Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[C:17]([F:20])([F:19])[O:18][C:13]=3[CH:12]=2)[CH2:6]1)=O.[CH3:25][NH2:26]>CO>[CH3:25][NH:26][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[C:17]([F:20])([F:19])[O:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:2]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)OC(F)(F)C(=O)N3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)OC(F)(F)C(=O)N3C)C(=O)O1
Reaction time: 16 h
Yield: 50 %

Procedure:
To a stirred solution of (5R)-3-(2,2-Difluoro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 80, Step 3,50 mg, 0.14 mmol) in MeOH (1 mL) is added 2M MeNH2 in MeOH (2 mL, 4 mmol). The resulting mixture is stirred for 16 h at which time a precipitate forms. The mixture is heated until it becomes clear, and the product is allowed to crystallize at room temperature in the form of white needles. The crystals are separated, washed with ether and dried under high vacuum at 50° C. to give the title compound (25 mg, 50%), 1H NMR (300 MHz, DMSO) δ 8.38 (br d, 1H), 7.60 (d, 1H), 7.51-7.41 (m, 2H), 5.06 (dd, 1H), 4.29 (t, 1H), 4.03 (dd, 1H), 3.41 (s, 3H), 2.65 (d, 2H); MS for C14H13F2N3O5 m/z 342.5 (M+H)+.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.CS([Cl:30])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:30][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: COc1ccc(CCN2CCCC[C@@H]2CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 4 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-methoxyphenethyl)piperidine (617 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (0.30 g, 2.7 mmol) and methanesulfonyl chloride (0.30 g, 2.6 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 4 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-methoxy-phenethyl)homopiperidine in the form of a light yellow oil (632 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[C:12]=1[F:27])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[C:12]=1[F:27])=[O:8]
Reactant: Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (73.0 mg, 0.131 mmol) in DCM (5 ml) was added TFA (1.5 mL) and the reaction mixture was stirred for 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (32 mg, 0.075 mmol, 57% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 12.74-13.45 (m, 1H), 7.97-8.44 (m, 1H), 7.73 (s, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 6.98 (s, 1H), 6.69 (d, 2H), 4.27-4.76 (m, 2 H), 2.23 (s, 3H). LC-MS (ES+) m/z 427.91, [M+H].
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(Cl)cc1
Yield: 29.3 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 63 mg, 0.2 mmol) was reacted with 4-chlorophenylboronic acid (available from Combi-Blocks Inc.; 56 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (27 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.51 (d, J=6.8 Hz, 2H), 7.42 (d, J=6.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: COc1ccc(CC(=O)O)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)c(F)c1

Procedure:
(3-Fluoro-4-methoxyphenyl)acetic acid (5.0 g, 27.1 mmol) is dissolved in MeOH (100 mL). To it is added concentrated H2SO4 (5 mL) and the solution is warmed to reflux for 2 h. At that point, the solution is evaporated to dryness and taken up in EtOAc. The solution is washed with saturated aqueous NaHCO3, dried (Na2SO4) and evaporated to give (3-fluoro-4-methoxyphenyl)acetic acid methyl ester (cas# 588-14-7) as a yellow oil. MS (ESI) m/z 199.3 (M+H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]([N:35]=[C:36]=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:36]([NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 50 mg (0.13 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 37.2 μl (0.27 mmol) of triethylamine and 26.5 mg (0.27 mmol) of tert-butyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 19 mg (32.6% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]#[N:2].C([O:6][C@H:7]1[C@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C@H:10]([CH3:21])[O:9][C@@H:8]1[S:22][CH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:58]([NH:60][C@H:61]([C:91]([OH:93])=[O:92])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:67](=[O:90])[CH2:68][CH2:69][S:70][C@H:71]1[O:88][C@@H:87]([CH3:89])[C@@H:82]([O:83]C(=O)C)[C@@H:77]([O:78]C(=O)C)[C@@H:72]1[O:73]C(=O)C)=[O:59])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:57])[CH2:35][CH2:36][S:37][C@H:38]1[O:55][C@@H:54]([CH3:56])[C@@H:49]([O:50]C(=O)C)[C@@H:44]([O:45]C(=O)C)[C@@H:39]1[O:40]C(=O)C)=[O:26])(=O)C>CO.O.C(N(CC)CC)C>[N:1]#[N:2].[C@H:8]1([S:22][CH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:58]([NH:60][C@H:61]([C:91]([OH:93])=[O:92])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:67](=[O:90])[CH2:68][CH2:69][S:70][C@H:71]2[O:88][C@@H:87]([CH3:89])[C@@H:82]([OH:83])[C@@H:77]([OH:78])[C@@H:72]2[OH:73])=[O:59])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:57])[CH2:35][CH2:36][S:37][C@H:38]2[O:55][C@@H:54]([CH3:56])[C@@H:49]([OH:50])[C@@H:44]([OH:45])[C@@H:39]2[OH:40])=[O:26])[O:9][C@@H:10]([CH3:21])[C@@H:11]([OH:17])[C@@H:12]([OH:13])[C@@H:7]1[OH:6]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)NC(=O)CCS[C@H]2O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)C(=O)O)[C@H]1OC(C)=O
Agent: N#N
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H]1O[C@H](SCCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)NC(=O)CCS[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 82.6 %

