Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[CH3:20][Si:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.CO>COCCOC.O>[CH3:20][Si:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][C:11]#[N:12]
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccnc1CC#N
Temperature: -60 °C
Reaction time: 2 h
Yield: 4151.6 %

Procedure:
1.73 g (8.84 mmol) tosylmethylisocyanide were solved in 10 ml DME and cooled down to −60° C. At this temperature first 1.98 g potassium tert-butoxide was added then slowly a solution of 2.00 g (8.84 mmol) 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde in 5 ml DME. After 2 hours stirring at −60° C. the reaction was allowed to reach 0° C. and 5 ml methanol (123.60 mmol) was added to the solution. The reaction was stirred for further 24 hours at ambient temperature and for 2 hours at 40° C. Excess water was added and the solution was extracted 3 times with dichloromethane. The organic phase was dried over Na2SO4, after evaporation of the solvent under reduced pressure the raw material was purified by reverse phase column chromatography (water 0.1% TFA/acetonitrile=80/20 to yield 0.87 g (0.367 mol) of the SEM-protected imidazole-acetonitrile.
Reaction SMILES: [C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][C:3]([CH3:5])=[CH2:4].C(Cl)(Cl)[Cl:18]>C(OCC)C>[C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][C:3]([Cl:18])([CH3:5])[CH3:4]
Reactant: C=C(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(Cl)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
The isopropenyl carbonate from step 88a (7.5 g, 33.6 mmol) was dissolved in a mixture of ethyl ether (100 mL) and chloroform (100 mL). The mixture was cooled to 0° C. and then bubbled with HCl gas. After standing at room temperature for 16 hours the mixture was purged with nitrogen to remove the excess HCl, and the solvent was evaporated to give the title compound (8.0 g, 92%): 1H NMR (CDCl3, 300 MHz) δ 2.11 (s, 6H), 7.39-7.44 (m, 2H), 8.27-8.32 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=O)=[CH:25]2.N1CCCCC1>C(O)C>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=[C:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]1=[O:16])=[CH:25]2
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccccc5)cc43)cc2c1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
A mixture of 5-phenyl-2-oxindole (41 mg, 0.2 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (46 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 58 mg (68%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].[OH-].[Na+].[CH3:12][C:13]([CH3:18])=[CH:14][C:15](Cl)=[O:16]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15](=[O:16])[CH:14]=[C:13]([CH3:18])[CH3:12])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: CC(C)=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1ccc(Br)c(C)c1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
In accordance with Scheme 15, to the solution of 4-bromo-3-methyl-phenylamine (2 g, 1 eq.) in 5 mL of CH2Cl2 was added 10 mL of 2 M NaOH followed by dropwise addition of 3,3-dimethylacryloyl chloride (1.32 mL, 1.1 eq.) in 5 mL of CH2Cl2. The reaction was allowed to stir overnight and then partitioned between EtOAc and brine. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to afford 2.84 g (98.6%) of product Compound 53A as beige solid. Crude product was used for the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([NH:15]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].[ClH:23]>O1CCOCC1>[ClH:23].[NH2:15][C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:12])([F:13])[F:14])[CH2:3][CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCO)c1ccccc1C(F)(F)F

Procedure:
Of the compound from Example 79A, 150 mg (0.47 mmol) were stirred for 20 min in 3 ml of a 4N solution of hydrogen chloride in dioxane. The volatile components were removed on a rotary evaporator and the residue was dried in an HV. This gave 140 mg (87% purity) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH:19]([C:23]([NH:25][C:26]5[CH:27]=[C:28]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=5)[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[C:5]=2[CH:4]=[CH:3]1>CC(O)=O.[Pt](=O)=O>[O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH:19]([C:23]([NH:25][C:26]5[CH:27]=[C:28]([CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=5)[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[C:5]=2[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc5[nH]c(=O)ccc45)cc3C2)cc(C(F)(F)F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc5c4CCC(=O)N5)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 44.7 %

