Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][CH:7]=1.O.NN>CCO>[F:34][C:2]([F:1])([F:33])[CH:3]([C:24]1[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Nc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Temperature: 85 °C
Yield: 65.2 %

Procedure:
To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenylamino) isoindoline-1,3-dione (0.16 g, 0.31 mmol) in EtOH (5 mL), was added hydrazine hydrate (0.076 g, 1.52 mmol), and the reaction mixture was heated at 85° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a solid (0.08 g, 66%) which was carried on to the next step without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([C:9]1[CH:13]=[CH:12][NH:11][N:10]=1)([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.O[CH:24]1[S:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:25]1=[O:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:5][C:6]([C:9]1[CH:13]=[CH:12][N:11]([CH:24]2[S:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=3)[C:25]2=[O:39])[N:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc[nH]n1
Reactant: O=C1C(O)SCN1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccn(C2SCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of thionyl chloride (5.3 mL, 73 mmol) in 120 mL of methylene chloride at ˜10° C. was slowly added 3-(1,1-dimethylethyl)-1H-pyrazole (11.32 g, 91 mmol). The resulting solution was stirred for ˜20 minutes and was then cooled further to ˜0° C. To this solution was added N,N-diisopropylethylamine (26.5 mL, 152 mmol) dropwise at ˜0° C. and then 5-hydroxy-3-[3-(trifluoromethyl)phenyl]4thiazolidinone (16 g, 61 mmol) portionwise at temperatures between 0° C. and 10° C. After the addition, the reaction mixture was allowed to warm up to room temperature, and stirred at room temperature for 3 days. To the reaction mixture was then added 120 mL of concentrated sodium bicarbonate aqueous solution. The methylene chloride layer was separated and the aqueous layer was extracted twice with methylene chloride (˜120 mL each). The methylene chloride layers were combined, dried over MgSO4 and then concentrated. The residue was loaded on silica gel in a flash chromatography column and eluted with hexanes followed by methylene chloride to give 15.74 g of a crude product. The crude product was further purified by trituration in hexanes followed by filtration to give the title compound, a compound of this invention, as a tan solid (11.8 g) melting at 66–69° C.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][CH:5]=1)([OH:3])=[O:2].[OH:14]O>C(O)(=O)C>[C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N+:6]([O-:14])[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cncc2ccccc12
Reactant: OO
Solvent: CC(=O)O
Product: O=C(O)c1c[n+]([O-])cc2ccccc12

Procedure:
4-Carboxy-isoquinoline [J. Amer. Chem. Soc. 67, 1268 (1945)](10 g, 0.058 mol) is refluxed in 100 ml of acetic acid containing 13 ml of hydrogen peroxide (30%) overnight. After cooling, the solution is evaporated to dryness and the residue is purified by column chromatography (ethyl acetate/methanol/formic acid 3:2:1) to yield 4-carboxy-isoquinoline N-oxide, m.p. 280°-283°, Rf =0.3.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][S:8][CH2:9]Cl.C(N(CC)CC)C>>[C:1]([O:6][CH2:7][S:8][CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CSCCl
Reactant: CC(C)C(=O)O
Solvent: CCN(CC)CC
Product: CSCOC(=O)C(C)C

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting isobutyric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 64° C./12 mm Hg, nD20 1.4470.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:24])[C:15]2[C:20]([C:21](=O)[CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:24])[C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 1-benzyl-4-(N-methyl-N-(3-acetyl-2-pyridyl)amino)piperidine (XXXIV, EXAMPLE 43, 260 mg), hydrazine monohydrate (0.78 ml) and powdered potassium hydroxide (0.90 g) in triethylene glycol (16 ml) is stirred at 120° for 2 hrs. The condenser is removed, the mixture is heated up to approximately 185°-190°, the condenser is replaced, and the mixture is stirred at 190° for 3 hrs. After cooling to 20°-25°, the mixture is added to water (50 ml) and extracted with methylene chloride (2×50 ml), and the organic phase is washed with water (20 ml) and saline (20 ml), dried over sodium sulfate, concentrated under reduced pressure and chromatographed (silica gel, 70-230 mesh, 25 g; eluting with a gradient of ethyl acetate/hexane (25/75→50/50)) to give the title compound, NMR (CDCl3, 400 MHz) 8.16, 7.46, 7.31, 7.26, 6.88, 3.50, 3.15, 2.92, 2.73, 2.63, 2.00, 1.82, 1.73 and 1.23δ.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])=[C:8]([N+:20]([O-])=O)[CH:7]=[CH:6][N:5]2[C:23]=1[CH3:24]>[Ni].C(O)C>[NH2:20][C:8]1[CH:7]=[CH:6][N:5]2[C:23]([CH3:24])=[C:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[NH:10][CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19]
Reactant: Cc1cccc(C)c1CNc1c([N+](=O)[O-])ccn2c(C)c(C)nc12
Agent: [Ni]
Solvent: CCO
Product: Cc1cccc(C)c1CNc1c(N)ccn2c(C)c(C)nc12
Yield: 97.7 %

