Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][Si:7]([CH3:10])(Cl)Cl>C(OCC)C>[C:1]([O:4][Si:7]([O:4][C:1](=[O:3])[CH3:2])([CH3:10])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C[Si](C)(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)O[Si](C)(C)OC(C)=O
Yield: 69.2 %

Procedure:
To a slurry of sodium acetate (8.2 g, 100 mmol, 2.0 equiv.) in anhydrous diethyl ether (40 mL) was slowly added a solution of dimethyldichloro silane 11A (6.45 g, 50 mmol, 1.0 equiv.) in anhydrous diethyl ether (10 mL). After addition was completed, the mixture was heated at reflux for 2 hours, and then filtered under N2. The filtrate was concentrated under vacuum at 40° C. to give diacetate 11B as a colorless oil (6.1 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]Cl>>[CH3:9][O:10][CH2:11][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: COCCl
Product: COCOc1cccc(Br)c1
Yield: 107.9 %

Procedure:
In a manner similar to that of Example 7(a), by reaction of 100.00 g (577.9 mmol) of 3-bromophenol with 48.28 g (635.8 mmol) of chloromethyl methyl ether, 135.32 g (100%) of the expected product are obtained in the form of a pale beige oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C(C)=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][S:22]([CH2:21][CH2:20][CH2:19][Cl:18])(=[O:24])=[O:23])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1cc(N)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cc(NS(=O)(=O)CCCCl)cc(OC)c1
Yield: 30.1 %

Procedure:
3,5-Dimethoxyaniline (34.62 g, 0.226 mol) in xylene (500 mL) containing suspended sodium carbonate (12.0 g, 0.113 mol) was treated with 3-chloropropane sulfonyl chloride (40.0 g, 0.226 mol) added dropwise with stirring. Stirring was continued for twenty-four hours and the solvent was stripped to provide a black partially crystalline gum. Filtration through dry-column silica gel combined with crystallization from ethyl acetate/hexane provided N-(3,5-dimethoxyphenyl)-3-chloro-1-propanesulfonamide (20 g), m.p. 68°-71° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=1)=[N+:2]=[N-:3].[CH2:19]([Sn:23]([C:32]#[C:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].C1(C)C=CC=CC=1>>[F:18][C:15]([F:16])([F:17])[C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=1)[CH2:4][N:1]1[C:33]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:32]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[N:3]=[N:2]1
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCCC[Sn](C#CN1CCOCC1)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1
Temperature: 100 °C
Yield: 66 %

Procedure:
Add 1-azidomethyl-3,5-bis-trifluoromethyl-benzene (1.21 g, 4.5 mmol) to a solution of 4-tributylstannanylethynyl-morpholine in toluene (5 mL) (1.20 g, 3.0 mmol). See Berger, D., et al., Helv. Chim. Acta (1996) 79(I): 179-91. Flush with N2, seal in reaction vessel, and heat at 100° C. overnight. Concentrate, dissolve residue in CHCl3, dry over MgSO4, concentrate. Purify by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford the title compound (710 mg, 66%); MS(IS) 669 (M+1); TLC: Rf=0.53 (25% EtOAc/hexanes).
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16].CI>COCCOC>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: CC[Mg]Br
Solvent: CI
Solvent: COCCOC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 60 ml of a 1,2-dimethoxy ethane (chain ether solvent) solution containing 0.088 mol of suspended ethyl magnesium bromide was charged to the reaction vessel. Meanwhile, 0.081 mol of bromopentafluorobenzene was charged to the dropping funnel. Further, 0.5 g of methyl iodide was charged to the reaction vessel through a micro-syringe, and the reaction solution was stirred for 10 minutes at room temperature. Then, bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 45 minutes at room temperature, and the reaction solution was stirred for 4 hours at room temperature. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a colorless 1,2-dimethoxy ethane solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 98.5 mol % based on bromopentafluorobenzene.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([CH:40]([OH:43])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:45].O1CCOCC1>O1CCOCC1>[ClH:45].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([CH:40]([OH:43])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCC(O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C

