Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[NH2:18])=[O:12])=[CH:6][CH:5]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=O)=[CH:23][CH:22]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[F:20][C:2]([F:19])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[NH:18][CH2:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][CH:23]=2)=[O:12])=[CH:8][CH:9]=1
Reactant: Nc1ccsc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccnc2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1sccc1NCc1ccnc2ccccc12
Temperature: 25 °C

Procedure:
A solution of N-(4-trifluoromethoxyphenyl) 3-aminothiophene-2-carboxamide (1 g, 3.31 mmol) and quinoline-4-carboxaldehyde (347 mg, 2.21 mmol) in trifluoroacetic acid:dichloromethane (1:1, 30 mL) was heated at reflux for 2 h under nitrogen. The reaction was cooled to RT and triethylsilane (0.71 mL, 4.42 mmol) was added. The resulting solution was then stirred at reflux for 16 h under nitrogen. After cooling to RT, the reaction mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (3×100 mL) and saturated sodium bicarbonate solution (50 mL). The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20–30% ethyl acetate in hexane) to give EXAMPLE 1 as a light yellow solid, mp: 168–170° C. 1H-NMR (400 MHz/CDCl3): δ=5.01 (d, J=6.2 Hz, 2 H), 6.56 (d, J=5.4 Hz, 1 H), 7.12 (s, 1 H), 7.22 (d, J=8.7 Hz, 2 H), 7.25 (s, 1 H), 7.44 (d, J=4.3 Hz, 1 H), 7.58 (d, J=9.0 Hz, 2 H), 7.62 (t, J=8.2 Hz, 1 H), 7.76 (t, J=8.3 Hz, 1 H), 8.02 (d, J=7.5 Hz, 2 H), 8.17 (d, J=8.3 Hz, 1 H), 8.86 (d, J=4.5 Hz, 1 H). MS (ES+): 444 [MH+]. 13C-NMR (400 MHz/CDCl3): δ=45.9, 101.4, 117.9, 118.9, 119.5, 121.9, 122.0, 122.6, 126.5, 127.2, 129.1, 129.7, 130.6, 136.8, 144.5, 145.4, 148.3, 150.7, 155.9, 163.8. Anal. Calcd for C22H16F3N3O2S: C, 59.59; H, 3.64; N, 9.48; F, 12.85; S, 7.23. Found: C, 59.59; H, 3.67; N, 9.46; F, 13.01; S, 7.23.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]=[CH:11]C[O:9]2)=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][O:9]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Brc1ccc(C2CC=CCO2)cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(C2CCCO2)cc1
Yield: 37.6 %

Procedure:
A solution of 2-(4-bromophenyl)-3,6-dihydro-2H-pyran (140 mg, 0.586 mmol) in toluene/ethanol (10 mL, v/v=1/1) was charged into a hydrogenation Parr bottle followed by tris(triphenylphosphine)rhodium(I) chloride (55 mg, 0.0586 mmol). The mixture was set up for 45 psi of hydrogen at 80° C. overnight. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by silica gel chromatography to give the title compound (50 mg, 35%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.46 (d, 2H) 7.23 (d, 2H) 4.29 (d, 1H) 4.13 (m, 1H) 3.60 (t, 1H) 1.95 (m, 1H) 1.81 (d, 1H) 1.60 (m, 3H) 1.27 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[O:13]1[CH2:15][C@H:14]1[CH2:16]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:16][C@@H:14]2[CH2:15][O:13]2)=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)ccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of N-(5-chloro-2-hydroxyphenyl)acetamide (500 mg, 2.69 mmol), (2S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (697 mg, 2.69 mmol) and Cs2CO3 (1.04 g, 3.22 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in petroleum ether) to give the subtitled compound (600 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][CH2:7][C:8]([NH2:20])([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:9]([F:12])([F:11])[F:10])C>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[Br:19][C:15]1[CH:14]=[C:13]([C:8]2([C:9]([F:12])([F:11])[F:10])[NH:20][C:4](=[O:3])[CH2:5][O:6][CH2:7]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)COCC(N)(c1cccc(Br)c1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1COCC(c2cccc(Br)c2)(C(F)(F)F)N1

