Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:33][C:34]1[C:39]([CH:40]([CH3:42])[CH3:41])=[CH:38][C:37](B(O)O)=[C:36]([O:46][CH3:47])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O.O>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:37]3[CH:38]=[C:39]([CH:40]([CH3:42])[CH3:41])[C:34]([F:33])=[CH:35][C:36]=3[O:46][CH3:47])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1cc(C(F)(F)F)ccc1I
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC1=O

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (60 mg; 0.103 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (27 mg; 0.129 mmol), palladium acetate (7 mg; 0.0103 mmol), and potassium carbonate (36 mg; 0.257 mmol) in 5:1 acetone/water (6 mL) was heated at reflux for 1 h. Acetone was removed in vacuo and the residue was diluted with H2O (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a clear glass. LCMS=624.2 (M+1)+. 1H NMR (benzene-d6, 500 MHz, 1:1 mixture of atropisomers): δ 7.60 (s, 1.5 H), 7.45 (s, 0.5 H), 7.31-7.25 (m, 3 H), 6.98-6.94 (m, 1 H), 6.87-6.82 (m, 1 H), 6.43-6.37 (m, 1 H), 4.54 (d, J=15.6 Hz, 0.5 H), 4.40-4.36 (m, 1 H), 4.47 (d, J=15.6 Hz, 0.5 H), 3.96 (d, J=15.5 Hz, 0.5 H), 3.80 (d, J=15.8 Hz, 0.5 H), 3.24-3.15 (m, 1 H), 3.02 (s, 3H), 2.62-2.58 (m, 0.5 H), 2.53-2.48 (m, 0.5 H), 2.12-2.07 (m, 0.5 H), 2.04-2.00 (m, 0.5 H) 1.22-1.11 (m, 6 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]([OH:11])=O)[CH:2]=1.[Cl:12][C:13]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20].ClCCl.CO.N>>[Cl:12][C:13]1[CH:26]=[C:25]([NH:27][C:9](=[O:11])[C:8]#[C:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20]
Reactant: O=C(O)C#Cc1cccnc1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2cccnc2)cc1Cl

Procedure:
Prepared analogously to Example 2.3.f. from pyridin-3-ylpropynoic acid and [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine. Yield: 0.42 g (66.4% of theory); melting point: 118° C.-120° C.; C20H22ClN3O2 (M=371.86); calc.: molecular ion peak (M+H)+: 372/374; found: molecular ion peak (M+H)+: 372/374; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][NH:12][C:13]3=[O:18])O1.Br[C:21]1[N:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[O:29])=[CH:23][CH:22]=1.NC1C=C(Br)C=CN=1.C1(C)C=CC=C(N=C=O)C=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]([NH:27][C:24]2[CH:25]=[N:26][C:21]([C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[CH2:11][NH:12][C:13]4=[O:18])=[CH:22][CH:23]=2)=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: CC1(C)OB(c2cccc3c2CNC3=O)OC1(C)C
Reactant: Cc1cccc(NC(=O)Nc2ccc(Br)nc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cccc(N=C=O)c1
Agent: Nc1cc(Br)ccn1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(-c3cccc4c3CNC4=O)nc2)c1
Temperature: 25 °C
Yield: 14.2 %

Procedure:
A solution of Example 54A (259 mg, 1 mmol) and N-(6-bromo-3-pyridinyl)-N′-(3-methylphenyl)urea (367 mg, 1.2 mmol) (prepared from 2-amino-4-bromopyridine and m-tolylisocyanate following the procedure of Example 1E) in toluene (6 mL) and ethanol (6 mL) was degassed with N2 then treated sequentially with a solution of Na2CO3 (509 mg, 4.8 mmol) in water (3 mL) and tetrakis(triphenylphosphine)palladium (0) (208 mg, 0.187 mmol) and stirred at reflux overnight. The resulting suspension was cooled to room temperature, diluted with diethyl ether, and filtered. The filter cake was washed with water, diethyl ether, dichloromethane, ethyl acetate, and methanol. The combined filtrates were concentrated to give 51 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 10.35 (s,1H), 9.58 (s,1H), 8.73 (s, 1H), 8.56 (s,1H), 8.06 (d, J=6 Hz, 1H), 7.56–7.81 (m, 4H), 7.3–7.46 (m, 2H), 7.20 (t, J=6 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 4.56 (s, 2H), 2.31 (s,3H); MS (ESI(+)) m/e 359 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:11]=[CH:10]3)[N:5]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[N:35]=[C:36]=[O:37]>>[C:23]([C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=2[Cl:27])=[O:37])[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]=[CH:10]3)[N:5]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Product: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)ccc21
Yield: 50.4 %

