([OH:40])=[O:39])[CH2:35][CH2:36]1)[C:13]1[CH:14]=[CH:15][CH:16]=[C:17](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[N:30]=2)[CH:18]=1)[CH3:1]
Reactant: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)[O-])CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: C1=CCOC=C1
Agent: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: COC(=O)CC1(CSC(C)=O)CC1
Solvent: CC#N
Product: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)O)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
EP 480717 discloses a process for preparing montelukast sodium by reacting 2-(2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-(methanesulfonyloxy)propyl)phenyl)-2-propoxy)tetra hydro pyran with Methyl 1-(acetylthiomethyl)cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as solvent to get methyl ester of Montelukast in pyran protected form, which is further reacted with pyridinium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford Montelukast sodium of Formula (I).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH2:12]([O:14][C:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16])[CH3:13].[F-].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([O:14][C:12]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1)=[CH2:13])[CH3:16]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A solution of 2-chloro-4-trifluoromethylpyridine (3.33 g), (1-ethoxyvinyl)tri-n-butyltin (5.95 g) and bis(triphenylphosphine)palladium(II) chloride (0.4 g) in DMF (40 ml) was heated at 70° C. for 16 hours. The reaction mixture was cooled to room temperature, potassium fluoride (60 ml of a 10% aqueous solution) was added and the resulting mixture was stirred for 1 hour then filtered through Hyflo supercel filter aid which was rinsed through with ether. The filtrate was extracted with ether (×2) and the combined extracts were washed with brine, then dried, concentrated and chromatographed using ether:hexane 1:4 as the eluant to give 1-ethoxy-1-(4-trifluoromethylpyrid-2-yl)-ethylene (1.4 g, 35% yield) as a pale yellow liquid; 1H NMR (270 MHz): δ1.45(3H,t), 4.00(2H,q), 4.42(1H,d), 5.50(1H,d), 7.40(1H,d), 7.88(1H,s), 8.72(1H,d) ppm.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][CH:24]([NH2:26])[CH3:25]>>[CH:24]([NH:26][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:25])[CH3:23]
Reactant: CC(C)N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)C
Temperature: 100 °C
Yield: 47 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 45 mg, 0.152 mmol) and propan-2-amine (38.8 μl, 0.456 mmol, Aldrich), heating at 100° C. for 30 min. Purification by silica gel (100% DCM to 3% MeOH/DCM) provided 2-(3-(isopropylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4 (5H)-one (47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (d, J=6.46 Hz, 6H) 2.56 (s, 3H) 2.90 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.80, 2.25 Hz, 2H) 4.30 (dq, J=13.23, 6.48 Hz, 1H) 6.88 (d, J=7.04 Hz, 1H) 6.96 (br. s., 1H) 7.12 (s, 1H) 7.33 (t, J=7.82 Hz, 1H) 7.57 (dd, J=7.92, 1.27 Hz, 1H) 7.90 (dd, J=7.63, 1.17 Hz, 1H) 12.23 (br. s., 1H). MS (ESI, pos. ion) m/z: 336.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:16][C:17]2[CH:30]=[CH:29][C:28]3[C:19](=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: BrCc1ccc2cc3ccccc3cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2cc3ccccc3cc2c1
Temperature: 60 °C

Procedure:
Sodium hydride (50% dispersion in oil, 1.37 g, 28.6 mmol, 1.1 eq) was added to a DMF solution (50 mL) containing 2-n-butyl-4-chloroimidazole-5-carboxaldehyde (prepared as in European Patent Application Number 89100144.8, published 7.19.89) (4.85 g, 26.0 mmol, 1.0 eq). The contents were heated with stirring at 60° C. until everything was dissolved. The reaction was then cooled to 0° C. and a DMF solution (75 mL) of 2-bromomethylanthracene (entire contents from the previous step: 7.77 g of impure material, theoretically 26.0 mmol, 1.0 eq) was added and the entire contents stirred at room temperature overnight. The solvent was removed in vacuo and the residue flash chromatographed in 9:1 toluene/ethyl acetate to 75:25 toluene/ethyl acetate to yield 3.73 g of an amber glass. This material could not be crystallized and was used without further purification for the next step. NMR (CDCl3): δ 9.80 (s, 1H); 8.40 (s, 1H); 8.33 (s, 1H); 7.98 (m, 3H); 7.48 (m, 3H); 7.23 (m, 1H); 5.72 (s, 2H); 2.79 (t, 2H, J=7Hz); 1.69 (t of t, 2H, J=7,7Hz); 1.33 (t of q, 2H, J=7,7Hz); 0.84 (t, 3H, J=7Hz). ##STR56##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[S]>>[C:2]1([CH:1]=[CH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: [S]
Product: O=C(O)c1ccc(C=Cc2ccc(C(=O)O)cc2)cc1
Yield: 34 %

