Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>>[C:27]([O:26][C:24]([N:18]1[CH2:23][CH2:22][N:21]([C:7](=[O:9])[C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:20][CH2:19]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96.9 %

Procedure:
A solution of 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2, 1.0 g), tert-butyl 1-piperazinecarboxylate (0.78 g), TBTU (1.4 g) and N-ethyldiisopropylamine (4 mL) was stirred at room temperature for 2 hours. After such time, the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2) to give 4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless foam (1.6 g). The latter was dissolved in dichloromethane (11 mL) and treated with trifluoroacetic acid (4.2 mL) for 30 minutes. After such time the reaction mixture was concentrated in vacuo to yield the title compound (1.6 g) as light yellow oil. MS (m/e): 327.1 (M+H+, 100%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C(Cl)Cl.CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:15])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 3-oxo-2,3-dihydro-1H-indene-5-carboxylic acid (3 g, 17 mmol) in DCM (50 mL) and MeOH (10 mL) was added TMSCHN2 (17 mL, 34 mmol) dropwise and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient solvent system of 10:1 to 3:1 petroleum ether/EtOAc to give methyl 3-oxo-2,3-dihydro-1H-indene-5-carboxylate (2.0 g, 61%). MS ESI calcd for C11H10O3 [M+H]+ 191, found 191.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH2:9]([O:16][NH:17][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CCCCCCBr
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCCBr)NOCc1ccccc1
Reaction time: 18 h
Yield: 29 %

Procedure:
In an ice bath, 2.4 ml triethylamine was added to a suspension of 2.7 g (17 mmol) O-benzylhydroxylamine hydrochloride in 100 ml dichloromethane. 3.6 g (17 mmol)7-bromo heptanoic acid was added, followed by 5.3 g (21 mmol) bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride Stirring was continued at ambient temperature for 18 h. The solution was extracted twice with 150 ml each of 1M aqueous hydrochloric acid and twice with 150 ml each of 1M aqueous sodium bicarbonate. The organic solvent was removed i. vac. and the residue was purified by column chromatography (silica gel; ethyl acetate: heptane 1:1) to give 1.55 g (30%) of 7-bromo-heptanoic acid benzyloxy-amide as a colorless oil. MS: 314 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[F:21])=[O:4].BrC1C=CC(N)=C(F)C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC(C1C=CC(=O)NC=1)=O>C1COCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]2[N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])=[C:15]([F:21])[CH:16]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: COC(=O)c1ccc(=O)[nH]c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Nc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-Oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester: To a solution of 4-bromo-2-fluorophenylamine (0.192 g, 1.01 mmol) in THF (5 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. 2-Chloro-1-methyl-(6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.202 g, 1.00 mmol) was then added dropwise as a solution in THF (5 mL) and the reaction mixture was stirred for one hour at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to pH 7 with saturated NH4Cl and then diluted with EtOAc. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.232 g (65%) pure desired product as a white crystalline solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([I:9])[C:6]([O:10]COC)=[CH:5][N:4]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:2][C:3]1[N:4]=[CH:5][C:6]([OH:10])=[C:7]([I:9])[CH:8]=1
Reactant: COCOc1cnc(F)cc1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnc(F)cc1I
Temperature: 60 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Add HCl (3 M in water, 31 mL, 93.0 mmol) to a solution of 2-fluoro-4-iodo-5-methoxymethoxy-pyridine (3.9 g, 13.8 mmol) in THF (20 mL). Stir the mixture at 60° C. for 3 h and cool down the mixture. Adjust the pH to 7 with slow addition of a saturated aqueous sodium bicarbonate solution. Extract the solution with ethyl acetate three times. Wash the organic layer with aqueous saturated sodium chloride. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to afford the title compound (3.2 g, 97%) as a yellow solid. MS (ES) m/z 240 [M+1]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.Cl[Mg]C(C)C.[F:13][C:14]1[C:19]([C:20](N(OC)C)=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>CCOCC>[Br:7][C:5]1[N:6]=[C:2]([C:20]([C:19]2[C:14]([F:13])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[S:3][CH:4]=1
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: Brc1csc(Br)n1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Product: O=C(c1nc(Br)cs1)c1cccnc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
2,4-dibromothiazole (3 g, 12.35 mmol) was dissolved in ether (100 mL) and cooled to 0° C. Chloro-isopropyl-magnesium (7.41 mL, 14.82 mmol, 2M in diethyl ether) was then added dropwise at 0° C. over approximtely 5 mins. During addition, a white precipitate formed. After complete addition, the mixture was stirred at 0° C. for 2 hours. A solution of 2-fluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (2.389 g, 12.97 mmol) in ether (10 mL) was then added dropwise over 5 mins at 0° C. Left to warm to room temperature over 3 days. The reaction was quenched with water, extracted with EtOAc, organics combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (80 g SiO2, 0 to 25% EtOAc/petrol) to leave impure product as a cream solid. Purified again by flash chromatography (40 g SiO2, 10 to 20% EtOAc/petrol) to leave product as a cream solid (1.088 g, 31%); 1H NMR DMSO-d6 δ7.64-7.60 (m, 1H), 8.57-8.50 (m, 3H), ES+ 288.85.
Reaction SMILES: F[B-](F)(F)F.[C:6]([NH:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([N+]#N)=[CH:12][C:11]=1[Cl:19])(=[O:8])[CH3:7].C1([OH:26])C=CC=CC=1>O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[Cu-]=O>[C:6]([NH:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([OH:26])=[CH:12][C:11]=1[Cl:19])(=[O:8])[CH3:7]
Reactant: Oc1ccccc1
Reactant: CC(=O)Nc1c(Cl)cc([N+]#N)cc1Cl
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: F[B-](F)(F)F
Solvent: O
Product: CC(=O)Nc1c(Cl)cc(O)cc1Cl
Reaction time: 0.58 h
Yield: 35 %