Procedure:
Platinum dioxide (1.9 mg, 0.0082 mmol) was added to a solution of tert-butyl [3-[({7-[(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbonyl)amino]-5-(trifluoromethyl)benzyl]carbamate (20 mg, 0.033 mmol) in AcOH (0.5 mL). The solution was allowed to stir under an atmosphere of hydrogen at rt. After 28 hr, an additional amount of platinum dioxide was added (1.9 mg, 0.0082 mmol) and the reaction continued to stir under an atmosphere of hydrogen for a total of 46 h. The reaction mixture was then filtered through Celite and the residue was purified by column chromatography to give tert-butyl [3-[({7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4tetrahydronaphthalen-2-yl}carbonyl)amino]-5-(trifluoromethyl)benzyl]carbamate (9.0 mg, 45%) as a white solid. LCMS: (FA) ES+ 611.4.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([C:31]#[C:32][CH2:33][O:34][Si](C(C)(C)C)(C)C)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:42])([CH3:43])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([C:31]#[C:32][CH2:33][OH:34])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(C#CCO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1cc(C#CCO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 59.7 %

Procedure:
To a solution of 167 mg (0.257 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-{6-[3-(tert-butyl-dimethyl-silanyloxy)-prop-1-ynyl]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide in 1.5 ml tetrahydrofuran a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added at room temperature. After stirring for 0.5 h water was added, followed by extraction with four portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 82 mg (60%) of the title compound as a brown viscous oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl>ClCCl.C(Cl)(Cl)Cl>[C:1]([NH:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:3])[CH3:2]
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
Acetyl chloride (410 mg, 5.2 mmol) and triethylamine (620 mg, 6.2 mmol) were added to a solution of 3-aminoquinoline (710 mg, 4.9 mmol) in dichloromethane (50 ml) and the mixture was stirred at room temperature for 18 h. Chloroform (100 ml) was added, the mixture acidified with 1N hydrochloric acid (50 ml) and the phases separated. The aqueous phase was basified with 1N sodium hydroxide solution and extracted with chloroform/IPA (85:15, 175 ml). The organic extract was washed with water, brine, dried and reduced to afford 3-acetamidoquinoline (780 mg, 84%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])O[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[N:21]([OH:22])[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NO
Reactant: CCCCCCCCCCc1c(C)oc(C)cc1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCc1c(C)n(O)c(C)cc1=O
Temperature: 25 °C

Procedure:
A mixture of 21 (200 mg, 0.75 mmol), hydroxylamine hydrochloride (1.05 g, 15.2 mmol), sodium acetate (1.24 g, 15.2 mmol), water (1 mL), and ethanol (2 mL) was heated at reflux for 3 days. After the reaction mixture was cooled to room temperature, the crude was concentrated under diminished pressure to afford a yellow oil. The residue was purified by chromatography on a silica gel column. Elution with 5:1 chloroform/methanol gave 3-decyl-1-hydroxy-2,6-dimethylpyridin-4(1H)-one (CPD-7) as a light yellow oil: yield 0.08 g (40%); silica gel TLC Rf 0.4 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3, 400 MHz) δ 0.84-0.88 (m, 3H), 1.24-1.44 (m, 16H), 2.27 (s, 3H), 2.48 (s, 3H), 2.57-2.61 (m, 2H) and 6.65 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13].N([O-])=O.[Na+].[ClH:21]>Cl[Cu]>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:21])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:16]
Reactant: Cl
Reactant: COC(=O)Cc1ccc(N)cc1C(=O)OC
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)Cc1ccc(Cl)cc1C(=O)OC

Procedure:
5-amino-2-methoxycarbonylmethyl-benzoic acid methyl ester (5 g, 22.4 mmol) was dissolved in hydrochloric acid (50 mL). To the solution was added dropwise aq.NaNO2 (1.7 g, 24.6 mmol) at below 5° C. After addition completed, the color became maroon. Then CuCl (2.4 g, 24.6 mmol) solution was added to the reaction mixture. The reaction mixture was reacted at below 5° C. for 1 hour. The reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2.3 g of 5-chloro-2-methoxycarbonylmethyl-benzoic acid methyl ester (18E).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([OH:19])=[C:8]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][C:12]([C:11]2[O:19][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:21])([F:20])[F:1])=[CH:9][C:8]=3[N:10]=2)=[CH:13][CH:14]=1
Reactant: O=C(Nc1cc(OC(F)(F)F)ccc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc2oc(-c3ccncc3)nc2c1
Reaction time: 1 h

