Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]([C:15](Cl)=[O:16])=[CH2:14]>[OH-].[Na+].ClCCl>[C:15]([O:11][C:9]1[CH:10]=[C:2]([OH:1])[C:3](=[CH:7][CH:8]=1)[C:4]([OH:6])=[O:5])(=[O:16])[C:13]([CH3:14])=[CH2:12]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(C(=O)O)c(O)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2,4-dihydroxybenzoic acid (64.88 millimole, 10.0 g) was dissolved in an aqueous solution (300 g) of sodium hydroxide (1.7% by weight) to give an orange solution and the solution was cooled to 0° C. by ice bath. While stirring under a flow of nitrogen gas, a solution of methacryl chloride (8.0 g) in dichoromethane (100 ml) was added to the solution over a period of 60 minutes, and the solution was kept stirred at 0° C. for four hours after completing the addition. After the solution was stood to slowly warm to room temperature, the solution was further stirred overnight. The aqueous layer was separated from the organic layer, and to the aqueous layer was added an aqueous solution of 1N HCl so as to adjust its pH to 1. The solution was stood overnight to give colorless powder, and the powder was filtrated. The powder was washed by cold acidic water (100 ml) three times. After drying the powder under a reduced pressure at room temperature, the powder was recrystallized at 60° C. by an aqueous solution of methanol containing a small amount of hydroquinone to give colorless crystal having a needle shape: yield 10.11 g, 70.1%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[O:9][CH:28]=[N:27][CH:26]=2)[N:7]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cccc(-c2cnco2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
To a stirred solution of 6-bromopyridine-2-carboxaldehyde (5.90 g, 31.7 mmol) in methanol (150 ml) was added K2CO3 (5.25 g, 38.0 mmol) and TosMIC (7.43 g, 38.0 mmol). After stirring at ambient temperature for 1.5 h, the mixture was concentrated under vacuum and the product precipitated by addition of water. The solid was collected by filtration and dried in a vacuum dessicator at 50° C. to afford 2-bromo-6-oxazol-5-ylpyridine compound as a beige solid (6.81 g, 95% yield). 1H NMR (CDCl3, 300 MHz): δ=7.97 (s, 1H), 7.76 (s, 1H), 7.65-7.57 (m, 2H), 7.48-7.37 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH3:7])=[O:4].[CH3:15][C:16]([O:27][Si](C)(C)C)([CH3:26])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([Zn]CC)C.Cl>C(OC(C)C)(=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:6]([NH:5][C:3](=[O:4])[CH2:2][C@@:18]([OH:19])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][C:16]([OH:27])([CH3:26])[CH3:15])[CH3:7])=[CH:9][CH:10]=1
Reactant: CC(C)(CC(=O)c1ccccc1)O[Si](C)(C)C
Reactant: C[C@H](NC(=O)CBr)c1ccc(Br)cc1
Agent: CC[Zn]CC
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: C[C@H](NC(=O)C[C@](O)(CC(C)(C)O)c1ccccc1)c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A flask is charged with 1 (120.0 g, 0.366 mol), 2 (120.0 g, 0.479 mol) and NiCl2(dppe) (1.93 g, 3.66 mmol). The flask is purged with nitrogen and charged with DME (240 mL). The resultant slurry is cooled to about −20° C. and treated with diethylzinc (30 wt. % solution in toluene, 477 mL, 1.097 mol) at a rate to keep the temperature of the reaction mixture between −15 to −5° C. The reaction mixture is then stirred at −5 to 0° C. for 2 hours, treated with 6N aqueous HCl (600 mL), and stirred for 15 minutes. The reaction mixture is treated with isopropyl acetate (120 mL), stirred at 25° C. for 30 minutes, cooled to 10° C., and held at 10° C. for 30 minutes. The resultant solids are collected by filtration, and washed with water, toluene, and heptane. The solid is then dried at 70° C. for 18 hours to provide 3 as a white solid. Yield: 98.3 g, 62.1%; 97.1 wt. % purity. Diastereomeric ratio: 98.9:1.1. Melting point: 150-152° C. LC-MS: 419.8/421.8 (100%, 95%); calculated exact mass: 419.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([N:13]([CH2:15][CH3:16])[CH3:14])=[O:12])=[C:4]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[F:28])(=[O:20])=[O:19])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][C:11]([N:13]([CH2:15][CH3:16])[CH3:14])=[O:12])=[O:37])=[C:4]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[F:28])(=[O:20])=[O:19])[CH:3]=1
Reactant: CCN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCN(C)C(=O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]-N-ethyl-N-methylpropanamide (119 mg, 0.256 mmol) in CH2Cl2 (5 ml) was added mCPBA (61 mg, ˜0.26 mmol). The reaction was stirred at room temperature for 1 hour and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane, then 10% MeOH in CH2Cl2) to yield the title compound (53 mg, 43%) as a mixture of amide bond cis-trans isomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:19][C:20](=[O:25])[C@H:21]([CH2:23][SH:24])[NH2:22])[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:24][CH2:23][CH:21]([C:20]([O:19][CH2:17][CH3:18])=[O:25])[N:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CSC(C2CCN(C(=O)OC(C)(C)C)CC2)=N1

