Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9][C:8]2=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:18]>ClCCl>[CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][CH3:18])[CH2:9][C:8]2=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C1CC(CO)CN1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COCC1CC(=O)N(C2CCCCC2)C1
Temperature: 0 °C
Yield: 71 %

Procedure:
Dissolve 1-cyclohexyl-4-hydroxymethyl-pyrrolidin-2-one (preparation 2) (280 mg, 1.4 mmol) in dichloromethane (30 mL) and cool to 0° C. Add sodium hydride (57 mg, 1.4 mmol) and stir for 20 minutes. Add iodomethane (302 mg, 2.1 mmol) and stir for 24 hours. Quench reaction with water and extract with dichloromethane. Combine extracts, dry over sodium sulfate, filter, and concentrate. Purify by silica gel (1% methanol in ethyl acetate) to give 210 mg (70%) of the title compound. NMR (CDCl3) δ 3.90 (m, 1H), 3.40 (m, 1H), 3.31 (m, 4H), 3.25 (m, 1H), 3.11 (m, 1H), 2.50 (m, 2H), 2.12 (m, 1H), 1.75 (m, 2H), 1.65 (m, 3H), 1.33 (m, 4H), 1.05 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:23][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:23][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(OCCOC2CCCCO2)c(Oc2cccc(OC)c2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cc(N)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1

Procedure:
3.5 g of methyl 3-nitro-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in methanol (100 ml), treated with 0.5 g of Ra-Ni catalyst and hydrogenated at room temperature for 1 hour. The catalyst was filtered off and the solution was concentrated on a rotary evaporator. There was thus obtained the desired methyl 3-amino-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]1([CH:26](O)[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccccc1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(c1ccccc1)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330 mmol) obtained in Example 5, and DL-1-phenylethyl alcohol (79.9 μl, 0.661 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (159 μl, 0.661 mmol). The resulting mixture was heated under reflux for 13 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was separated and purified by flash chromatography on a silica gel column (hexane:ethyl acetate=85:15). The solids thus obtained were each washed with hexane, whereby obtained were the title Isomer 299-A (low-polarity compound) (53 mg, 0.130 mmol, 40%) as a white powder and the title Isomer 299-B (high-polarity compound) (20 mg, 0.0492 mmol, 15%) as colorless columnar crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:21]1[N:26]=[CH:25][C:24]([CH2:27][NH:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:31]1([CH2:30][CH2:29][NH:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=3[CH3:1])[C:6]([NH2:8])=[O:7])=[N:26][CH:25]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1ccc(C(N)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(CNCCC2CCCCC2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(C(N)=O)cc1-c1ccc(CNCCC2CCCCC2)cn1
Temperature: 70 °C

Procedure:
To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (Preparation 18, 150 mg, 0.57 mmol) and (6-bromopyridin-3-ylmethyl)-(2-cyclohexylethyl)amine (Preparation 15, 188 mg, 0.63 mmol) in dioxane (3 mL) was added 2M Na2CO3 (1 mL) and bis(diphenylphosphinoferrocene)-palladium dichloride (47 mg, 0.06 mmol). The mixture was purged with argon for 10 min and the mixture heated to 70° C. for 6 h. On cooling to rt, EtOAc (50 mL) was added and the organic phase washed with water (2×30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (0.4% NH3: 4% MeOH: DCM) to give the title compound: RT=2.53 min; m/z (ES+)=352.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH2:10][C:11]([CH3:13])=[CH2:12])[CH:3]=1.C([O-])=O.[Na+].CCN(CC)CC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:4]=2[CH:3]=1
Reactant: C=C(C)COc1cc(Cl)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)COc2cc(Cl)ccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a mixture of 4-chloro-1-iodo-2-((2-methylallyl)oxy)benzene (160 mg, 0.519 mmol), sodium formate (35.3 mg, 0.519 mmol), tetrabutylammonium chloride (144 mg, 0.519 mmol), and Pd(OAc)2 (23.3 mg, 0.104 mmol) in degassed DMF (1.5 mL) was added Et3N (0.181 ml, 1.30 mmol) and the reaction was heated to 80° C. After 1 hour, the reaction was cooled, diluted with water and EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (1x). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (5-20% EtOAc in hexanes) to afford 6-chloro-3,3-dimethyl-2,3-dihydrobenzofuran 7.48 (55 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[NH2:12][C:13]1[NH:17][N:16]=[CH:15][CH:14]=1>CO>[CH3:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[N:17]3[N:16]=[CH:15][CH:14]=[C:13]3[NH:12][C:2]=2[N:3]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: Nc1ccn[nH]1
Solvent: CO
Product: Cc1ccc2c(=O)n3nccc3[nH]c2n1
Temperature: 25 °C