Procedure:
A solution of 598 mg (1.616 mmol) [2-Amino-2-(3-bromo-phenyl)-3,3,3-trifluoro-propoxy]-acetic acid ethyl ester in 5.4 ml toluene and 2.7 ml TFA was heated at reflux temperature for 5 h. The cooled down mixture was evaporated, taken up in EtOAc, washed with 5% aqueous NaHCO3, dried with Na2SO4 and evaporated to give the essentially pure title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH3:40][Sn](C)(C)C>CN(C=O)C.CCOC(C)=O.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:8]2[C:14]([CH3:40])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1ncc2c(c(Br)c(-c3ccc(Cl)cc3)n2Cc2ccc3c(c2)OCO3)c1OC(=O)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2c(c(C)c(-c3ccc(Cl)cc3)n2Cc2ccc3c(c2)OCO3)c1OC(=O)C(C)(C)C
Temperature: 130 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a mixture of 1-benzo[1,3]dioxol-5-ylmethyl-3-bromo-2-(4-chloro-phenyl)-4-(2,2-dimethyl-propionyloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (from Example 38(a))(180 mg, 0.29 mmol) in DMF (2.5 mL) was added tetramethyltin (207 mg, 1.16 mmol) and Pd(PPh3)2Cl2 (30 mg, 0.044 mmol). Resulting mixture was stirred at 130° C. for 2 h. Reaction mixture was diluted with EtOAc and filtered. Filtrate was washed with water and brine, dried over MgSO4, filtered, and concentrated to give the title product 161 mg. MS-(+)-ion: M+1=549.14.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[C:8](Cl)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>N1C=CC=CC=1>[C:8]([O:1][C@@H:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CC(O)CO1
Solvent: c1ccncc1
Product: O=C1C[C@H](OC(=O)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To the solution of (S)-(3-Hydroxy-γ-butyrolactone (1.0 g, 9.8 mmol) in 25 mL pyridine was added dropwise BzCl (1.4 mL, 12.2 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was concentrated and coevaporated with toluene two times in vacuo. The residue was partitioned between H2O (15 mL) and EtOAc (40 mL). The organic layer was washed with water and brine, and concentrated in vacuo. The residue was purified by chromatography on a silica gel column (n-hexane/EtOAc=8:1) to afford 101 (1.78 g, 8.6 mmol) as a white solid, in 89% yield, which was characterized as follows:
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[S:15])[CH:11]=[C:10]2[OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:4][C:5]1[CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([S:15][CH2:2][CH3:3])=[CH:11][C:10]2=[O:16]
Reactant: COC(=O)c1cc(Br)c2oc(=S)cc(O)c2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSc1cc(=O)c2cc(C(=O)OC)cc(Br)c2o1
Yield: 99.8 %

Procedure:
Iodoethane (37.1 mL, 463.51 mmol) was added in one portion to a stirred suspension of methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (48.69 g, 154.5 mmol) and potassium carbonate (21.35 g, 154.50 mmol) in acetone (490 mL). The resulting suspension was stirred at reflux for 1 h under nitrogen in a flask equipped with a bleach trap. The reaction mixture was concentrated, the residue was diluted with DCM (980 mL)/water (490 mL). The phases were separated and the aqueous layer was extracted with DCM (490 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was triturated with petroleum ether, filtered and dried under vacuum to give methyl 8-bromo-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (52.9 g, 100%) as a pale brown solid. Mass Spectrum: m/z [M+H]+=345
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([O:32][CH3:33])[CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])=[O:28])=[C:25]([O:32][CH3:33])[CH:24]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(Cl)cc1OC

Procedure:
Ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-chloro-2-methoxybenzoic acid were treated in the same manners as in Example 20d) and then in Example 1d), to give 3-(3-{[(4-chloro-2-methoxybenzoyl)amino]methyl}-4-methoxyphenyl)-2-isopropoxypropanoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)([O-])=O>C(O)C.[Pd]>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[NH2:1])=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: O=[N+]([O-])c1cnccc1Oc1ccc2[nH]ccc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnccc1Oc1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a slurry of 10% Pd/C (1.0 g) in 10 ml of ethanol was added 5-[(3-nitro-4-pyridinyl)oxy]-1H-indole (3.7 g) in 240 ml ethanol and this was shaken on a Parr apparatus for 1 hour. The mixture was filtered and the filtrate concentrated to yield an oil (3.1 g) which was eluted with ethyl acetate on a silica gel column via HPLC. The desired fractions were concentrated to an oil which solidified on standing to yield 2.6 g, m.p. 155°-157° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[N:24]=[N:23][C:22]([CH3:25])=[N:21]4)[O:16][C:15]3=[O:26])=[CH:9][C:8]=2[F:27])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:29].[Na+].CO>ClCCl>[O:29]=[S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([F:27])=[CH:9][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[N:24]=[N:23][C:22]([CH3:25])=[N:21]4)[O:16][C:15]3=[O:26])=[CH:11][C:12]=2[F:13])[CH2:3][CH2:2]1
Reactant: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4CCSCC4)c(F)c3)C(=O)O2)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4CCS(=O)CC4)c(F)c3)C(=O)O2)n1
Yield: 9.1 %