Procedure:
Using general method A, t-butyl 5-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (0.150 g, 0.422 mmol, 1.00 eq) and 2,3-dichlorophenyl isocyanate (0.0557 ml, 0.422 mmol, 1.00 eq). were combined to yield t-butyl 5-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (115.5 mg, 50% yield). 1H NMR (DMSO-d6): δ 9.25 (s, 1H), 8.73 (s, 1H), 8.53 (brs, 1H), 8.22-8.19 (m, 1H), 8.06-8.01 (m, 2H), 7.79-7.76 (m, 1H), 7.33-7.29 (m, 2H), 6.43 (s, 1H), 1.67 (s, 9H), 1.30 (s, 9H); MS (ESI) m/z: 543.0 (M+H+), 545.0 (M+2+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)([Cl:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:40]([Cl:42])=[O:41])[C:10]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C#N)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C#N)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Yield: 94 %

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole (1.25 g, 2.88 mmol, example 25) was dissolved in methylene chloride and diisopropylethylamine (2.41 mL, 13.8 mmol) was added. The mixture was cooled in an ice bath and phosgene (6.09 mL, 11.52 mmol, 20% in toluene) was added. The reaction mixture was stirred for 30 mm at ice temperature and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (1.35 g, 94%).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=1>C(NC(C)C)(C)C.[Cu](I)I>[CH:1]1([C:4]#[C:5][C:7]2[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: C#CC1CC1
Reactant: CCOC(=O)c1ccc(Br)cn1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#CC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Cyclopropylacetylene (73.7 μL), copper iodide (3.16 mg) and tetrakis (triphenylphosphine)palladium (9.59 mg) were added to a solution of ethyl 5-bromopyridine-2-carboxylate (95.5 mg) in diisopropylamine (2 mL) at room temperature, and the mixture was stirred at room temperature for 17 hours and five minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (19.4 mg).
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH3:10])=[C:7]([Br:11])[CH:6]=[C:5]([F:12])[C:3]=1[NH2:4].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[C:7]([Br:11])[CH:6]=[C:5]([F:12])[C:3]=1[NH:4][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(Br)cc(F)c(N)c1Br
Product: COc1c(Br)cc(F)c(NC(C)=O)c1Br
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Compound 8-5 (212.7 g, 0.711 mol) was added to acetic anhydride (200 mL) in one portion at 20° C. The reaction mixture was stirred for 30 minutes and then was filtered to get 8-6 (192 g, 79.2%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH:8]=[CH:9][CH:10]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:37]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2cccc(OCCO)c2)C(OCc2ccc3ccccc3c2)C1
Product: O=C(OCCOc1cccc(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2OCc2ccc3ccccc3c2)c1)c1ccccc1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating 2,2,2-trichloro-ethyl (3RS,4RS)-4-[3-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained 2,2,2-trichloroethyl (3RS,4RS)-4-[3-(2-benzoyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][NH2:11].Cl>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:11][CH3:10])=[CH:4][CH:3]=1
Reactant: CN
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
4-Bromobenzyl bromide (200 mg, 0.800 mmol) was added slowly to a 2 M solution (4 ml) of methanamine in tetrahydrofuran, and the solution was stirred at room temperature for 24 hr. The reaction solution was adjusted to pH 3 by the addition of 1 N hydrochloric acid and was then washed twice with diethyl ether. A saturated aqueous sodium hydrogencarbonate solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure to give 136.1 mg (yield 85%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=[C:11]2[O:19][C@H:20]3[CH2:47][N:23]([C:24](=[O:46])[C@H:25]([CH:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[NH:26][C:27](=[O:40])[O:28][C@:29]4([CH3:39])[CH2:38][CH2:37][CH2:36][C@H:30]4[CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][C:10]=12)[C@H:22]([C:48]([OH:50])=[O:49])[CH2:21]3)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH:41]1([C@H:25]2[C:24](=[O:46])[N:23]3[CH2:47][C@@H:20]([CH2:21][C@H:22]3[C:48]([OH:50])=[O:49])[O:19][C:11]3=[N:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]([OH:8])=[C:10]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]3[CH2:36][CH2:37][CH2:38][C@@:29]3([CH3:39])[O:28][C:27](=[O:40])[NH:26]2)[CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: C[C@@]12CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCc1ccccc1)O[C@@H]1C[C@@H](C(=O)O)N(C1)C(=O)[C@H](C1CCCC1)NC(=O)O2
Agent: [Pd]
Agent: C[C@@]12CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCc1ccccc1)O[C@@H]1C[C@@H](C(=O)O)N(C1)C(=O)[C@H](C1CCCC1)NC(=O)O2
Solvent: CCOC(C)=O
Product: C[C@@]12CCC[C@H]1CCCCCc1c(nc3ccccc3c1O)O[C@@H]1C[C@@H](C(=O)O)N(C1)C(=O)[C@H](C1CCCC1)NC(=O)O2
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of (3aR,7S,10S,12R,21E,24aS)-19-(benzyloxy)-7-cyclopentyl-3a-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxylic acid (synthesized as described in Example 1 with intermediates B7 and C3) (113 mg) in ethyl acetate (5 ml) was added 10% Pd/C (20 mg) and the mixture was stirred for 18 hours under hydrogen atmosphere. After exchanging the atmosphere for nitrogen, the reaction mixture was filtered and concentrated to give the desired product (93 mg). LRMS (ES+) M/Z (M+H)+ 594.7.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[N:10][CH:9]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Fc1ccc(Br)cc1-c1ccnnc1
Product: OB(O)c1ccc(F)c(-c2ccnnc2)c1