Procedure:
A solution of 25 (500 mg) in methanol-water-triethylamine 5:4:1 (v/v/v, 5 ml) is kept for 3 hours at room temperature and worked-up in the same manner as for 5 to give the title compound (300 mg, 83%): [α]D27 +28.4±0.9° (c 1.0 H2O); NMR (D2O)δ: 4.48 (d, J1,2 =9.5 Hz, 1H, H-1), 4.46 (d, J1,2 =9.5 Hz, 2H, H-1), 4.17, 4.32 (q,q, α-CH), 3.22 (m, ε-CH2), 2.98 (m, SCH2), 2.69 (t, 1H), 2.61 (t, 2H) (SCH2CH2), 1.34-1.90 (m, C-CH2CH2CH2C), 1.25 (d, J=6.0 Hz, CH3 -6).
Reaction SMILES: CCN(CC)CC.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[CH:10]=[CH:9]1>[Pd].C(O)=O>[NH:8]1[C:16]2=[N:15][CH:14]=[CH:13][CH:12]=[C:11]2[CH2:10][CH2:9]1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: c1cnc2c(c1)CCN2
Temperature: 25 °C

Procedure:
98% Formic acid (37.5 mL, 0.97 mol) was added to a stirred and cooled (ice bath) neat Et3N (150 mL, 1.08 mol). A two-phase system, which was formed, was then added to a mixture of 7-azaindole (50.0 g, 0.424 mol), formic acid (750 mL), and 10% palladium on activated carbon (26.75 g, Degussa type), and stirred at 80° C. for 4 d. The mixture was cooled to r.t., the catalyst was filtered off and washed with formic acid (100 mL). The filtrate and washings were combined and concentrated in vacuum. The residual liquid was cooled (ice bath) and basified to pH 13 by slow addition of 50% aqueous NaOH (total of about 500 mL). Then, the mixture was refluxed for 2 h until TLC showed completion. Ice was added in amount sufficient to lower the temperature of the mixture to 20° C. The two-phase system was then extracted with AcOEt (5×500 mL). Combined extracts were washed with brine, dried MgSO4, and concentrated in vacuum. The residual brown solid was separated by means of SGC with AcOEt:MeOH as eluent to afford recovered 1 (12.57 g, 25%) and desired 2 (36.05 g, 71%). 1H NMR (400 MHz, CDCl3) δ 3.05 (t, J=8.4 Hz, 2H), 3.60 (t, J=8.4 Hz, 2H), 4.52 (bs, 1H), 6.49 (dd, J=7.0, 5.3 Hz, 1H), 7.23 (dq, J=7.0, 1.3 Hz, 1H), 7.81 (ddt, J=5.3, 1.3, 1.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]2[N:47]=[CH:46][CH:45]=[N:44]2)[C:35]=1[C:36](O)=[O:37].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:36]([C:35]4[C:39]([N:43]5[N:47]=[CH:46][CH:45]=[N:44]5)=[CH:40][CH:41]=[CH:42][C:34]=4[F:33])=[O:37])[CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1cnc(C)c(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(C)c(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(3,6-Dimethyl-pyrazin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 10) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C21H22FN7O, 407.45; m/z found 408.2 [M+H]+. 1H NMR (CD3OD): 7.96-7.23 (m, 6H), 4.50-4.44 (m, 1H), 4.31-4.19 (m, 2H), 4.11-3.77 (m, 3H), 3.62-3.42 (m, 1H), 2.86-2.77 (m, 1H), 2.40-2.36 (m, 3H), 2.31-2.05 (m, 2H), 2.04-1.92 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:19][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: CN(C[C@H](c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C[C@@H](N)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 89.3 %