Procedure:
A mixture of 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-7-nitroimidazo[1,2-a]pyridine (45 mg, 0.139 mmol) Raney-Ni (0.1 g) and ethyl alcohol 4 ml was hydrogenated (H2, 1 bar) at 40° C. for 3 h. The mixture was filtrated using a small amount of silica gel and the solvent was removed under reduced pressure. 40 mg (97%) of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of 4-bromo-2-cyclopentyl-phenol (2.0 g, 8.29 mmol) and Cs2CO3 (3.24 g, 9.95 mmol) in DMF (13.0 mL) was added benzyl bromide (1.6 g, 1.09 mL, 9.12 mmol) dropwise. The reaction was stirred at room temperature under inert atmosphere for 2 h. The reaction was quenched with water and the aqueous layer was extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexane) provided 1-benzyloxy-4-bromo-2-cyclopentyl-benzene (1.8 g, 64% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.43-7.40 (m, 4H), 7.35-7.28 (m, 3H), 6.99 (d, J=9.4 Hz, 1H), 5.12 (s, 2H), 3.28-3.24 (m, 1H), 1.94-1.92 (m, 2H), 1.70-1.69 (m, 2H), 1.61-1.52 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Br-].O=[C:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[N+]1CCCC1>CO.C(#N)C>[C:7]([C:6]1[CH:10]=[C:2]([N:1]2[C:17]3[CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[CH:15]=[C:14]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=[CH:4][C:5]=1[OH:11])([OH:9])=[O:8]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1C(=[N+]2CCCC2)CCc2ccccc21)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Solvent: CO
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A mixture of 1.92 g of 5-aminosalicylic acid and 5.0 g of tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide (Example 1a), in 75 ml of methanol is refluxed under nitrogen for 9 hours. The solution is allowed to reach ambient temperature before being filtered. The methanol is removed under a vacuum to give a viscous oil which is dissolved in acetonitrile. This solution immediately crystallizes to give a yellow crystalline solid which is collected by filtration and washed with acetonitrile to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[OH:36]>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@H:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11][CH2:10]3)[N:7]=2)[CH:24]=[CH:23][C:22]=1[OH:36]
Reactant: Clc1cncc(N[C@@H]2CCCc3ccccc32)n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cncc(N[C@@H]3CCCc4ccccc43)n2)ccc1O
Yield: 46.7 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine (139 mg, 0.536 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (147 mg, 0.59 mmol) furnished the product (87 mg, 47%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[N:3]1.S(Cl)(Cl)=O.[Cl:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:17][C:18]1[C:23]([NH:24][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[O:9])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cn1ncc([N+](=O)[O-])c1C(=O)O
Reactant: Nc1cccnc1Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cn1ncc([N+](=O)[O-])c1C(=O)Nc1cccnc1Cl

Procedure:
Prepared analogously to Example A(a) from 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid, thionyl chloride, and 2-chloro-3-aminopyridine in hexamethylphosphoric acid triamide.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].O.[S-:53][C:54]#[N:55].[Na+]>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[C:54]([SH:53])#[N:55]
Reactant: N#C[S-]
Agent: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CS

Procedure:
Crude erythromycin (a mixture of erythromycin and other impurities) (30 g) was added into pure water (300 mL). The solution was stirred. Glacial acetic acid 20% (9.9 mL) was slowly added dropwise to the solution followed by stirring for 20 minutes. Then the mixture was filtered to remove the insoluble impurities in crude. Sodium thiocyanate solution 20% (18.4 mL, 0.038 mol) was added dropwise into the filtrate. The solution was stirred, adjusted to pH 7.2, and allowed to react for 1.5 h. After precipitation, the mixture was cooled for crystallization. The precipitate was filtered and washed with pure water for 3 times, and then dried to obtain erythromycin thiocyanate. The amount of the main component dried erythromycin A was 74.3% (detected by HPLC).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.[Li]CCCC.[O:20]1[CH2:23][C:22](=[O:24])[CH2:21]1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:22]2([OH:24])[CH2:23][O:20][CH2:21]2)[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[CH:6]=1
Reactant: Cc1cn(COCC[Si](C)(C)C)cn1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cn(COCC[Si](C)(C)C)c(C2(O)COC2)n1
Reaction time: 1 h