Procedure:
It also is known to heat a stoichiometric excess of p-toluic acid with sulfur at 265° C. at a pressure of about 5.5 bars absolute in the presence of nitrogen to obtain 4,4'-stilbenedicarboxylic acid in a 34% yield based on the amount of sulfur used A known method for synthesizing dimethyl 4,4'-stilbenedicarboxylate comprises the steps of (1) contacting methyl p-formylbenzoate with hydrogen sulfide at 0° C. in the presence of hydrochloric acid to produce a cyclic trisulfide compound and (2) heating the cyclic trisulfide compound at 220° to 260° C. in the presence of copper and diphenyl ether. Dimethyl 4,4'-stilbenedicarboxylate is obtained in an overall yield, based on the methyl p-formylbenzoate starting material, of 37.5%. Both of these methods, like the process of U.S. Pat. No. 2,677,703, produce hydrogen sulfide. These processes require the use of special, dedicated equipment and are not well suited for use in general purpose equipment. Additional methods for preparing stilbene compounds are described by K. B. Becker, Synthesis of Stilbenes, Synthesis, May 1983, 341-368 and U.S. Pat. No. 5,113,010.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(C(C)C)C(C)C)C>S(Cl)(Cl)=O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=2)=[O:10])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1cccc(C(=O)Nc2cccc(C(F)(F)F)c2)c1

Procedure:
Using 3-(acetyloxy)benzoic acid (9.01 g, 50.0 mmol), thionyl chloride (10 mL), 3-(trifluoromethyl)aniline (12.1 g, 75.0 mmol) and N-ethyl-N-isopropylpropane-2-amine (12.9 g, 100 mmol), and in the same manner as in Example A25(i), the title compound (16.2 g, quantitatively) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@@H:49]([CH2:63][C:64]1[CH:69]=[C:68]([F:70])[CH:67]=[C:66]([F:71])[CH:65]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1>C(Cl)Cl>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:48][C@@H:49]([CH2:63][C:64]3[CH:65]=[C:66]([F:71])[CH:67]=[C:68]([F:70])[CH:69]=3)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=3)=[O:16])[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCc1c[nH]c2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1c[nH]c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.4 %

Procedure:
To a mixture of 3-Butyl-1H-indole-5-carboxylic acid (0.145 g) in methylene chloride (15 mL) was added triethylamine (0.068 g), and HATU (0.255 g). The mixture was stirred at room temperature for 15 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.224 g) was added. The mixture was stirred at room temperature for 72 h then poured into methylene chloride (50 mL), washed with water then saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under vacuum. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride with 0.15% HOAc as eluent to give 0.247 g of the title compound: MS (ESI+) for C32H37F2N3O2 m/z 534.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](=[CH2:15])[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][C:33]=1[CH3:39].C(N(CC)CC)C.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSC>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:14]([CH2:15][S:38][C:35]2[CH:36]=[CH:37][C:32]([F:31])=[C:33]([CH3:39])[CH:34]=2)[C@H:13]([OH:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1cc(S)ccc1F
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CSC
Product: Cc1cc(SC[C@@H]2[C@H](O)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
Di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-methylene-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (8 g, 18.9 mmol) in diethyl ether (80 mL) is bubbled with nitrogen gas for 10 minutes. 4-fluoro-3-methyl-benzenethiol (2.7 g, 18.9 mmol) and triethylamine (0.26 mL, 1.89 mmol) are added. The mixture is warmed to 40° C. and stirred for 15 minutes. The mixture is then allowed to cool to ambient temperature, transferred to addition funnel and added slowly over 2 hours to a 200 ml ether solution at −10° C. which contains S-(−)-2-methyl-CBS-oxazaborolidine (1M in tetrahydrofuran) (5.67 mL, 5.67 mmol) and borane-methyl sulfide complex (2M in tetrahydrofuran, 8.5 mL, 17 mmol). The mixture is stirred for an additional hour after final addition. Silica gel (40 g) is added over 30 minutes and the reaction mixture is gradually warmed to ambient temperature. The suspension is filtered, and washed with 300 ml of diethyl ether. The solvent is concentrated under reduced pressure giving a residue. The residue is purified by flash chromatography, eluting with (0 to 25% ethyl acetate/hexanes) to give the title compound (9.8 g, 17.3 mmol, 91.5% yield). MS (m/z): 565.8 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[N:13]1[CH:18]=[CH:17][N:16]=[C:15]([N:19]2[CH2:23][CH2:22][CH:21](O)[CH2:20]2)[N:14]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:21]1[CH2:22][CH2:23][N:19]([C:15]2[N:14]=[N:13][CH:18]=[CH:17][N:16]=2)[CH2:20]1
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: OC1CCN(c2nccnn2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Cl)c(OC2CCN(c3nccnn3)C2)c1

Procedure:
Compound 42 is prepared from 2-chloro-5-trifluoromethylphenol and intermediate 5d according to synthesis method 3 in toluene in the presence of DIAD, under the operating conditions described for example 8 (86% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:12](=O)[NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:12]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[N:13]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NCc2ccccc2)c(NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c1
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)nc(C(NC(=O)OC(C)(C)C)C(C)C)n2Cc1ccccc1
Yield: 78.6 %