Procedure:
To 1 mL of a 1,4-dioxane solution containing 165 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-hydroxypropyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature. The solvent was removed under reduced pressure to give 24 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-(1-hydroxypropyl)-7-methoxyquinolin-2(1H)-one hydrochloride as a brown solid.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[C:25]([N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)(=[S:27])[NH2:26]>CCO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:26]=[C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:27][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Solvent: CCO
Product: CC(C)c1nnc2ccc(-c3sc(N4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Yield: 9.9 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.61 g, 1.5 mmol; Preparation #A.2) and tert-butyl 4-carbamothioylpiperazine-1-carboxylate (Beta Pharma Inc, 0.341 g, 1.39 mmol) in EtOH (3 mL) was heated to reflux overnight. After cooling to ambient temperature, the crude mixture was partitioned between DCM and 1N aqueous HCl. The aqueous layer was basified with saturated aqueous Na2CO3 and extracted with DCM. The organics were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using DCM/MeOH (linear gradient, 100:0 to 90:10) to give the title compound (0.061 g, 10%): LC/MS (Table 1, Method a) Rt=2.31 min; MS m/z: 442.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl[C:20]([C:22]1([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:21]>ClCCl>[OH:12][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][C:20]([C:22]1([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:21]
Reactant: CC1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)C2(C)CCCN2C(=O)OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a stirred solution of methyl 3-amino-2-hydroxybenzoate (0.576 g, 3.45 mmol) and pyridine (0.546 g, 6.9 mmol) in anhydrous dichloromethane (20 mL) was added drop wise a solution of benzyl 2-(chlorocarbonyl)-2-methylpyrrolidine-1-carboxylate (1.07 g, 3.8 mmol) in anhydrous dichloromethane (5 mL). After the addition, the mixture was stirred at room temperature overnight. Removed the solvents and purified by silica gel chromatography (petroleum ether/ethyl acetate=100:1 to 25:1) to obtain a yellow oil of benzyl 2-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)-2-methylpyrrolidine-1-carboxylate (1 g, yield 66%). 1H-NMR (400 MHz, DMSO-d6): δ 1.53-1.58 (m, 3H), 1.88-1.91 (m, 3H), 1.28 (brs, 1H), 3.53-3.65 (m, 2H), 3.92 (s, 3H), 5.02-5.15 (m, 2H), 6.92-6.96 (m, 1H), 7.16-7.34 (m, 5H), 7.55-7.57 (d, J=7.8 Hz, 1H), 7.88-8.12 (m, 1H), 8.72-8.89 (d, 1H), 10.82 (s, 1H); LC-MS (ESI) m/z: 413 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a mixture of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (389 mg) and 4-hydroxymethyl-1-(pyridin-4-yl)piperidine (300 mg) in tetrahydrofuran (15 ml) and methylene chloride (5 ml) were added triphenylphosphine (450 mg) and diisopropyl azodicarboxylate (0.34 ml) and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:acetone=3:2-1:1, 1% triethylamine) and dried under reduced pressure to give the title compound (500 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH2:6][NH2:7].CO.Cl>O>[NH:2]=[C:3]([NH:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:8]([OH:10])=[O:9])[NH2:2])[CH2:4][CH:5]=[CH2:6]
Reactant: NCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Solvent: CO
Product: C=CCC(=N)NCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
L-Ornithine HCl (1.68 g, 10 mmol) and cupric acetate (0.5 g, 10 mmol) were dissolved in water (20 ml) and stirred for 10 minutes at room temperature. The solution was then filtered to remove minor impurities and cooled to 0° C., and the pH was adjusted to 9.5 by addition of cold 10% NaOH. 3-Butenyl imidate (15 mmol), prepared separately from the corresponding nitrile, methanol and gaseous HCl by the method described in Scannell, J. P., J. Antibiot. 25, 179-184 (1972) was then added, and the mixture was allowed to stir at pH 9.0-9.5 for 1 hour at 0° C. and for 2 hours at room temperature. The pH was then adjusted to 7.4 with cold dilute HCl, and the mixture was stirred at room temperature overnight. Hydrogen sulfide gas was bubbled through the solution, and the resulting copper sulfide precipitate was removed by filtration through charcoal. The filtrate was passed through Chelex to remove any residual Cu2+, and the clear solution was evaporated to dryness by rotary evaporation under reduced pressure. The residue was washed with ethyl acetate, and the product was crystallized from ethanol to give pure N5 -(1-imino-3-butenyl)-L-ornithine, which may be referred to as L-VNIO--m.p. 162° C. (dec); H NMR(D2O) ; δ1.65-2.1 (m, 4H), 3.3 (d, 2H), 3.4 (t, 2H), 3.8 (t, 1H), 5.4 (m, 2H), and 5.95 (m, 1H); 13C NMR (D2O): δ25.43, 30.35, 39.37, 44.28, 56.93, 124.16, 131.55, 168.72, and 176.98; FABMS (fast atom bombardment mass spectrometry): m/e 200 (M+H). Examples below establish L-VNIO as the first neuronal isoform selective, mechanism-based amino acid inactivator of NOS.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13](CCNC1C=CC=CN=1)[C:12]2=O)=[O:8].[OH-:40].[Na+]>CO>[CH2:14]1[C:15]2[C:11](=[CH:10][C:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:28][C:29]([O:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[C:3]([OH:2])=[O:39])=[O:8])=[CH:17][CH:16]=2)[CH2:12][NH:13]1
Reactant: [OH-]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2)NC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@@H](CNC(=O)c1ccc2c(c1)CNC2)C(=O)O)OC(=O)c1ccccc1