Procedure:
Into a 1000-mL three-neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 192.1, 9 g, 42.38 mmol) in tetrahydrofuran (200 mL). This was followed by the addition of n-BuLi (34 mL, 2.5 M in THF) dropwise at −78° C. and stirred for 1 h. To this was added a solution of oxetan-3-one (6.11 g, 84.79 mmol) in tetrahydrofuran (30 mL) dropwise at −78° C. The reaction mixture was stirred for 1 h at −78° C., then quenched with 50 mL of NH4Cl (sat.). The aqueous phase was extracted with 1×600 mL of ethyl acetate. The organic layer was washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 13 g (crude) of the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH2:11]([N:13](CC)[CH2:14][CH3:15])[CH3:12]>C(OCC)C>[C:7]([C:6](=[C:14]1[CH2:15][CH2:12][CH2:11][NH:13]1)[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)#[N:8]
Reactant: CCN(CC)CC
Reactant: N#CCc1ccc(Cl)cc1
Solvent: CCOCC
Product: N#CC(=C1CCCN1)c1ccc(Cl)cc1

Procedure:
Stir 106 g of 2-methoxypyrroline-1, 243.5 g of 4-chlorobenzylcyanide and 9 ml of triethylamine for 20 hours at 110°. After cooling, add 200 ml of diethyl ether thereto and filter off the formed precipitate (80.9 of the title compound). Distil off the solvent and the 4-chlorobenzylcyanide under a vacuum to obtain a further 42 g of the title compound (m.p. 135° to 137°) for a total yield of 122.9 g (52% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.Cl.C([O-])(=O)C.[NH4+].C(N(CC)C(C)C)(C)C>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN1CCC(C=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)CC1
Yield: 21 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 1-Methyl-piperidine-4-carbaldehyde; hydrochloride (46.0 mg, 0.281 mmol), Ammonium acetate (39.4 mg, 0.511 mmol), and N,N-Diisopropylethylamine (53.37 uL, 0.3064 mmol) were reacted to produce 21.99 mg (21%) of the title compound. (300 MHz, DMSO-d6) 12.52 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.18 (s, 1H), 6.95 (d, J=9 Hz, 1H), 6.29 (m, 2H), 5.09 (t, J=17 Hz, 8.5 Hz, 1H), 2.87-2.54 (m, 7H), 2.18 (s, 3H), 1.98 (m, 4H), 1.81 (m, 2H), 1.38 (d, J=8 Hz, 1H). MS=499 (M+H), HPLC: 2.47 min. (G Method)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:13][CH3:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH2:23][C:24](Cl)=[O:25].Cl>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([N:13]([C:24](=[O:25])[CH2:23][C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[CH3:15])[CH3:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CNC1(C(=O)OC)CCN(OC)CC1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)C1(N(C)C(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid methyl ester (200 mg, 0.99 mmol) in pyridine (5 ml) was added (2,5-dimethyl-phenyl)-acetyl chloride (240 mg, 1.31 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for one hour and at room temperature for 6 hours, poured on ice water, acidified to pH 7 with an aqueous 2N HCl solution and diluted with ethyl acetate (50 ml). The layers were separated, the aqueous phase extracted with ethyl acetate (3×25 ml), the combined organic phases washed with water (3×15 ml) and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 2:1). Yield: 170 mg of 4-{[2-(2,5-dimethyl-phenyl)-acetyl]-methyl-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (title compound P4.46) as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=O)[NH:6]2.[BH4-].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: O=C1Cc2c(Cl)cccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Clc1cccc2c1CCN2
Temperature: 25 °C
Yield: 77.4 %