Procedure:
4-(5-Bromo-2-fluorophenyl)pyridazine (1.0 g, 3.95 mmol) was reacted with bis(neopentyl glycolato)diboron (982 mg, 4.35 mmol) using the method in Example 51 to give 4-fluoro-3-(pyridazin-4-yl)phenylboronic acid: m/z (ES+) 219 (M++H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14]>>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:14]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)CN1CCCC1=O

Procedure:
From 12.8 g. of ethyl 2-oxo-1-pyrrolidineacetate and 17.4 g. of 2-(diethylamino)ethylamine [J.A.C.S. 68, 2006 (1946)], following the procedure of Example 1, there is obtained N-[2-(diethylamino)ethyl]-2-oxo-1-pyrrolidineacetamide; b.p. 157° C./0.1 mm.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1cccc(C(=O)O)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cccc(CO)c1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a mixture of 2-fluoro-3-methoxybenzoic acid (14.5 g, 85.2 mmol) in dry ethyl ether (300 mL) at 0° C., LiAlH4 (9.3 g, 245 mmol) was added over a 20 min period. The resulting mixture was heated at 80° C. for 20 min and then stirred at room temperature for 1 h. The mixture was carefully quenched with 15% NaOH (10 mL) at 0° C., and water (100 mL) was added. The mixture was extracted with ethyl acetate (3×100 mL), and the combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the title compound (13.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([O:20][C:21]3[C:28]([CH3:29])=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[CH3:30])[C:13]3[N:18]([CH3:19])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Cl:38])C(=O)C1>C(Cl)Cl>[Cl:38][C:16]1[C:14]2[N:15]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:11]=[C:12]([O:20][C:21]3[C:22]([CH3:30])=[CH:23][C:24]([C:25]#[N:26])=[CH:27][C:28]=3[CH3:29])[C:13]=2[N:18]([CH3:19])[CH:17]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(C)c12
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c(Cl)cn(C)c12
Yield: 51.3 %