Procedure:
17.1 g. of 2-chloro-6-methylpyridine-3-carboxylic acid and 16.6 g. of 5-aminopyrazole are heated together at 180°-190° for 10 minutes. The mixture is cooled to room temperature and treated with methanol. The crystalline 6-methylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is filtered off and recrystallized from dimethylformamide, yield: 11.3 g. (56%); m.p. >300°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-])=O.[H][H]>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1
Reactant: [H][H]
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 500 mL 3-necked round bottom flask was added a solution of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (12 g, 61.86 mmol) in DMF (150 mL). To the mixture was added Pd/C (5 g) followed by addition of hydrogen gas. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The product was precipitated by the addition of H2O. A filtration was performed. The filter cake was washed 3 times with 300 mL of hexane. This resulted in 7.3 g (68%) of 7-amino-2H-benzo[b][1,4]oxazin-3(4H)-one as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](I)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](/[CH:3]=[CH:2]/[CH2:1][C@H:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Ic1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](C/C=C/c1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a stirred solution of di-tert-butyl (4S)-4-allyl-N-(tert-butoxycarbonyl)-L-glutamate (345 mg, 0.86 mmol) in acetonitrile (5 ml) at room temperature was slowly added 1-(benzyloxy)-4-iodobenzene (ABCR GmbH & CO. KG) (321 mg, 1.04 mmol) in 3 ml acetonitrile, triethylamine (144 μl, 1.04 mmol) in 3 ml acetonitrile, and palladium(II) acetate (Aldrich) (39 mg, 0.17 mmol). The mixture was heated in a pressure tube at 80° C. for 2 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude material was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]=3[C:24]([F:27])([F:26])[F:25])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:28].[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:28][C:3]1[CH:4]=[C:5]([C:8]2[N:12]=[C:11]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]=3[C:24]([F:27])([F:26])[F:25])[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[CH:29]=[CH2:30]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)ccc1I
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1C
Reaction time: 0.08 h
Yield: 44.3 %

Procedure:
To a solution of 3-(4-iodo-3-methylphenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (1.45 g, 2.92 mmol) in dioxane (5 mL) in a sealed tube was added sequentially tributyl(vinyl)stannane (0.942 mL, 3.21 mmol) and lithium chloride (0.371 g, 8.75 mmol). The mixture was degassed under reduced pressure and charged with nitrogen (2×). To the mixture was added tetrakis(triphenylphosphine) palladium(0) (0.337 g, 0.292 mmol), and the mixture was stirred under a strong stream of nitrogen for 5 min. The reaction mixture was sealed, immersed in an oil bath at 100° C., and stirred overnight. The reaction mixture was diluted with ethyl acetate and filtered. The solid was rinsed with ethyl acetate (3×). The filtrate was concentrated, diluted with ether, and filtered under reduced pressure. HPLC indicated that the product was in the filtrate, which was concentrated under reduced pressure and purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (1%-2.5%) to give 3-(3-methyl-4-vinylphenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (0.514 g, 1.294 mmol, 44.4% yield) as an white solid. The compound had an HPLC ret. time=3.85 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=398.0. 1H NMR (500 MHz, CDCl3) δ ppm 2.47 (s, 3H), 5.43-5.46 (m, 1H), 7.00 (dd, J=17.34, 10.96 Hz, 1H), 7.53-7.62 (m, 3H) 7.65 (d, J=8.32 Hz, 1H), 7.69 (d, J=6.94 Hz, 2H), and 7.99-8.04 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[CH:4]=[C:3]([NH2:11])[CH:2]=1.[CH2:12]([O:14][C:15](=[O:29])[CH:16]([C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][C:18](=O)[CH3:19])[CH3:13].[OH-].[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.Cl>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:17]=[C:18]([CH3:19])[N:11]([C:3]2[CH:2]=[CH:1][CH:6]=[C:5]([S:7]([OH:10])(=[O:8])=[O:9])[CH:4]=2)[C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:29])[CH3:13]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(S(=O)(=O)O)c2)c1-c1ccccc1