Procedure:
4-Acetamido-3,5-dichlorobenzenediazonium tetrafluoroborate was converted to the corresponding phenol according to the procedure of T. Cohen, et. al., J. Org. Chem., 42, 2053-2058 (1977). Thus, 22 g (94 rnmol) of copper (II) nitrate was dissolved in 100 mL of water and 300 mg (0.94 mmol) of 4-acetamido-3,5-dichlorobenzenediazonium tetrafluoroborate was added. Copper (I) oxide (405 mg, 2.8 mmol) was added. The mixture was stirred for 35 min, then filtered through Celite, diluted with 1N aqueous sodium bisulfate, and extracted with 4 portions of dichloromethane and 8 portions of ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica, 50% ethyl acetate/hexanes) gave 72 mg (35%)of 4-acetamido-3,5-dichlorophenol. This compound was convened to the title compound in a manner analogous to that of Example 1: 1H NMR (400 MHz, CDCl3) δ6.97 (s, 2H), 4.21 (dd, 1H), 3.86 (dd, 1H), 3.32 (m, 1H), 2.91 (t, 1H), 2.73 (dd, 1H), 2.20 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2]>C(Cl)Cl>[C:7]([C:6]1[CH:5]=[C:4]([C@H:1]([OH:3])[CH3:2])[CH:11]=[CH:10][CH:9]=1)#[N:8]
Reactant: CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Product: C[C@@H](O)c1cccc(C#N)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of (S)-oxazaborolidine (3.44 mmol) in CH2Cl2 (3.5 mL) at −20° C. was added a solution of 3-acetylbenzonitrile (3.47 mmol) in CH2Cl2 (3.5 mL) over a period of approximately 30 minutes. The mixture was then allowed to warm to room temperature for 1 hour then quenched by transferring to a stirred flask of methanol at −20° C. The resultant mixture was concentrated under reduced pressure and the residue taken up in methanol and concentrated twice more and dried overnight under high vacuum. This residue was purified on silica gel chromatography (70:30 hexanes:ethyl acetate) to yield the title compound (373 mg). 1H NMR (500 MHz, CDCl3): δ 7.71 (m, 1H); 7.63 (d, J=7.8 Hz, 1H); 7.58 (m, 1H); 7.48 (t, J=7.7 Hz, 1H); 4.97 (m, 1H); 1.90 (d, J=3.9 Hz,, 1H); 1.53 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25][C:24]1=[O:32]>>[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[C:28](=[O:29])[CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25][C:24]3=[O:32])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Reactant: CC1(C)CC(=O)N(CCCCCCBr)C(=O)C1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCCN1C(=O)CC(C)(C)CC1=O
Yield: 72 %