Procedure:
4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution L-cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>O>[CH:22]([NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
To a mixture of 1.05 g of 4-fluoro-3-nitro-benzo trifluoride and 10 ml of N-methylpyrrolidone was added 1.10 g of sec-butylamine under ice cool, and the mixture was heated up to room temperature and stirred for 1.5 hours. Into the reaction mixture was poured water, and the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 1.16 g of N-sec-butyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=1.[Cl:11]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10][Cl:11])=[CH2:9])[N:3]=1
Reactant: C=C(C)c1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C=C(CCl)c1cccc(Br)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
A mixture of 3.60 g of 2-bromo-6-isopropenylpyridine, 2.91 g of N-chlorosuccinimide and 8 ml of benzene was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane - ethyl acetate 20:1) to obtain 1.50 g of the objective compound.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:11])[CH2:6][CH2:7][C@@H:8]([OH:10])[CH3:9])[CH2:2][CH3:3].[Na].Cl[C:14]1[N:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1.O>C1(C)C=CC=CC=1>[CH3:9][C@H:8]([O:10][C:14]1[N:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:6][C@@H:5]([O:4][CH2:1][CH2:2][CH3:3])[CH3:11]
Reactant: CCCCCCCCOc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCCO[C@@H](C)CC[C@H](C)O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(O[C@@H](C)CC[C@H](C)OCCC)nn2)cc1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
320 mg (2.0 mM) of the (2S,5S)-5-propoxy-2-hexanol obtained in Reference Example 1 was dissolved in 15 ml of anhydrous toluene. Thereto was added metallic sodium with stirring at room temperature. To the mixture was added 478 g (1.5 mM) of 3-chloro-6-(4-octyloxyphenyl)pyridazine. The resulting mixture was refluxed for 3 hours. The reaction mixture was cooled and mixed with water and toluene. The toluene layer was separated and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluting solvent: n-hexane-ethyl acetate (4:1)] to obtain 190 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH3:6])=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>ClCCl>[C:17](=[O:18])([O:1][CH2:2][C:3]([NH:5][CH3:6])=[O:4])[O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC(=O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h

Procedure:
A suspension of 2.62 g (29.4 mmol) of 2-hydroxy-N-methylacetamide and 16.5 g (58.7 mmol) of supported diisopropylethylamine (Ps-DIEA from Argonaut, loading=3.56 mmol/g) in 250 ml of dichloromethane is admixed in small portions and at ambient temperature with 5.93 g (29.4 mmol) of 4-nitrophenyl chloroformate. Orbital stirring is continued at ambient temperature for 16 hours. The resin is filtered off and rinsed with 150 ml of dichloromethane and the filtrate is concentrated under reduced pressure. This gives 6 g of product in the form or a light yellow solid, which is used as it is in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:34])[CH:40]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: Oc1cccc(Cl)c1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccc(Cl)c2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 85.2 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (401 mg) was reacted with 3-chlorophenol (198.7 mg) and was recrystallized from hexane-ethyl acetate to obtain (RS)-2-(4-chlorobenzenesulfonyl-amino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (363.2 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[C:11]([CH3:19])[N:10]=1.OC1C([N+]([O-])=O)=C(O)C=C(C)N=1.OC1C([N+]([O-])=O)=C(O)C(C)=C(C)N=1.Cl.[CH2:46]([O:53][CH2:54][CH2:55][NH2:56])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O>[CH2:46]([O:53][CH2:54][CH2:55][NH:56][C:13]1[CH:12]=[C:11]([CH3:19])[N:10]=[C:9]([Cl:8])[C:14]=1[N+:15]([O-:17])=[O:16])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCCOCc1ccccc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: Cc1cc(O)c([N+](=O)[O-])c(O)n1
Agent: Cc1nc(O)c([N+](=O)[O-])c(O)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NCCOCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 23 h
Yield: 25.2 %