Procedure:
(5R)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[(5-methyl-2H-tetrazol-2-yl)methyl]oxazolidin-2-one (Example 34) (0.53 g, 1.34 mmol) was oxidized with sodium periodate (0.314 g, 1.47 mmol) as described for Intermediates 42 and 43. Chromatography on silica gel with 0-5% methanol in dichloromethane gave a mixture together with the corresponding E-isomer, which was separated on a Chiracel OD chiral chromatography column using hexanes/isopropanol (1:1) as eluant to give the title compound (50 mg) as a colourless solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:14][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[C:12]([CH3:13])[N:11]=1)(=[O:26])=[O:25]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Cc1nc(N)ccc1COCC1CC1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1ccc(COCC2CC2)c(C)n1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-ylamine (0.06 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.089 g) as an amorphous light yellow solid (0.058 g). MS (ESI−): 413.1 ([M−H]−)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[CH:13][C:12]=2[O:21][CH:22]([F:24])[F:23])[CH2:5][CH2:4]1.C1COCC1.[Cl:33][C:34]1[C:47]([N:48]=[C:49]=S)=[C:46]([Cl:51])[CH:45]=[CH:44][C:35]=1[CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].CC(C)N=C=NC(C)C>CC#N.[Pd]>[F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([O:21][CH:22]([F:24])[F:23])=[CH:13][C:14]3[NH:18][C:49]([NH:48][C:47]4[C:46]([Cl:51])=[CH:45][CH:44]=[C:35]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42])[C:34]=4[Cl:33])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OC(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: [Pd]
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OC(F)F)cc3[nH]2)c1Cl
Reaction time: 2 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-(difluoromethoxy)-5-amino-4-nitro-benzoic acid amide (70 mg, 0.176 mmol), Pd/C (15 mg) and 10 mL THF is stirred under a H2-atmosphere (3 bar) for 2 h. The crude mixture is filtered into a flask charged with N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (59 mg, 0.185 mmol) and the filter cake is washed with 40 mL THF. The mixture is stirred for 4 h at rt and overnight at 60° C. Then the reaction mixture is concentrated to −10 mL and stirred for additional 8 h at 60° C. Then it is concentrated i. vac., diluted with MeCN (2.0 mL) and DIC (29 μl, 0.186 mmol) is added and it is stirred for 4 d. Then the mixture is concentrated, diluted with DMF and THF and purified via HPLC.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:25][C:24]([F:27])([F:26])[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[N:7]=2)[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)n3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2nccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)cn1

Procedure:
The title compound was prepared from 2′-chloro-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyrimidinyl (example E.42) (g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.17 g, %). MS (ISP) 463.1 [(M+H)+]; mp 236.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([NH:28][CH3:29])[CH:26]=[CH2:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:28]([CH2:25][CH:26]=[CH2:27])[CH3:29])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCCBr)ccc21
Reactant: C=CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN(C)CCCCCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Yield: 72.1 %

Procedure:
1.5 g (3.75 mmol) 6-(5-Bromo-pentyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester were treated with 355 mg (5 mmol) N-allyl-methylamine and 830 mg (6 mmol) K2CO3 (powdered) in 8 ml DMF at 60° C. for 3 h. The mixture was concentrated in vacuo, dissolved in acetone and filtered. The filtrate was concentrated and purified by column chromatography on silica gel with CH2Cl2/MeOH 19:1 to yield 1.05 g (72%) 6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless oil, MS: 389 (MH+).
Reaction SMILES: C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC([C:14]3[CH:15]=[CH:16][C:17]4[NH:18][C:19]5[C:24]([C:25]=4[CH:26]=3)=[CH:23][C:22](C3C=CC([Si](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)=CC=3)=[CH:21][CH:20]=5)=CC=2)C=CC=CC=1.[OH:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74]1[CH:79]=[CH:78][C:77](I)=[CH:76][CH:75]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]>[OH:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=1[C:26]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc(-c3ccc4[nH]c5ccc(-c6ccc([Si](c7ccccc7)(c7ccccc7)c7ccccc7)cc6)cc5c4c3)cc2)cc1
Reactant: OCCCCCCCCOc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: OCCCCCCCCOc1ccccc1-c1cccc2[nH]c3ccccc3c12

