Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C:7]1=O)=[O:5])C.FC(F)(F)C([O-])=O.[CH2:28]([N+:30]([CH2:34][CH3:35])=[C:31]([NH2:33])[NH2:32])[CH3:29].[O-]CC.[Na+]>CCO.O>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C:6]2[C:4]([OH:5])=[N:32][C:31]([N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[N:33][C:7]=2[CH2:8]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC[N+](CC)=C(N)N
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1=O
Agent: CC[O-]
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)c1nc(O)c2c(n1)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Yield: 0 %

Procedure:
To a solution of 3-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.67 g, 2.3 mmol) in EtOH (10 mL) was added diethyl guanidinium trifluoroacetate (0.54 g, 2.3 mmol) and sodium ethoxide (21 wt % in EtOH, 2.3 mL). The reaction was heated at reflux for 16 h then cooled to room temperature (rt). The reaction mixture was diluted with H2O and extracted with CH2Cl2 (2×). The combined organic extracts were dried and concentrated. The resulting material was triturated with hexanes/Et2O (9:1) to give the title compound (0.334 mg, 43%) as a light brown solid. MS (ESI): mass calcd. for C17H28N4O3, 336.4; m/z found, 337.4 [M+H]+. 1H NMR (CDCl3): 4.34-4.25 (m, 2H), 3.62-3.46 (m, 6H), 2.66-2.58 (m, 2H), 1.88-1.77 (m, 2H), 1.50-1.36 (m, 9H), 1.21-1.14 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]2[C:23](Br)=[CH:22][CH:21]=[CH:20][N:19]2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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>[C:26]1([CH3:35])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:23]1[C:18]2[N:19]([CH:25]=[C:16]([C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1-c1cccn2cc([C@@H]3CCCN3C(=O)OCc3ccccc3)nc12
Yield: 96.8 %

Procedure:
Following procedures of example 14, (S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.250 g, 0.62 mmol), o-tolyl boronic acid (0.1101 g, 0.81 mmol), potassium carbonate (0.1292 g, 0.93 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0360 g, 0.03 mmol) were reacted to give crude (2S)-benzyl 2-(8-o-tolylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate. The crude material was adsorbed onto silica gel and purified by flash chromatography (4 g SiO2, 0-70% ethyl acetate in hexanes) to give the final product (0.247 g, 0.60 mmol, 74%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:20]=[C:16]([C:17](O)=[O:18])[C:15]([NH2:21])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:20]=[C:16]2[C:15](=[CH:14][CH:13]=1)[N:21]=[C:2]1[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]1[C:17]2=[O:18]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Clc1nc2ccccc2[nH]1
Product: O=c1c2cc(Cl)ccc2nc2[nH]c3ccccc3n12

Procedure:
2-Chlorobenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazole and 5-chloroanthranilic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3](COCC[Si](C)(C)C)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15][O:16][CH2:17][C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:15][O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[CH:7]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1c2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c2nn1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1n[nH]c2c(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)cc12

Procedure:
tert-Butyl 4-(((3-methyl-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (100 mg, 0.16 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 3 mL) for 4 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated and the compound purified by reverse phase HPLC to afford 24 mg (38%) as a clear oil. 1H-NMR (CD3OD, 500 MHz) δ 8.02 (s, 1H), 7.39-7.45 (m, 5H), 7.29-7.45 (m, 1H), 4.76 (s, 2H), 3.56 (s, 2H), 3.27-3.31 (m, 2H), 2.89-2.96 (m, 2H), 2.60 (s, 3H), 2.49-2.52 (m, 2H), 2.16-2.22 (m, 2H). Mass spec.: 404.14 (MH)+. Accurate mass spec.: m/z 404.1930 [MH]+, Δ=4.9 ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>>[CH3:1][S:2]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(N)cc1
Product: CS(=O)c1ccc(N)cc1

Procedure:
Following a similar procedure to that described in reference example 1, but starting from 4-methylthioaniline and using 1 equivalent of m-chloroperbenzoic acid, the title compound of the example was obtained as a white solid (80% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:4]([CH2:16][CH3:17])[CH:3]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([CH2:16][CH3:17])[CH:3]=1
Reactant: CCOC(=O)CNc1cc(Cl)c(Cl)cc1CC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(Cl)c(Cl)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of ethyl 2-(4,5-dichloro-2-ethylphenylamino)acetate (390 mg, 1.41 mmol) and LiOH.H2O (592 mg, 14.1 mmol) in THF (8 mL) and water (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in H2O and diluted with ethyl acetate. The mixture was acidified with aqueous HCl (10%) to adjust the pH to 3-4 and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product (300 mg, 85.75% yield) as a yellow solid. ESI-MS m/z: 246.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])=[CH:11][C:10]=1[C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>O1CCCC1>[C:25]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[C:20]([CH3:23])([CH3:24])[CH2:21][CH3:22])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(C)(C)c1ccc(Oc2ccncc2N)c(C(C)(C)CC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(Oc2ccncc2NC(=O)c2ccccc2)c(C(C)(C)CC)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3-Amino-4-(2,4-bis(1,1-dimethylpropyl)phenoxy)-pyridine (3.0 g, 9.2 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 10° C. Benzoyl chloride (1.3 g, 9.2 mmol) in tetrahydrofuran (10 mL) was added dropwise. Triethylamine (0.93 g, 9.2 mmol) in tetrahydrofuran (5 mL) was added and the mixture warmed to room temperature and stirred for 2 hours. The mixture was submitted to standard aqueous acidic workup. The crude solid obtained was recrystallized from acetonitrile to yield the title product as a white solid in 80% yield, m.p. 253° C. Mass spectral and NMR data were consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[CH3:7][C:8]1([CH3:16])[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9]1=O>>[C:1]([NH:5][N:6]=[C:9]1[C:8]([CH3:16])([CH3:7])[C:11](=[O:12])[C:10]1([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Reactant: CC(C)(C)NN
Product: CC(C)(C)NN=C1C(C)(C)C(=O)C1(C)C