Procedure:
Metanilic acid (5 mmol, 0.2 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), sodium hydroxide (5 mmol, 0.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was treated with HCl (hydrochloric acid) at 0° C. to 50° C. to precipitate the unreacted metanilic acid. The remaining material was concentrated under vacuum and purified over silica gel. The named product was collected as brown crystals (m.p. 91° C.-92.5° C.).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3CC(C)(C)C([O-])=O)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CC[O:34]C(C)=O.CCCCCC>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([OH:34])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(Cc1cccc2nc(C#Cc3ccccc3)ccc12)C(=O)[O-]
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1cccc2nc(C#Cc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(Phenylethynyl)quinoline-5-ylpivalate (15.4 mg, 0.0468 mmol) was dissolved in THF (0.78 mL), followed by cooling down to 0° C. After LiAlH4 (0.06 mL, 0.117 mmol) was added thereto, the resulting mixture was warmed to room temperature and stirred for 1 hr. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:1). When the reaction was completed, a saturated aqueous solution was added thereto, and the resulting mixture was extracted with diethylether, to thereby obtain an organic layer. The organic layer was dried over anhydrous MgSO4 and filtrated. The filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/Hexane=1:1, R.f: 0.7), to thereby obtain 2-(phenylethynyl)quinoline-5-ol (5.6 mg, 49%) as a yellow solid.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][NH:6][C:5]=1[C:11]([O:13]C)=[O:12]>C1COCC1.CO>[Cl:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][NH:6][C:5]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1[nH]cc(C=O)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1c[nH]c(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
LiOH (1 N in water, 2 mL, 2 mmol) was added to a solution of methyl 3-chloro-4-formyl-1H-pyrrole-2-carboxylate (0.050 g, 0.26 mmol) in THF (2 mL) and methanol (2 mL). The solution was stirred at RT overnight. The solvents were evaporated to afford a residue which was partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4, filtered and evaporated to a solid to afford the title compound (0.038 g, 83%) as a crude product which was used with no further purification. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.76 (br. s., 1H), 9.90 (s, 1H), 7.72 (d, 1H). LCMS: m/z=174.2 (M+1).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN(C(=O)OC(C)(C)C)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC1CCNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To rac-tert-Butyl 8-acetoxy-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 3)(110 mg, 0.232 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (0.089 ml, 1.161 mmol). The solution was stirred at room temperature for 4 hrs. To the reaction mixture was added a saturated aqueous sodium carbonate (2 ml) and the mixture was vigorously stirred for 10 minutes. The organic layer was separated and concentrated in vacuo to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:12].C1C(C(OO)=O)=CC=CC=1.BrN1C(=O)CCC1=O.Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:12][NH:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38])=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(OO)c1ccccc1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)CNCc1c(OC)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h