Procedure:
To a solution of (S)-tert-butyl (2-(3-chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate (1.96 g, 4.72 mmol) in ethanol (15.75 mL) was added hydrazine hydrate (2.296 mL, 47.2 mmol). The reaction mixture was heated at 60° C. for 2 h. The reaction mixture was then filtered through Celite pad and the filtrate was concentrated. The residue was re-dissolved in ethanol and filtered through Celite® pad to remove extra white solid. NMR showed there was impurity in crude material. The crude product was filtered through a plug of silica, washed by DCM/EtOAc (2:1 ratio) and flashed with DCM/EtOAc (20% methanol, 0.5% NH3 in methanol) (1:1 ratio) to provide (s)-tert-butyl (2-amino-2-(3-chlorophenyl)ethyl)(methyl)carbamate (1.2 g, 89% yield). LCMS (m/z): 285.1 (MH+), 0.65 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (s, 1H) 7.26 (3H), 4.20 (br. s., 1H), 2.85-2.77 (m, 3H), 1.51-1.38 (m, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C:11]([O:12][CH3:13])=[N:10][C@H:9]([CH:14]([CH3:16])[CH3:15])[C:8]([O:17][CH3:18])=[N:7]1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C:11]([O:12][CH3:13])=[N:10][C@H:9]([CH:14]([CH3:16])[CH3:15])[C:8]([O:17][CH3:18])=[N:7]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCCCN=[N+]=[N-]
Reaction time: 8 h

Procedure:
1-Bromo-4-[(2R,5S)-3,6-dimethoxy-2-isopropyl-2,5-dihydro-5-pyrazinyl]-butane (3.81 g, 11.95 mmol) were dissolved in 40 ml DMF and 3.25 g NaN3 (50 mmol) and 0.1 g NBu4I were added. The solution was kept between 70° and 80° C. overnight and diluted with 50 ml water. After extraction with chloroform the organic layers were collected and dried (MgSO4). The residue was purified by flash chromatography (hexane/ethyl acetate 9/1).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Br:17])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28]>>[Cl-:18].[NH2:1][C:2]1[N:6]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[C:5]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Br:17])=[CH:10][C:4]=2[N+:3]=1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:28])([F:29])[F:30]
Reactant: Nc1nc2ccc(-c3ccccc3Br)cc2[nH]1
Reactant: FC(F)(F)c1ccccc1OCCl
Product: Nc1n(COc2ccccc2C(F)(F)F)c2ccc(-c3ccccc3Br)cc2[n+]1COc1ccccc1C(F)(F)F
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5-(2-bromophenyl)benzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-trifluoromethylphenyl chloromethyl ether, the title compound is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:11][C:10]=2[CH3:21])=[N:6][CH:7]=1.Cl.[Cl:23][C:24]1[CH:45]=[CH:44][C:27]([O:28][CH2:29][CH2:30][C:31]2[CH:43]=[CH:42][C:34]([CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:33][CH:32]=2)=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.CCN(CC)CC.CN(C=O)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][C:31]2[CH:43]=[CH:42][C:34]([CH2:35][N:36]3[CH2:37][CH2:38][N:39]([C:18](=[O:20])/[CH:17]=[CH:16]/[C:12]4[CH:11]=[C:10]([CH3:21])[C:9]([O:8][C:5]5[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=5)=[C:14]([CH3:15])[CH:13]=4)[CH2:40][CH2:41]3)=[CH:33][CH:32]=2)=[CH:44][CH:45]=1
Reactant: Clc1ccc(OCCc2ccc(CN3CCNCC3)cc2)cc1
Reactant: Cc1cc(/C=C/C(=O)O)cc(C)c1Oc1ccc(O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(/C=C/C(=O)N2CCN(Cc3ccc(CCOc4ccc(Cl)cc4)cc3)CC2)cc(C)c1Oc1ccc(O)cn1
Yield: 94.3 %

Procedure:
To a DMF (26 mL) solution of (E)-3-{4-[(5-hydroxypyridin-2-yl)oxy]-3,5-dimethylphenyl}prop-2-enoic acid (1.300 g) and 1-{4-[2-(4-chlorophenoxy)ethyl]benzyl}-piperazine hydrochloride (2.116 g) were added HOBT (0.070 g), WSC (1.310 g), and Et3N (1.905 mL) at room temperature, then the resultant mixture was stirred at room temperature over night. The mixture was poured into water, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 1/0 and then AcOEt/MeOH=4/1) to afford (E)-1-(4-{4-[2-(4-chlorophenoxy)ethyl]benzyl}piperazin-1-yl)-3-{4-[(5-hydroxypyridin-2-yl)oxy]-3,5-dimethylphenyl}prop-2-en-1-one as a pale yellow amorphous powder (2.57 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(OCC)(O[CH2:23][CH3:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([NH:4][C:5]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:23][CH3:24])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2nc3ccccc3nc12
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1c2ccccc2Nc2c(NC(C)=O)cccc21