Procedure:
2,2,4,4-Tetramethylcyclobutan-1,3-dione mono-t-butylhydrazone was prepared by refluxing an aqueous solution of t-butylhydrazine with an equimolar amount of 2,2,4,4-tetramethylcyclobutan-1,3-dione.
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[NH:3]1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1>>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:18][CH2:19]1)[C:7]([C:4]1[NH:3][C:2](=[O:1])[O:6][N:5]=1)=[O:9]
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1noc(=O)[nH]1
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1noc(=O)[nH]1

Procedure:
The title compound was prepared from commercially available 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) analogously to Example 15 step 3;
Reaction SMILES: O[CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23]>C(OCC)(=O)C.CCCCCC>[CH2:2]([C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c2c(c(C(O)c3ccccc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(Cc2ccccc2)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Yield: 74 %

Procedure:
Using N-(7-(1-hydroxy(phenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 355, the title compound was synthesized in the same manner as in Example 271. Yield: 74%. Melting point: 129-130° C. (ethyl acetate-hexane).
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[Cl:29][C:30]1[N:35]=[C:34]([Cl:36])[C:33]([CH2:37]I)=[CH:32][N:31]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:28])[CH:19]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:37][C:33]1[C:34]([Cl:36])=[N:35][C:30]([Cl:29])=[N:31][CH:32]=1
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (720 mg, 5.0 mmol) (Aldrich) in dry tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 2.0 mL, 5.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 4-methoxyphenylacetic acid methyl ester (900 mg, 5.0 mmol) (Aldrich) in tetrahydrofuran (3 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To this reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (722. 5 mg, 2.5 mmol) (from Example 1c supra) in tetrahydrofuran (3 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour, then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (50 mL), water (30 mL), and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester as a yellow oil. (Yield 620 mg, 72.7%).
Reaction SMILES: Cl[C:2]([F:27])([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:18]2[CH2:20][CH:19]2[CH3:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>C(O)C.[Pd]>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:18]2[CH2:20][CH:19]2[CH3:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N1CC1C
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N1CC1C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
A mixture of 2.5 g (0.0059 mol) of product of Example 81, 0.6 g (0.0059 mol) of triethylamine and 0.25 g of 5% Pd/C (50% water coated) in 100 ml of ethanol was hydrogenated (446 kPa, for 18 hours at 50° C. The mixture was then filtered through celite and concentrated in vacuo to remove the ethyl alcohol. The residue was poured into water, and extracted with diethyl ether. The ether extract was washed with water, then dried over MgSO4. The dry ether phase was then concentrated in vacuo to yield 2.00 g of a yellow solid. This solid was then recrystallized in hexane to yield 1.28 g (56%) of product as a tan solid; mp 61° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[CH3:29][NH2:30]>C(O)C.CN(C)C(=O)C>[CH3:29][NH:30][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[C:2]([CH3:1])[S:6][C:5]=2[CH:7]=1
Reactant: CN
Reactant: Cc1sc2cc(OCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: CNCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)c(C)sc2c1

Procedure:
In analogy to the method described in example 17.1, Methanesulfonic acid 2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl ester (example 50.2) was treated with methylamine in ethanol and N,N-dimethylacetamide to yield Methyl-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine as colorless oil, MS: 366 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)[C:7]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:6][CH:5]=1.C1COCC1.O.[OH-].[Li+].Cl>O>[C:10]1([C:8]2[C:7]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:22])=[O:2])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
5-Cyclohex-1-enyl-6-(2,2,2-trifluoroethoxy)nicotinic acid methylester (0.03 g, 95.2 μmol) was combined with THF (0.3 mL) and water (0.15 mL) to give a light yellow solution. Lithium hydroxide hydrate (7.99 mg, 190 μmol) was added under argon. The reaction mixture was stirred at room temperature overnight, poured into 2 mL 2 M HCl and extracted with i-propyl acetate (2×20 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give the title compound (30 mg, quant) as white solid that was used in the subsequent reactions without further purification; MS (ESI) 300.2 (M−H)−.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: FC(F)(F)c1nc2ncc(Cl)cc2n1OCc1ccccc1