Procedure:
To a mixture of 1.96 g of N-[5-(trifluoromethoxy)-2-hydroxyphenyl]isonicotinamide, 35 ml of tetrahydrofuran and 1.73 g of triphenylphosphine, a mixture of 1.26 g of diethyl azodicarboxylate and 5 ml of THF was added dropwise at room temperature. The resultant mixture was stirred at room temperature for two hours. To the mixture, 1.73 g of triphenylphosphine and 3.15 g of 40% toluene solution of diethyl azodicarboxylate were added and stirred for one hour. Furthermore, to the mixture, 0.58 g of triphenylphosphine and 1.05 g of 40% toluene solution of diethyl azodicarboxylate were added and stirred for one hour. The mixture solution was poured into water, followed by extraction with ethyl acetate. The combined organic layers were washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. The reaction mixture was concentrated. The residue was subjected to silica gel column chromatography to give 2-(pyridin-4-yl)-5-(trifluoromethoxy)benzoxazole (hereinafter, referred to as “active compound 12”).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][C:29]1[CH:30]=[C:31]([NH:44][C:45]2[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][N:46]=2)[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O1CCOCC1>[OH:21][C:8]1([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:33]3[CH:32]=[C:31]([NH:44][C:45]4[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][N:46]=4)[CH:30]=[C:29]([CH3:28])[CH:34]=3)[CH:3]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cncc(Br)c2)CC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Temperature: 100 °C

Procedure:
Dioxane (2.70 mL), tert-butyl 4-(5-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (207 mg, 0.580 mmol), and sodium carbonate (2 M, 791 μL, 1.58 mmol) was added to N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (200 mg, 0.527 mmol) and purged and flushed with Ar(g) (3×). PdCl2(dppf)-dichloromethane adduct (21.5 mg, 0.026 mmol) was added to the reaction mixture and heated to 100° C. for 8 hours. The reaction mixture was cooled to room temperature, filtered through CELITE, washed with dichloromethane and extracted with water. The organic layer was dried over sodium sulfate, and was concentrated under reduced pressure. The residue was purified by silica gel chromatography (acetone/hexanes) to yield tert-butyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperidine-1-carboxylate. MS APCI calc'd for C27H31F3N5O3 [M+H]+ 530. found 530.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[Br:13]Br>CO>[Br:13][CH2:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: CC(=O)CCc1ccc(Br)cc1
Reactant: BrBr
Solvent: CO
Product: O=C(CBr)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a solution of 4-(4-bromophenyl)-2-butanone (1 mmol) in methanol (8 mL) stirred at room temperature, a solution of bromine (160 mg, 51.6 μL, 1 mmol) in methanol (1 mL) was added in one portion. The orange reaction mixture was then stirred at room temperature for 2 b, and, after the starting material had been consumed (TLC monitoring, hexanes-ethyl acetate 4:1 v/v), the reaction was quenched by adding a 0.3 M sodium thiosulfate solution (618 μL), and diluted with ethyl acetate (15 mL). The resulting mixture was washed with water (15 mL), the organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue that was chromatographed on a silica gel column using hexanes-ethyl acetate (15:1 v/v) as mobile phase to give 1-bromo-4-(4-bromophenyl)-2-butanone as a white solid (193 mg, 63%): mp 63-64° C., Rf=0.42 (hexanes-ethyl acetate 4:1 v/v); 1H NMR (400 MHz, CDCl3): δ 2.89 (t, J=6.8 Hz, 2H), 2.96 (t, J=6.8 Hz, 2H), 3.84 (s, 2H), 7.07 (d, J=8 Hz, 2H), 7.41 (d, J=8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 29.3, 34.3, 41.2, 120.2, 130.2, 131.7, 139.4, 201.0; HRMS (EI) Calcd. for C10H10Br2O: 303.9093 (M+). Found: 303.9090.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)[CH3:2].C([NH:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[O:40])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.NCCN1C(=O)/C(=C/C2C=CC=CC=2)/SC1=O>>[NH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])/[C:37](=[CH:7]/[C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)/[S:36][C:35]1=[O:40]
Reactant: CCOc1cccc(C=O)c1
Reactant: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Solvent: C1CCNCC1
Product: CCOc1cccc(/C=C2\SC(=O)N(CCN)C2=O)c1