Procedure:
5.0 g (29 mmol) of 1-methoxy-2-methyl-3-nitrobenzene was added to a mixture of 50 ml of benzene, 50 ml of perbenzoic acid and 8 g (45 mmol) of N-bromosuccinimide, and they were stirred at 80° C. for one day. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 50 ml of ethanol. 8.4 g (60 mmol) of glycine ethyl ester hydrochloride and 5.0 g (60 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70° C. overnight. The solvent was evaporated. After the extraction with ethyl acetate, the obtained extract was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][O:7][C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH2:4][CH2:3]1.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:8][O:7][C:6]1=[O:9]
Reactant: CC1CCN(Cc2ccccc2[N+](=O)[O-])C(=O)OC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1CCN(Cc2ccccc2N)C(=O)OC1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
6-Methyl-3-(2-nitrobenzyl)-[1,3]-oxazepan-2-one (1.91 g, 7.23 mmol), iron powder (2.02 g, 36.2 mmol), ammonium chloride (0.19 g, 3.55 mmol) were suspended in ethanol (30 ml) and water (15 ml) and heated to reflux for one hour. After cooling to room temperature, the reaction mixture was filtered with suction and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and 3-(2-aminobenzyl)-6-methyl-[1,3]-oxazepan-2-one (1.02 g) was obtained by evaporating the solvent under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([CH3:13])[CH3:12].FC1C=CC([Cl:34])=CC=1CBr>>[F:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:34])=[CH:21][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: Fc1ccc(Cl)cc1CBr
Reactant: CC(C)N(CCCCOCc1ccccc1F)C(=O)OC(C)(C)C
Product: CC(C)N(CCCCOCc1cc(Cl)ccc1F)C(=O)OC(C)(C)C

Procedure:
The title intermediate was prepared essentially as described supra for 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine, except that an equimolar amount of 2-fluoro-5-chlorobenzyl bromide was employed instead of the 2-fluorobenzyl bromide employed therein.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:13][CH2:14][CH2:15][OH:16]>>[OH:16][CH2:15][CH2:14][CH2:13][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: OCCCBr
Reactant: O=C1NCCc2ccccc21
Product: O=C1c2ccccc2CCN1CCCO

Procedure:
from 3,4-dihydroisoquinolin-1(2H)-one and 3-bromopropanol
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[NH2:26][C@H:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][NH:26][C@H:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (R)-(−)-1-aminoindan.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:14]([NH:16][CH:17]([CH:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27])[C:18]([OH:20])=[O:19])=[O:15])[CH3:13])=O)C1C=CC=CC=1.[H][H]>O.CO.C(O)(=O)C.[Pd]>[NH2:11][C@@H:12]([C:14]([NH:16][CH:17]([CH:21]1[CH2:25][CH:24]([OH:26])[NH:23][C:22]1=[O:27])[C:18]([OH:20])=[O:19])=[O:15])[CH3:13]
Reactant: [H][H]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NC(C(=O)O)C1CC(=O)NC1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: C[C@@H](N)C(=O)NC(C(=O)O)C1CC(O)NC1=O
Reaction time: 0.5 h

Procedure:
In 100 ml of water-methanol-acetic acid (1:1:0.2) was dissolved 2.0 g of benzyloxycarbonyl-D-alanyl-2-(2,5-dioxopyrrolidin-3-yl)glycine, and the solution was stirred with 600 mg of palladium black in a stream of hydrogen at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 70 ml of water and, following addition of 580 mg of sodium borohydride at 0°-5° C., the mixture was stirred for 30 minutes with adjusting pH to 8.5-9.2 with 2 N hydrochloric acid. This reaction mixture was adsorbed on a column (150 ml) of Amberlite IRA-68 (OH- -form) and after the column was washed with water, elution was carried out with 0.3 N acetic acid. The eluate was concentrated to dryness under reduced pressure and the resultant powder was subjected to column chromatography on activated carbon (250 ml) and eluted with water. The eluate was concentrated under reduced pressure and lyophilized to give D-alanyl-2-(5-hydroxy-2-oxopyrrolidin-3-yl)glycine as a white powder.