Procedure:
A methanol solution (25 mL) of 5-2 (328 mg, 0.61 mmol) and 1N NaOH (5 mL, 5 mmol) was stirred under ambient conditions overnight. The reaction was concentrated to dryness and the residue dissolved in H2O and the solution acidified with 6 N HCl to provide 5-3 as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6](O)=O.C1(C)C=CC(S([NH2:22])(=O)=O)=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]#[N:22])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(C(=O)O)ccc1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc(C#N)ccc1C
Temperature: 200 °C
Yield: 84.1 %

Procedure:
A mixture of 49 grams (295 millimoles) of 3-methoxy-4-methylbenzoic acid, 53.9 grams (315 millimoles) of p-toluene-sulfonamide, and 129 grams (619 millimoles) of phosphorus pentachloride was prepared and then heated at 200° C. while stirring. Phosphorus oxychloride was distilled at 106°-112° C.; and the mixture was further heated at 200° C. while stirring until no distillated came out. To the reaction mixture was added while stirring and cooling with ice 120 milliliters of pyridine in small portions and further 550 milliliters of water. Crystals precipitated were separated by filtration, suspended in 200 milliliters of a 5% aqueous sodium hydroxide solution, and then stirred at room temperature for 30 minutes. These crystals were separated by filtration and the crude product thus obtained was purified by steam distillation to obtain 36.5 grams of 3-methoxy-4-methylcyano-benzene (yield, 84%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[OH-].[Na+]>O.C(O)C>[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:2][OH:3])=[CH:7][CH:6]=1
Reactant: NO
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=NO)cc1
Yield: 68.7 %

Procedure:
Hydroxylamine hydrochloride (41.7 g) in 70 ml of water was added to a solution of 36.1 g of 4-methylbenzaldehyde in 180 ml of absolute ethanol. A solution of 18 g of sodium hydroxide in 36 ml of water was added in portions during 5 to 10 minutes. The reaction mixture was then heated to boiling and filtered hot, and the filtrate was cooled in a dry ice-acetone bath. Water was added to the cooled filtrate until solid product precipitated. The solid was separated by filtration, air-dried overnight, and recrystallized from hexane to give 27.9 g of 4-methylbenzaldoxime, m.p. 73°-77°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[O:19]1[C:23]2[CH:24]=[CH:25][C:26](B(O)O)=[CH:27][C:22]=2[O:21][CH2:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:2]3[CH:3]=[C:4]([N:8]4[CH2:16][CH:15]5[CH2:17][N:11]6[CH2:12][CH:13]([CH2:18][CH:9]4[CH2:10]6)[CH2:14]5)[CH:5]=[N:6][CH:7]=3)=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: c1cc2c(cc1-c1cncc(N3CC4CC5CC3CN(C5)C4)c1)OCO2

Procedure:
The title compound was prepared from the product of Example 65A and 1,3-benzodioxol-5-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 350.0 (M+H)+, retention time 1.37 minutes.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[C:18]([F:21])([F:20])[F:19].[OH-].[Li+]>C1COCC1.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:18]([F:20])([F:19])[F:21]
Reactant: COC(=O)c1ccc(N2CCCCC2C)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl 4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)benzoate obtained in step 2 (6.6 g, 21.9 mmol) in THF (50 mL) and water (5 mL) was added lithium hydroxide (1.84 g, 43.8 mmol). The resulting mixture was stirred at RT for 12 h. Solvents were removed under vacuum and the resulting mass was diluted with water. The aqueous layer was washed with DCM (2×50 mL) and was acidified with conc HCl (pH=4). It was extracted with EtOAc (2×100 mL). The EtOAc layer was washed with brine and dried over sodium sulfate, affording the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 13.30 (bs, 1H), 8.15-8.19 (m, 2H), 7.67-7.70 (d, 1H), 3.08 (m, 1H), 2.86-2.89 (m, 1H), 2.49-2.50 (m, 1H), 1.89-1.90 (m, 2H), 1.74-1.76 (m, 2H), 1.43-1.46 (m, 1H), 1.40-1.41 (m, 1H), 0.77 (d, 3H). LC/MS (Method A): 288.1 (M+H)+. HPLC (Method B) Rt 3.71 min (Purity: 98.3%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:28])[NH:24][N+]([O-])=O)=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].CO.Cl>[Pd].O>[NH2:1][C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:24])[NH2:28])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: C[C@@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 4 h
Yield: 78.2 %