Procedure:
5.5 g of 4-chlorooxindole was dissolved in 80 ml of dioxane and 6.2 g of sodium borohydride was suspended in the resulting solution. 12.7 ml of trifluoroacetic acid (d=1.48) was added thereto dropwise at room temperature while stirring. After heat-refluxing the mixture for 4.5 hours, the solvent was removed therefrom under reduced pressure. Water was added to the residue and the water-insoluble materials were removed by filtration and washed with diethyl ether. The filtrate was extracted with diethyl ether and the ether layer was dried over anhydrous sodium sulfate followed by removing the solvent. The residue was distilled under reduced pressure to obtain 3.9 g of 4-chloroindoline as a colorless oily product having a boiling point of 135° C. at 10 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])=[O:12].[C:21]1([CH2:26]O)([CH2:24]O)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[S:11]1(=[O:13])[N:10]([C:3]2[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:26][C:21]2([CH2:23][CH2:22]2)[CH2:24][N:14]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: OCC1(CO)CC1
Reactant: CCOC(=O)CNS(=O)(=O)Nc1c(Cl)cc(Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC2(CC2)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Temperature: -20 °C
Reaction time: 5 h
Yield: 44.1 %

Procedure:
Ethyl 2-((N-(2,4,6-trichlorophenyl)sulfamoyl)amino)acetate (380 mg, 1.05 mmol), cyclopropane-1,1-diyldimethanol (107 mg, 1.05 mmol) and triphenylphosphine (689 mg, 2.63 mmol) were dissolved in anhydrous THF (30 mL) in a reactor, and then cooled down −20° C. after removal of air in the reactor by purging nitrogen gas. DIAD (532 mg, 2.63 mmol) was dropwisely added to the reaction mixture and agitated for 5 hr at room temperature. The resultant was concentrated under reduced pressure and purified by column chromatography (dichloromethane:hexane:ethyl acetate=5:4:1), finally yielding the title compound (198 mg, 44%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.39 (s, 2H), 4.39 (s, 2H), 4.26-4.19 (q, 2H, J=7.1, 7.1, 7.1 Hz), 3.73 (s, 2H), 3.57 (s, 2H), 1.32-1.27 (t, 3H, J=7.1, 7.1 Hz), 0.66-0.64 (m, 4H).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([O:45]C)=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].C(O)(=O)C>O1CCOCC1.O.C(OCC)(=O)C>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:19]=[C:20]([C:28]([F:30])([F:29])[F:31])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCc1ccc(OC)c(-c2ccc(N3CCC3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Methyl 3-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}propanoate (93 mg, 0.143 mmol) was dissolved in dioxane (2 mL) and water (0.5 mL). As the solution was stirred vigorously, 1M lithium hydroxide (0.285 mL, 0.285 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hr and then quenched with acetic acid (0.020 mL, 0.357 mmol). The reaction was diluted with ethyl acetate (15 mL) and washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was redissolved in dichloromethane (2 mL) and heptanes (2 mL) and concentrated again. Purification of the residue by flash chromatography on silica gel (0 to 100% ethyl acetate/hexanes) afforded 3-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}propanoic acid. LCMS=638.2 (M+H)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.72 (s, 2H), 7.30 (d, J=8.7 Hz, 1H), 7.17 (dd, J=8.4, 2.2 Hz, 1H), 7.00 (bs, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.27 (d, J=8.3 Hz, 1H), 5.61 (bs, 1H), 4.8-4.4 (m, 2H), 4.07 (m, 4H), 3.85 (m, 1H), 3.75 (s, 3H), 2.92 (m, 2H), 2.64 (m, 2H), 2.41 (m, 2H), 0.75-0.58 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[NH2:12][C:13]1[C:14]([C:30](O)=[O:31])=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)=[CH:17][N:18]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[NH2:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:26]([CH3:27])[CH3:28])=[O:29])=[CH:23][CH:24]=2)=[N:15][C:14]=1[C:30]([NH:8][NH:7][C:5]([C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=1)=[O:6])=[O:31]
Reactant: NNC(=O)c1cccc(F)c1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3cccc(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
3-fluorobenzohydrazide (80.77 mg, 0.5240 mmol) was added to a solution of 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylic acid (150 mg, 0.5240 mmol), triethylamine (53.02 mg, 73.03 μL, 0.5240 mmol) and TBTU (252.4 mg, 0.7860 mmol) in DMF (3.000 mL) and the resulting solution stirred at RT for 2 hours. The reaction was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc (2×) and the combined organics washed with water (3×), dried (MgSO4), filtered and concentrated to give the desired product as a yellow solid (172 mg, 78% Yield). MS (ES+) 423.13