Procedure:
Under a nitrogen atmosphere, triethylamine (40.4 mL, 290 mmol) was added to a solution of 2,4-dichloro-6-methyl-3-nitropyridine (12.0 g, 58.0 mmol), prepared according to the general method of Part A of Example 1 using 2,4-dihydroxy-6-methyl-3-nitropyridine in lieu of 2,4-dihydroxy-5,6-dimethyl-3-nitropyridine, in anhydrous N,N-dimethylformamide (DMF) (200 mL). To the resulting dark brown solution was added 2-(benzyloxy)ethylamine hydrochloride (11.97 g, 63.76 mmol), and the mixture was stirred at room temperature for 23 hours. The volatiles were then removed under reduced pressure, and the residue was mixed with water and ethyl acetate. The organic layer was washed with water (3×200 mL), aqueous sodium bicarbonate (2×200 mL), and brine (3×250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil. The crude product (18.1 g) was purified by column chromatography on silica gel (700 g, eluting with 80:20 hexane:ethyl acetate) to provide an oil which was triturated with 80:20 hexane:ethyl acetate. The resulting crystals were isolated by filtration and dried to provide 4.7 g of [2-(benzyloxy)ethyl]-(2-chloro-6-methyl-3-nitropyridin-4-yl)amine as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:14]=[N:13][N:12]([C@@H:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[OH:20])[C:4]=2[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:31][C@H:30]2[NH2:32])=[CH:25][CH:24]=1.O[C@H]([C@@H](O)C([O-])=O)C([O-])=O>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:31][CH:30]2[NH:32][C:2]2[C:3]3[N:14]=[N:13][N:12]([CH:15]4[CH2:19][CH2:18][CH2:17][CH:16]4[OH:20])[C:4]=3[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=2)=[CH:27][CH:28]=1
Reactant: CCCSc1nc(Cl)c2nnn([C@@H]3CCC[C@H]3O)c2n1
Reactant: COc1ccc([C@@H]2C[C@H]2N)cc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Product: CCCSc1nc(NC2CC2c2ccc(OC)cc2)c2nnn(C3CCCC3O)c2n1

Procedure:
Prepared using the product from step b) (0.15 g) and (1R,2S)-2-(4-methoxyphenyl)cyclopropanamine, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (0.20 g) (prepared as described in WO 9905143) by the method of Example 1, step d). Purified by chromatography (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to afford the title compound (0.12 g).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]([CH2:16][S:17]([OH:20])(=[O:19])=[O:18])[CH2:14][NH2:15].[CH2:21]([OH:23])C>O1CCOCC1.[OH-].[Na+].O>[NH2:15][C@H:14]([C:21]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:23])[CH2:13][C:16]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:10]=1.[CH2:13]([CH2:16][S:17]([OH:20])(=[O:19])=[O:18])[CH2:14][NH2:15]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCO
Agent: NCCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N—BOC-L-phenylalanine-N-hydroxusuccinimide ester (400 mg, 1.1 mmol) in a mixture of ethanol (6 mL) and 1,4-dioxane (4 mL) was added to a solution of L-Phe-Homotaurine (273 mg, 1.0 mmol) in 1N NaOH (1.05 mL), water (3 mL) and ethanol (4 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the solid (601.9 mg) was suspended in a mixture of acetone (8 mL) and isopropanol (0.2 mL) and stirred overnight at room temperature. The mixture was heated under refluxed for 30 minutes and then was cooled to room temperature. The white solid was collected by filtration, washed with ether, then dried in the vacuum oven for 45 minutes. The resulting solid (423.1 mg) was dissolved in a mixture of water/tert-butanol (7:3, 5 mL) and treated with Amberlite IR-120 plus (washed, 15 g dry weight) for 2 minutes at room temperature. The resin was removed by filtration and washed 3 times with the mixed solvents of water and tert-butanol (10 mL). Concentrated HCl (4 mL) was added. The solvents were removed under reduced pressure, and the resulting solid was dried in vacuum. The compound was purified by recrystallization from a mixed solvent of THF and MeOH. The resulting solid was heated under reflux in methanol (about 3 mL) to remove the yellowish color. The solid was dried in vacuo. Compound X was obtained as white solid (84.4 mg, 20%). The 1H and 13C NMR were consistent with the structure.
Reaction SMILES: [C:1]([CH:3]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1)#N.[H-].C([Al+]CC(C)C)C(C)C.[O:28]1CCCC1>>[CH:1]([CH:3]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(C#N)C2
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(C)(C)OC(=O)N1C2CCC1CC(C=O)C2