Procedure:
2.3 Grams (3.25 m moles) of Z-D-Ala-Phe-Arg(NO2)-CHA was suspended in a mixed solvent of 113 ml of MeOH, 35 ml of H2O and 2.1 ml of 1N-HCl. To this suspension was added 1 g of palladium black and reduced by hydrogenation at 30° C. for 4 hours. After the hydrogenation was completed the catalyst was removed by filtration, further the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by using a gel filtration column of TOYOPEARL HW 40F with MeOH as the developing solvent to obtain 1.5 g (78.2%) of H-D-Ala-Phe-Arg-CHA.2HCl.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([CH2:12][C:13](=[N:30]C(=O)OC(C)(C)C)[NH:14][C:15](=[O:29])[CH2:16][C:17](=[N:26][O:27][CH3:28])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:7][C:6]=1[Cl:38])(=[O:3])[CH3:2].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>ClCCl>[C:1]([NH:4][C:5]1[C:6]([Cl:38])=[CH:7][C:8]([CH2:12][C:13](=[N:14][C:15](=[O:29])[CH2:16][C:17](=[N:26][O:27][CH3:28])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[NH2:30])=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: CON=C(CC(=O)NC(Cc1cc(Cl)c(NC(C)=O)c(Cl)c1)=NC(=O)OC(C)(C)C)c1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON=C(CC(=O)N=C(N)Cc1cc(Cl)c(NC(C)=O)c(Cl)c1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 2-(4-acetamido-3,5-dichlorophenyl)-1-(3-(methoxyimino)-3-(4-methoxyphenyl)-propanamido)ethylidenecarbamate (12 mg) in dichloromethane (0.10 mL) was added TFA (0.10 mL), and the resulting mixture was stirred at room temperature for 12 h. The solvents were removed in vacuo to give the title compound as its TFA salt (10 mg). Retention time: 1.75 min (method A). MS (ESI) (M+H)+ 482.19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:15]#[N:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:24][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C#N)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)CCC(C#N)(Cc1ccc(Cl)cc1)C(=O)OCC

Procedure:
In the same manner as Example 1-(b), 47.5 g of ethyl 3-(4-chlorophenyl)-2-cyanopropionate was reacted with ethyl 2-bromopropionate to obtain ethyl 5-(4-chlorophenyl)-4-cyano-4-ethoxycarbonylvalerate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:10]2[O:18][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:11]2)[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN1C(=O)CCC1>[N:19]1([C:8]2[CH:7]=[CH:6][C:5]([B:10]3[O:18][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:11]3)=[CH:4][C:3]=2[C:1]#[N:2])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNC1
Reactant: CC1(C)OB(c2ccc(F)c(C#N)c2)OC1(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)OB(c2ccc(N3CCCC3)c(C#N)c2)OC1(C)C
Temperature: 140 °C
Yield: 943 %

Procedure:
3-Cyano-4-fluorophenyl-boronic acid pinacol ester (250 mg, 1.01 mmol) was dissolved in NMP (4 mL). Pyrrolidine (415 μL, 5.05 mmol) was added and the mixture heated at 140° C. in the microwave (300 W, stirring) for 5 minutes. The reaction was repeated 14 more times. The 15 reaction mixtures were combined and the solvent evaporated in vacuo (Genevac™). The residue was dissolved in EtOAc (200 mL) and the solution washed with saturated brine solution (2×75 mL). The organic phase was dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (40-63 mesh silica gel, 90% isohexane-EtOAc) to provide the title compound as an off-white solid (2.84 g, 63%); LC-MS, Rt=3.33 min (MeOH-FA method), m/z 298 (MH+).