Procedure:
In an analogous manner to that described in Example 20a), from rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole by reaction with N-(6-bromo-hexyl)-3,3-dimethylglutarimide there was obtained rac-cis-1-[6-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-hexyl]-4,4-dimethylpiperidine-2,6-dione; m.p. of the hydrochloride 99°-101°, yellowish crystals, yield 72%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[CH:21]=3)[CH:17]=1)[N:5]=2.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>N1C=CC=CC=1>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=[CH:14][C:15]=2[CH3:32])=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CO)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.453 mmol) produced in Example C29(iv) in pyridine (4.0 mL) was added 2-chloro-2-oxoethyl acetate (73 μL, 0.68 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with methanol (2.0 mL). 1N Aqueous sodium hydroxide solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to neutralize the residue, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/tetrahydrofuran/hexane to give the title compound (104 mg, 46%) as a colorless powder.
Reaction SMILES: [CH:1]([O:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[C:28](O)=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[Cl:22][C:23]1[C:28]([O:20][C:19](=[O:21])[CH2:18][NH:17][C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=C(O)CNC(=O)OC(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)OC(c1ccccc1)c1ccccc1)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
To a mixture consisting of 10 g. of N-benzhydryloxycarbonylglycine [this compound is reported in J. Am. Chem. Soc., 87, 3969 (1965)], 9.4 g. of pentachlorophenol, and 150 ml. of ethyl acetate, at 5° C., is added 7.3 g. of dicyclohexylcarbodiimide, and the resulting solution is kept at 5° C. for 5 hours and filtered. The filtrate is evaporated, and the residue is triturated with petroleum ether to give a solid precipitate of N-benzhydryloxycarbonylglycine pentachlorophenyl ester, which is isolated and dried; m.p. 171°-172° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([O:14][C:15]1[CH:20]=[CH:19][C:18](N)=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH:8]=[CH:7]2.[I:32]I.C(ON=O)CC(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Cu](I)I.C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([I:32])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH:8]=[CH:7]2
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reactant: II
Agent: I[Cu]I
Agent: CC(C)CCON=O
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2c(Oc3ccc(I)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 1 h

Procedure:
Place 6-methoxy-2-(4-methanesulfonylphenyl)-1-(4-aminophenoxy)naphthalene hydrochloride (1 eq.), iodine (0.6 eq.), copper iodide (1.05 eq.) and acetonitrile in a 3 neck flask equipped with a mechanical stirrer, addition funnel, nitrogen purge and temperature probe. Charge the addition funnel with isoamylnitrite (1.1 eq.) in acetonitrile and add this mixture dropwise at 20° C. or below. After the addition, stir the mixture for 1 hour. Once the reaction is complete, add saturated sodium thiosulfate and methylene chloride to the mixture and stir for 1 hour. Filter the reaction mixture and separate the layers. Concentrate the organic layer to form a solid. Purify the solid on silica gel to afford the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO.C(OCC)(=O)C.C1CCCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]([CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH3:27])[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: CN(Cc1ccc2c(c1)OCCO2)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.8 %

Procedure:
2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (153 mg, 0.93 mmol, 1.0 eq) is added at room temperature to a stirred solution of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol, 1.0 eq) in 1,2-dichloroethane (8 mL) and methanol (2 mL), followed by acetic acid (61 μL, 1.07 mmol, 1.15 eq) and sodium cyanoborohydride (76 mg, 1.21 mmol, 1.3 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate, 3:1 to 1:3, v/v) to afford 4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester as an off-white oil (195 mg, 55% yield).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].N[C@H](C(O)=O)CCCCN.N[C@@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCSC.N[C@H](C(O)=O)[C@H](CC)C.N[C@@H](C(O)=O)CCSC.N[C@@H](C(O)=O)[C@@H](CC)C.N[C@H](C(O)=O)CCCN.N[C@@H](C(O)=O)CCCN>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: N=C(N)NCCC[C@@H](N)C(=O)O
Agent: CC[C@@H](C)[C@@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: CSCC[C@@H](N)C(=O)O
Product: N=C(N)NCCC[C@H](N)C(=O)O