Procedure:
tert-Butyl 3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate was reacted in the presence of diisobutyl aluminum hydride in tetrahydrofuran to produce tert-butyl 3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[NH:15][N:14]=[N:13]1.[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1
Reactant: Cc1c(-n2nn[nH]c2=O)cccc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: Cc1c(-n2nnn(C)c2=O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(2-methyl-3-trifluoromethylphenyl)-1,4-dihydrotetrazole-5-one, potassium carbonate 11.20 g, dimethyl sulfate 3.71 g and N,N-dimethylformamide 150 mL was stirred at 25° C. for one hour. To the reaction mixtures was added aqueous saturated sodium bicarbonate solution and the mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The resulting mixtures were concentrated under reduced pressure to give 1-(2-methyl-3-trifluoromethylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 5.13 g.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12](OC)=[O:13])[C:3]=1[C:16]([O:18]C)=O.O.[NH2:21][NH2:22]>C(O)C>[OH:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12](=[O:13])[NH:21][NH:22][C:16](=[O:18])[C:3]=12
Reactant: NN
Reactant: COC(=O)c1nc2ccccc2c(O)c1C(=O)OC
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c(O)c3ccccc3nc12
Yield: 112.8 %

Procedure:
To a stirred suspension of dimethyl 4-hydroxyquinoline-2,3dicarboxylate (1.00 g, 3.83 mM, prepared as described by H. Biere and W. Seelen, Liebigs Ann. Chem. 1976, 1972) in ethanol (15 mL) was added hydrazine hydrate (9.64 g, 193 mM) whereupon the solids dissolved. The resulting solution was refluxed for 3 hr during which time a thick precipitate formed. The cooled reaction mixture was filtered and the collected yellow solids were washed with ethanol and then ether. Air drying provided 0.99 g of the hydrazine salt of 2,3-dihydro-10-hydroxypyridazino[4,5-b]quinoline-1,4-dione. This material was boiled in glacial acetic acid (40 mL) and, after cooling to room temperature, the mixture was filtered. The collected solids were washed with several portions of ethyl acetate and then ether. Air drying provided the title pyridazinodione (0.72 g, 82%) as a yellow solid, mp >400° C.; Mass Spectrum (Chemical Ionization): 230 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:42][CH2:41][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[O:33][CH3:32])[CH2:45][CH2:44]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=621.97 (M+H+); retention time=0.95 minutes.
Reaction SMILES: C12BC(CCC1)CCC2.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:30][C:31]([NH:33][C@@H:34]1[CH2:49][C:48]2=[CH:50][CH:51]=[C:45]([CH:46]=[CH:47]2)[O:44][CH2:43][CH:42]=[CH:41][CH2:40][O:39][CH2:38][C@H:37]([CH:52]([CH3:54])[CH3:53])[NH:36][C:35]1=[O:55])=[O:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-:56].[Na+].OO>C1COCC1>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:30][C:31]([NH:33][C@@H:34]1[CH2:49][C:48]2=[CH:47][CH:46]=[C:45]([CH:51]=[CH:50]2)[O:44][CH2:43][CH2:42][CH:41]([OH:56])[CH2:40][O:39][CH2:38][C@H:37]([CH:52]([CH3:53])[CH3:54])[NH:36][C:35]1=[O:55])=[O:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: [OH-]
Reactant: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COCC(O)CCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.55 ml (773 μmol) (0.5M in THF) of 9-borabicyclo[3.3.1]nonane were added to a solution of 50 mg (77 pmol) of tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-12-yl)ureido]hexanoate (8-1B) in 1.5 ml of THF, and the mixture was stirred at RT overnight. Addition of 250 μl (1.49 mmol) of 6N sodium hydroxide solution and 207 μl (1.83 mmol) of hydrogen peroxide was followed by extraction with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([OH:9])[C:7]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([NH:1][C@H:2]1[C@H:8]([OH:9])[C:7]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][CH2:4][CH2:3]1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc2c(c1)[C@@H](O)[C@H](N)CCO2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)[C@@H](O)[C@H](NC(=O)CCl)CCO2
Reaction time: 24 h
Yield: 81 %

Procedure:
A solution of 17 g of trans-4-amino-7-methoxy-2,3,4,5-tetrahydro-1-benzoxepin-5-ol dissolved in 700 ml of hydrocarbon-stabilized chloroform was treated with 16 ml of triethylamine at room temperature and 10 g of chloroacetyl chloride dissolved in 80 ml of chloroform was slowly added thereto. The reaction mixture was allowed to stand at room temperature for 24 hours and the solid removed by filtration and washed with chloroform. The filtrate was washed twice with dilute hydrochloric acid solution, followed by a wash with water and dried over anhydrous magnesium sulfate. The filtrate was evaporated to dryness and triturated with ether to yield 18.8 g of trans-2-chloro-N-(2,3,4,5-tetrahydro-5-hydroxy-7-methoxy-1-benzoxepin-4-yl)acetamide.