Procedure:
Scheme 8 provides a synthetic route to a 1-acetamido-N-ethyl phenazine derivative (35). A 3-amino-catechol hydrochloride (30) is reacted with silver oxide and anhydrous sodium sulfate in ethyl acetate to give 3-amino-1,2-quinone (31), which is further reacted in situ with ortho phenylenediamine (32) to give 1-amino phenazine (33). The amino phenazine (33) is acetylated with acetic anhydride in acetic acid to give 1-acetamido phenazine (34). The resulting 1-acetamido phenazine is reacted with diethyl sulfate in the presence of potassium carbonate to give N-ethyl-1-acetamido-phenazine (35).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.I[CH2:42][C:43]([NH2:45])=[O:44]>C(#N)C.CN(C)C=O>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][N:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)[CH2:42][C:43]([NH2:45])=[O:44])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCNCCCCc2ccc(O)cc2)c1
Reactant: NC(=O)CI
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN(CCCCc2ccc(O)cc2)CC(N)=O)c1
Temperature: 25 °C

Procedure:
To a solution of 4-[4-[[2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]amino]butyl]phenol (15 mg in a mixture of 0.7 mL acetonitrile and 0.2 mL N,N-dimethylformamide) was added 0.015 mL of diisopropylethyl amine followed by 8 mg of iodoacetamide and the mixture stirred at room temperature. After 4.5 hours the crude reaction mixture was applied to a silica gel preparative TLC plate and eluted with (methylene chloride:methanol, 93:7). Isolation of the desired band was followed by extraction with methylene chloride:methanol (95:5) and further purification of this material by flash chromatography on silica gel (hexane:ethyl acetate, 2:5) to give the title compound (16 mg). m/e=470 (M+H)
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][CH:14]=3)[C:9]2=[O:23])=CC=1.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.O>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][CH:14]=2)[C:9](=[O:23])[NH:8][CH2:17]1
Reactant: COc1ccc(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CNC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.7 %

Procedure:
A solution of 2-(4-methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (1.2 g, 3.52 mmol) and cerium ammonium nitrate (5.78 g, 10.56 mmol) in acetonitrile (30 ml) and water (15 ml) was stirred at 0° C. for 1 hrs, after this time the reaction was warmed to room temperature and stirred for a further 15 h. The solvent was evaporated in vacuo and dichloromethane added. The organic phase was separated, washed with saturated aqueous ammonium chloride solution and brine, then dried and evaporated in vacuo. The crude residue was purified by flash column chromatography (15% ethyl acetate in dichloromethane) to afford the title compound (300 mg, 39%). HPLC retention time 3.71 min. Mass spectrum (ES+) m/z 221 (M+H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:8][CH:7]=[N:6]1)#[N:2].[OH-:24].[K+].OO>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]3[N:5]([CH2:4][CH2:3][C:1]([NH2:2])=[O:24])[N:6]=[CH:7][CH:8]=3)=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: N#CCCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Product: NC(=O)CCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Reaction of 3-dimethylamino-1-[4-(4-fluorophenoxy)phenyl]-propenone with 2-cyanoethylhydrazine as described above gave 1-(2-cyanoethyl)-5-[4-(4-fluorophenoxy)phenyl]pyrazole. Reaction of a solution of the nitrile with 10 mL of a 20% aqueous KOH solution and 4 mL of an aqueous 30% H2O2 solution at reflux gave 64 mg of the amide as a white solid, mp 118-120° C. 1H NMR (CDCl3): δ7.54 (d, 1H, J=1.8 Hz), 7.35 (d, 2H, J=8.7 Hz), 7.10-6.98 (m, 6H), 6.26 (d, 1H, J=1.8 Hz), 6.08 (br s, H), 5.30 (br s, 1H), 4.39 (t, 2H, J=6.6 Hz), 2.86 (t, 3H, J=6.6 Hz).
Reaction SMILES: P(=O)([O-])O[C:3](CC)(CC)[C:4]#[N:5].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[F:23].O>C1COCC1>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:3][C:4]#[N:5])=[CH:17][C:16]=1[F:23]
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Cl)c(F)c1
Temperature: 25 °C

Procedure:
Diethylcyanomethyl phosphonate (3.2 ml, 18.9 mmol) was taken up in dry THF (20 ml) at 0° C. under nitrogen, and stirred as a 60% oil dispersion of NaH (756 mg, 18.9 mmol) was added portionwise over ca. 10 min. The resulting grey suspension was then stirred at 0° C. for 1 h, before a solution of 4-chloro-3-fluoro benzaldehyde (Lancaster Synthesis) (3 g, 18.9 mmol) in 5 ml THF was added dropwise. The whole reaction was then allowed to warm to room temperature over 60 h. Water (5 ml) was added, and the mixture extracted with EtOAc (3×50 ml). The combined organics were were dried (MgSO4) and evaporated to a yellow oil which was purified by column chromatography using 5% EtOAc in pentane as eluant to provide the title product as a mixture of geometric isomers (2.4 g, 70%); 1HNMR (400 MHz, CDCl3) δ: 5.82 (d, 1H), 7.19 (d, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.42 (app.t, 1H); LRMS TS+ 199.1 (M+NH4+).