Procedure:
The title compound 30b was prepared from 3-ethoxybenzaldehyde (87 μL, 0.62 mmol) and compound 29 (250 mg, 0.62 mmol) and piperidine (7.0 μL, 0.062 mmol) in a manner similar to that described for 30a in 20.4% (50 mg) yield as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]([C:16](=[O:37])[CH2:17][CH2:18][CH2:19][C:20]2[N:25]=[C:24]3[N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][CH2:29][C:23]3=[CH:22][CH:21]=2)[CH2:7][CH2:6]1.Cl.O1CCOCC1.[OH-].[Na+].Cl>>[NH:26]1[C:24]2=[N:25][C:20]([CH2:19][CH2:18][CH2:17][C:16]([N:8]3[CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:6][CH2:7]3)=[O:37])=[CH:21][CH:22]=[C:23]2[CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)CC1CCN(C(=O)CCCc2ccc3c(n2)N(C(=O)OC(C)(C)C)CCC3)Cc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC1CCN(C(=O)CCCc2ccc3c(n2)NCCC3)Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To methyl-2-[2-(4-{1-[(tert-butyl)oxycarbonyl]-1,2,3,4-tetrahydropyridino[2,3-b]pyridin-7-yl}butanoyl)-1H,3H,4H,5H-benzo[e]azepin-5-yl]acetate was added 4.0M HCl/dioxane (4 mL) and the resulting mixture was stirred for 18 hrs at room temperature, concentrated by rotary evaporation, diluted in MeOH followed by the addition of 1N NaOH (5 eq). The mixture was stirred at room temperature for 48 hrs., acidified with 1N HCl, concentrated by rotary evaporation and extracted with dichloromethane. The organic solvent was concentrated concentrated in vacuo to afford the desired product. EI-MS m/z 408 (M+H)+. 1H-NMR (400MHz, CDCl3): δ7.3-7.1 (m, 4H), 6.35 (m, 2H), 4.75 (d, J=15.1, 1H), 4.55 (m, 2H), 3.8 (m, 1H), 3.5 (m, 5H), 2.4 (m, 3H), 2.15 (m,2H), 2.0 (m,3H), 1.9 (m, 3H), 1.7 (m, 1H).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:38][C:39]3[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[C:42]([NH2:49])=[C:41]([Cl:50])[CH:40]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]([O:36]C)=[O:35])[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1.C(O)=O>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:38][C:39]3[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[C:42]([NH2:49])=[C:41]([Cl:50])[CH:40]=3)[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]([OH:36])=[O:35])[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.9 mg (0.12 mmol) LiOH in 1 mL water was added to a solution of 60 mg (0.08 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 3 mL THF and the reaction mixture was stirred overnight at RT. The solvent was eliminated in the nitrogen stream, the residue was taken up in 1 mL water, formic acid was added until an acidic reaction was obtained and the mixture was exhaustively extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated down i. vac. The residue was taken up in a little water and acetonitrile and freeze-dried.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:34])[C@H:7]([NH:18][C@H:19]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][CH2:9][O:10][Si](C(C)(C)C)(C)C)([CH3:4])[CH3:3]>C(O)(=O)C>[CH3:1][C:2]([O:5][C:6](=[O:34])[C@H:7]([NH:18][C@H:19]([C:24]([NH:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][CH2:9][OH:10])([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H](N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Solvent: CC(=O)O
Product: CC(C)C[C@H](N[C@H](CCO)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1

Procedure:
8.8 g of 2-(R)-[[3-methyl-1-(S)-[(benzylamino)carbonyl]butyl]amino]-4-[((1,1-dimethylethyl)dimethylsilyl)oxy]-butanoic acid-1,1-dimethylethyl ester, prepared as in Example M, in 300 mL acetic acid was stirred for 24 h at 45° C. and the solvent was removed by evaporation. The residue was dissolved in 300 mL ethyl acetate, washed with 3×100 mL sodium bicarbonate, dried (MgSO4), filtered, and the solvents were removed by evaporation. The residue was purified by silica chromatography using methylene chloride:acetone (2:1) as eluent to give the title compound; 5.9 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]1([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:22][CH2:23]2)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNC2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.0 g (16.561 mmol) of 4-methoxy-2-nitrobenzaldehyde, 3.2 g (16.817 mmol) of 1-phenylmethyl-4-piperidinamine and 30 mL of methanol was stirred for 2 hours at ambient temperature. Then 681 mg (18.0 mmol) of sodium borohydride was added and stirring was continued for one hour at ambient temperature. The mixture was stirred into 500 mL of ice water and carefully acidified with 10% hydrochloric acid. The solution obtained was washed twice with 50 mL of tert-butylmethylether, then made alkaline with 20% sodium hydroxide solution and extracted exhaustively with tert-butylmethylether. The final extracts obtained were combined, washed twice with 20 mL of water, dried over magnesium sulfate and evaporated down in vacuo. The colorless oil remaining was used in the next step without any further purification. Yield: 3.2 g (54% of theoretical). IR (KBr): no C═O; MS: M+=355.