Procedure:
A solution of [1-(2-benzylamino-5-methyl-phenylcarbamoyl)-2-methyl-propyl]carbamic acid tert-butyl ester (400 mg, 0.97 mmol) in acetic acid (4 mL) was heated at 100° C. for 2 h. The solvent was removed in vacuo and the resulting solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to give of [1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamic acid tert-butyl ester (300 mg).
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]([C:17]1[CH:39]=[CH:38][C:20]([O:21][C:22]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)[CH:25]=[CH:24][C:23]=2[NH2:37])=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:39]=[CH:38][C:20]([O:21][C:22]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)[CH:25]=[CH:24][C:23]=2[NH:37][S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)#[N:16]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)c2)cc1
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3cccc4ccccc34)c(Oc3ccc(C#N)cc3)c2)cc1
Yield: 68 %

Procedure:
1-Naphthalene sulfonyl chloride (0.148 g, 0.65 mmol) was added to a stirred solution of 1,5-bis-(4-cyano-phenoxy)-2-aminobenzene (0.175 g, 0.54 mmol) along with other reagents as mentioned in Example 20(c) to afford 0.19 g of the required product. 1H NMR (DMSO-d6): δ 6.45 (3H, m), 7.16 (5H, m), 7.42 (6H, m), 7.75 (2H, dd), 7.85 (3H, m).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH2:12])[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=1.I[C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.[Cu]I.C(OCC)(=O)C.O>[NH2:12][C:5]1[CH:4]=[C:3]([CH3:2])[CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][N:9]2[C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=1)[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: O=C(OCc1ccccc1)c1cccc(I)c1
Reactant: Cc1cc(N)c2cn[nH]c2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(N)c2cnn(-c3cccc(C(=O)OCc4ccccc4)c3)c2c1
Yield: 32.3 %

Procedure:
6-Methyl-1H-indazol-4-amine hydrochloride (0.5 g, 2.7 mmol), phenylmethyl 3-iodobenzoate (0.9 g, 2.6 mmol), copper (I) iodide (14 mg, 0.07 mmol), potassium carbonate (1.2 g, 8.68 mmol) and trans-N,N′-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol) were heated together in DMF (5 mL) at reflux overnight. The mixture was cooled, poured into a mixture of water and ethyl acetate and filtered through celite. The organic phase was separated, combined with a second ethyl acetate extract, washed successively with water and brine and then dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (75 g) eluting with 1 to 5% gradient of ethyl acetate in dichloromethane to give the title compound (0.3 g).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([OH:20])=[O:19]
Reactant: NC(Cc1cccs1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1cccs1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-thiophen-2-yl-propionic acid to provide the title compound in good yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
Nitration was performed as described in General Method 12 using tert-butyl-4-methylbenzene (25 g), concentrated H2SO4 (92 g), 70% HNO3 (82 g), and H2O (25 g). The crude product was purified via distillation under vacuum.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[C:11]([F:24])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Br[C:26]1[CH:31]=[C:30]([F:32])[C:29]([C:33]([F:48])([F:47])[O:34][C:35]2[CH:36]=[C:37]([F:46])[C:38]([C:42]([F:45])([F:44])[F:43])=[C:39]([F:41])[CH:40]=2)=[C:28]([F:49])[CH:27]=1.C(N(CC)CC)C.C(=O)([O-])O.[K+]>C1COCC1.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.CC(OC)(C)C>[F:41][C:39]1[CH:40]=[C:35]([CH:36]=[C:37]([F:46])[C:38]=1[C:42]([F:43])([F:45])[F:44])[O:34][C:33]([F:47])([F:48])[C:29]1[C:28]([F:49])=[CH:27][C:26]([C:12]2[CH:13]=[CH:14][C:9]([CH:6]3[CH2:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:8][O:7]3)=[CH:10][C:11]=2[F:24])=[CH:31][C:30]=1[F:32]
Reactant: Fc1cc(OC(F)(F)c2c(F)cc(Br)cc2F)cc(F)c1C(F)(F)F
Reactant: CCC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)OC1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC1CCC(c2ccc(-c3cc(F)c(C(F)(F)Oc4cc(F)c(C(F)(F)F)c(F)c4)c(F)c3)c(F)c2)OC1
Temperature: 50 °C

Procedure:
5.20 g (15.0 mmol) of 5-ethyl-2-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydropyran are initially introduced in 35 ml of THF together with 6.93 g (15.0 mmol) of 5-((4-bromo-2,6-difluorophenyl)-difluoromethoxy)-1,3-difluoro-2-(trifluoromethyl)benzene. 590 mg (0.75 mmol) of bis(tri-o-tolylphosphine)palladium(II) chloride and 0.1 ml (0.75 mmol) of triethylamine are added. The mixture is heated to 50° C., and a solution of 2.41 g (24.0 mmol) of potassium hydrogencarbonate in 15 ml of water is added. After 3 h at this temperature, water and MTBE are added, and the organic phase is separated off. The aqueous phase is washed with MTBE, and the combined organic phases are washed with saturated sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product is purified by column chromatography (SiO2, n-heptane:toluene=1:1). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-{4′-[(3,5-difluoro-4-trifluoromethylphenoxy)difluoromethyl]-2,3′,5′-trifluorobiphenyl-4-yl}-5-ethyltetrahydropyran as a colourless solid having an m.p. of 90° C.