Procedure:
To a solution of 4-(2-(4-cyanophenylamino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (21.5 mg, 0.06 mmol) in CH2Cl2 (3 mL) was added NCS (7.3 mg, 0.06 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with Hexanes:Ethyl acetate (3:1), to give the product as a light yellow solid (13.2 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[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]([CH:25]=C)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[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]([CH:25]=[O:32])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Cl)c2F)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C=O)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.260 g, 0.584 mmol) and sodium periodate (0.375 g, 1.752 mmol) in THF (4 ml) and water (2 ml) was added osmium tetroxide (2.5 weight % in t-butanol) (0.147 ml, 0.012 mmol) and the reaction mixture was stirred at rt for 3 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.245 g, 0.548 mmol, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.45-7.56 (m, 1H), 7.27-7.44 (m, 1H), 6.91 (d, 1H), 4.52 (d, 2H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(N)c(C(=O)c2ccccc2)c1
Yield: 49.3 %

Procedure:
The procedure was in the same manner as described in example 15, except that the starting material was benzoic acid instead of p-chlorobenzoic acid and p-toluidine instead of 4-chloroaniline. The title compound was obtained as yellow needle crystal, and yield 49.3%, m.p. 64-66° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:23]=2[N:22]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:21]([CH3:20])=[N:22][C:23]=2[CH:29]=1)=[O:31]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Product: Cc1nc2cc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)ccc2[nH]1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-methyl-1H-benzoimidazole-5-carboxylic acid. MS: 418.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl.[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][N:38]([C:46]([O:48][CH2:49][CH:50]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:56]3[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[C@H:37]1[C:63]([OH:65])=O.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27][C:63]([C@H:37]2[CH2:36][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][N:38]2[C:46]([O:48][CH2:49][CH:50]2[C:62]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[C:56]3[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])=[O:65])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CI
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1)[C@H]1Cc2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-[4-(2-nitrophenyl)piperazinyl]-2-oxoethyl}(tert-butoxy)-carboxamide (1.4 g, 2.8 mmol) was treated with satd HCl in EtOAc as described in Preparation XVI. The resulting crude material was diluted with EtOAc and washed with satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. This sample (1.05 g, 2.50 mmol), was coupled to N-Fmoc-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.1 g, 2.7 mmol) (Peptech), by the procedure for Preparation XIX using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (Aldrich) (1.6 g, 5.5 mmol) and HOAT (370 mg, 2.7 mmol). The crude compound was obtained in a quantitative yield (2.2 g). MS (ESI, pos. ion) m/z: 770 (M+H), (ESI, neg. ion) m/z: 768 (M−H). Calc'd for C44H40ClN5O6: 769.27.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:33])[C@H:15]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=1[CH3:32])[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[Li].[Li+].[O-:36][O-]>C1COCC1.O>[CH2:18]([O:17][CH2:16][C@@H:15]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=1[CH3:32])[C:14]([OH:33])=[O:36])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: [O-][O-]
Agent: [Li+]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of 16D (11.2 g, 22.03 mmol) in THF (70 ml) and water (20 ml) at 0° C. was added a solution of lithium peroxide [prepared by adding hydrogen peroxide (11.25 ml, 110 mmol) to lithium hydroxide (1.387 g, 33.0 mmol) in water (20 ml)] dropwise. The mixture was stirred at 0° C. for 1 h, then quenched with sat. sodium sulfite, and organic solvent was removed under reduced pressure. The remaining solution was diluted by 50 ml of water and extracted with dichloromethane (2×20 ml). The aqueous layer was acidified using conc. HCl. The solution was then extracted with ethyl acetate (3×). The organic extracts was combined and washed with brine and dried over sodium sulfate. The solution was filtered, concentrated and dried in vacuo to give 16E (8 g, 22.91 mmol, 104% yield) as an oil. MS (ESI) (m/z): 347, 349.4 (M−H)+.