Procedure:
1-Hydroxy-6-chloro-2 -(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine (5 grams), 10 milliliters of benzyl bromide, 20 grams of anhydrous potassium carbonate, and 100 milliliters of ethanol were mixed, heated to reflux, and refluxed for 1 hour. The reaction mixture was then filtered, evaporated under vacuum, and extracted with diethyl ether. The extract was filtered and evaporated under vacuum yielding a dark oil which on standing crystallized as the desired 1-benzyloxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine. It was recrystallized from a mixture of acetone and petroleum ether boiling at 60°-80°C., m.p., 107°-09°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:32]=[CH:31][C:18]2[NH:19][C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=3)=[N:21][C:17]=2[CH:16]=1>>[NH2:14][C:15]1[CH:32]=[CH:31][C:18]2[NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:27])=[CH:29][CH:30]=3)=[N:21][C:17]=2[CH:16]=1
Reactant: Nc1ccc2[nH]c(-c3ccc(C(=O)[O-])cc3)nc2c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: Nc1ccc2[nH]c(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc2c1

Procedure:
Compound 453 was prepared from 4-morpholinoaniline and 4-(5-amino-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C24H23N5O2: 414.19; found: 413.97.
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]1[C:12](=[O:13])[NH:11][CH2:10][CH2:9][N:8]1[C:14](=[O:38])[CH2:15][C@H:16]([NH:27]C(=O)OCC1C=CC=CC=1)[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CO.[Pd]>[NH2:27][C@H:16]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])[CH2:15][C:14]([N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C@H:7]1[CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:38]
Reactant: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Reaction time: 2 h
Yield: 70.7 %

Procedure:
65.7 g of benzyl(R)-4-[(R)-2-(t-butoxymethyl)-3-oxopiperazine-1-yl]-4-oxo-1-(2,4,5-trifluorophenyl)butane-2-ylcarbamate of the above Step 1 was dissolved in 409 mL of methanol; a solution in which 13.1 g of palladium/carbon was wetted with 92 ml of ethyl acetate was added; and then stirred for 2 hours under hydrogen pressure of 15 bar. The resulting reaction solution was filtered with diatomite, and then concentrated under reduced pressure to obtain 34.8 g of a title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].Cl[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:21]([CH:20]=[CH2:19])(=[O:23])=[O:22])[C:4]1=[O:17])#[N:13]
Reactant: O=S(=O)(Cl)CCCl
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: C=CS(=O)(=O)N[C@H]1CCN(Cc2cccc(C#N)c2)C1=O

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 2-chloroethanesulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography in a gradient of 10% EtOAc/CH2Cl2 to 40% EtOAc/CH2Cl2 to afford the title compound as a solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]([F:30])([F:29])[C:8]([N:10]1[CH2:28][CH2:27][C:13]2([C:18]3=[C:19]([CH3:22])[CH:20]=[CH:21][N:17]3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)[CH2:12][CH2:11]1)=[O:9].[OH-].[Na+].CN([CH:36]=[O:37])C>>[CH3:22][C:19]1[CH:20]=[C:21]([CH:36]=[O:37])[N:17]2[C:18]=1[C:13]1([CH2:27][CH2:28][N:10]([C:8](=[O:9])[C:7]([F:6])([F:29])[F:30])[CH2:11][CH2:12]1)[O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]2=1
Reactant: CN(C)C=O
Reactant: Cc1ccn2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)n2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Reaction time: 0.5 h
Yield: 24 %

Procedure:
POCl3 (38 μL, 0.41 mmol) was added dropwise at 0° C. under N2 to DMF (32 μL, 0.41 mmol). The reaction was stirred for 30 min at this temperature and a white solid formed, to which was slowly added a solution of 2,2,2-trifluoro-1-(3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)ethanone (95 mg, 0.27 mmol) in dry DMF (0.7 mL). The reaction stirred for 4 h, poured onto ice, 0.8 ml of 1M NaOH was added and the product was extracted with dichloromethane (3×5 mL). The organic phases were combined, washed with brine, dried, filtered and concentrated and the residue was purified by silica-gel column chromatography eluting with 5-40% EtOAc in hexanes to yield 3-methyl-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (25 mg, 24%). ESI-MS m/z calc. 378.1, found 379.3 (M+1)+; Retention time 1.83 minutes (3 min run).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:37])=[C:5]([C:28]([O:35]C)=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:32][O:31][C:30]1[C:3](=[O:2])[C:4]([CH3:37])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])[C:28](=[O:35])[C:29]=1[O:33][CH3:34]
Reactant: COc1c(C)c(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 1397.6 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyloxy)benzoyl]piperidine (0.021 g, 0.0415 mmol) was dissolved in a mixed solution of acetonitrile (6 ml) and water (2 ml) and after adding thereto CAN (0.057 g, 0.104 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.013 g, 0.580 mmol, 66%).