Procedure:
replace with: D-Arg, Lys, D-Lys, homo-Arg, D-homo-Arg, Met, Ile, D-Met, D-Ile, Orn, D-Orn;
Reaction SMILES: [CH:1]12[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH:5]1[CH2:4][CH2:3][N:2]2[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH:1]12[CH2:8][NH:7][CH2:6][CH:5]1[CH2:4][CH2:3][N:2]2[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)N1CCC2CN(C(=O)OC(C)(C)C)CC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC2CNCC21

Procedure:
15.2 g (53.5 mmol) of 2-ethyl 7-tert.-butyl 2,7-diazabicyclo[3.3.0]octane-2,7-dicarboxylate in 100 ml of chloroform are refluxed for 5 hours together with 10.5 g (55.3 mol) of para-toluenesulphonic acid. The mixture is washed with 50 ml of 10% strength sodium hydroxide solution, and the organic phase is dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CI.[C:21]([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH3:21])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc(Cl)c2)cc1F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CN(c1ccnc(Cl)c1)c1ccc([N+](=O)[O-])c(F)c1
Yield: 60.2 %

Procedure:
Add 2-chloro-N-(3-fluoro-4-nitro-phenyl)pyridin-4-amine (300 mg, 1.12 mmol), methyl iodide (174 mg, 1.23 mmol) and K2CO3 (201 mg, 1.45 mmol) in DMF (6 mL). Stir the reaction at 70° C. for 3 hrs. TLC (EtOAc:PE=1:1) shows the reaction is complete, cool the reaction to 0° C., add water, extract with EtOAc. Combine the organic layers. Wash with brine, dry over anhydrous Na2SO4. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (190 mg, 45%). MS: (M+1): 282.2.
Reaction SMILES: [C:1]12([C:14]([OH:16])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([C:11](O)=O)([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(C)N=C=NC(C)C.[CH2:26]([N:29]1[C:36]([NH2:37])=[C:35]([NH2:38])[C:33](=[O:34])[N:32]([CH2:39][CH2:40][CH3:41])[C:30]1=[O:31])[CH2:27][CH3:28].Cl.[OH-].[K+]>CN(C=O)C.C(O)(C)C.O>[O:31]=[C:30]1[N:29]([CH2:26][CH2:27][CH3:28])[C:36]2[N:37]=[C:11]([C:3]34[CH2:9][CH:7]5[CH2:6][CH:5]([CH2:10][C:1]([C:14]([OH:16])=[O:15])([CH2:8]5)[CH2:2]3)[CH2:4]4)[NH:38][C:35]=2[C:33](=[O:34])[N:32]1[CH2:39][CH2:40][CH3:41]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCCn1c(=O)c2[nH]c(C34CC5CC(CC(C(=O)O)(C5)C3)C4)nc2n(CCC)c1=O

Procedure:
Symmetrical anhydride prepared from adamantane 1,3-dicarboxylic acid using DIC in DMF was coupled to 1,3 dipropyl-5,6-diaminouracil.HCl. The product was cyclized using KOH in isopropanol/water. Mass (ES+ 415)
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[C:18]=1[C:19]#[N:20])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)[Si](C)(C)OCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 25 %

Procedure:
Prepared as in Example 215c from 4-(tert-butyldimethyl-silyloxy)butan-1-ol and 2,6-dinitrobenzonitrile in 25% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 0.01 (s, 6H), 0.81-0.83 (m, 9H), 1.61-1.66 (m, 2H), 1.76-1.81 (m, 2H), 3.63 (t, J=6.8 Hz, 2H), 4.26 (t, J=6.4 Hz, 2H), 7.68-7.70 (m, 1H), 7.84-7.89 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].O>Br.C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2cccc(C(C)=O)c2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cccc(-c2ccc(O)cc2)c1
Yield: 75.7 %

Procedure:
A solution of 3'-acetyl-4-methoxybiphenyl (2.07 g) in hydrobromic acid (48%, 25 ml) and glacial acetic acid (25 ml) was heated at reflux under nitrogen for 1 hour. After cooling the mixture was poured into water and extracted with ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a crude yellow/brown solid The latter was purified by column chromatography over silica eluting with diethyl ether:hexane (2:3) to give the sub-title compound as a cream/orange solid (1.47 g).