Procedure:
The 3,6-bis(4-triphenylsilylphenyl)carbazole (1.30 g), 4-(8-hydroxyoctyloxy)iodobenzene (0.65 g), potassium carbonate (0.54 g), copper powder (0.4 g) and nitrobenzene (5 mL) were stirred under nitrogen flow at 195° C. for 16 hours. The resultant mixture was filtrated through CELITE and the solvent was evaporated. The residue was treated through silica gel column chromatography (eluent: 10% ethyl acetate/toluene solution), to thereby obtain 1.50 g (89.8%) of 3,6-bis(4-triphenylsilylphenyl)-N-[4-(8-hydroxyoctyloxyphenyl]carbazole as colorless needle crystals.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10](=[O:20])[C:9]12[CH2:22][CH2:21]1)=[O:4].[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C.O>[F:24][C:2]([F:1])([F:23])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:25]([O-:27])=[O:26])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10](=[O:20])[C:9]12[CH2:22][CH2:21]1)=[O:4]
Reactant: CCCCCN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)ccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(2′-oxo-1′-pentyl-spiro[cyclopropane-1,3′-indole]-5′-yl)-acetamide (2.4 g) in acetic acid (20 ml) is added nitric acid (fuming, 0.9 ml) at 15° C. over a period of 3 min. The mixture is stirred at this temperature for 1 h and then diluted with water. The aqueous layer is extracted with Et2O (2×50 ml) The combined organic layer is washed with water, saturated K2CO3 solution and brine, dried over MgSO4 and evaporated. The compound (2.6 g) is obtained as brownish oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]12(O)[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1>C1C=CC=CC=1>[Cl:3][C:5]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1
Reactant: OC12CCCC(C1)C1CCC2C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClC12CCCC(C1)C1CCC2C1
Yield: 89 %

Procedure:
Five milliliters of thionyl chloride are added to a solution of 5.0 g (30 millimoles) tricyclo [4.3.1.12,5 ] undecane-1-ol in 30 ml dry anhydrous benzene and the entirety is refluxed for 1.5 hours. The reaction mixture is concentrated under reduced pressure and there is further added 20 ml of dry benzene. Reduced pressure concentration is repeated to distill out the excess thionyl chloride completely. The residue is distilled under reduced pressure to collect a fraction boiling at 95° C./3mmHg, to obtain 5.0 g (yield 89%) of 1-chlorotricyclo [4.3.1.12,5 ] undecane.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:29]([F:30])=[C:28](F)[C:27]([F:32])=[C:26]([F:33])[C:25]=3[F:34])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].CCCCCCC>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][C:27]([F:32])=[C:26]([F:33])[C:25]=3[F:34])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]
Reactant: Cc1c(CCCC(=O)O)c2c(F)ccc(C#Cc3ccc(OCCCCc4c(F)c(F)c(F)c(F)c4F)cc3)c2n1CCCC(=O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(CCCC(=O)O)c2c(F)ccc(C#Cc3ccc(OCCCCc4c(F)cc(F)c(F)c4F)cc3)c2n1CCCC(=O)O
Temperature: 0 °C
Yield: 80.2 %

Procedure:
The compound (50 mg) prepared in Example 14 (3) was dissolved in ethyl acetate (1.4 mL) at 70° C. To the solution, n-heptane (0.68 mL) was added at room temperature, which was then cooled to 0° C. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (39 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([OH:17])=[O:16])[C:8]2=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 84 %

Procedure:
To a solution of 20 mg (0.039 mmol) of biphenyl imidazolyl tert-butyl ester (the title compound of Example 17) in 0.5 mL of chloroform was added 0.25 mL of TFA, and the progress of the reaction was monitored by 1H NMR. The resulting solution was stirred at room temperature for 75 min. The mixture was quenched with methanol and concentrated in vacuo. The residue was dissolved in a minimum amount of methanol and triturated with dropwise addition of methylene chloride-ether-hexane to give 15 mg (84%) of the title compound of Example 18 as a solid: mp 148°-171° C. (decomposed); 1H NMR (CD3OD) δ 0.83 (t, J=7.25 Hz, 3H), 1.10-1.60 (m, 4H), 2.68-2.95 (m, 3H), 3.13-3.35 (m, 1H), 3.48-3.60 (m, 2H), 5.80-6.0 [m (with d at 5.87, J=7.66 Hz), 2H], 7.10 (br s, 4H), 7.40-7.75 (m, 5H); HRMS. calcd for M+H: 455.2195. Found: 455.2215.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].C(N(CC)CC)C.[C:19](=S)=[S:20]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:19]([SH:20])=[N:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: S=C=S
Reactant: NNC(=O)c1cccc(N)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cccc(-c2nnc(S)o2)c1

Procedure:
3-Aminobenzhydrazide (5.76 g) was dissolved in ethanol (40 mL), and triethylamine (4.8 mL) and carbon disulfide (2.1 mL) were added to the solution. The mixture was heated under reflux for 4 hrs. The solvent was evaporated, and water was added. The precipitated solids were collected by filtration to give the title compound (5.06 g) as a pale-yellow powder.