Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][NH2:35])=[CH:26]1>>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][NH:35][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)=[CH:26]1
Reactant: NCc1csc2ccccc12
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3csc4ccccc34)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1-benzothien-3-ylmethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 476.4. HPLC (Condition A), Rt: 4.82 min (HPLC purity: 77.5%).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[CH:42][CH:43]=[C:44]([CH3:45])[C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1cccc(C)c1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccc(C)c1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl -3-trifluoromethyl-benzenesulfonamide (984 mg, 2.0 mmol) in THF (10 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 2.5 mL, 5.0 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of 2-chloro-N-methoxy -3,N-dimethyl-benzamide (852 mg, 4.0 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. The residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (586 mg) in 52% yield. ESMS m/z (relative intensity): 534.9 [(M-32+H)]+ (70), 588.9 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[CH2:12][NH:13][C:7]=2[CH:6]=1)=[O:4].[CH:19]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCCl>[CH:19]1([C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:13]3[C:7]4[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:18]=[CH:17][C:8]=4[CH2:9][N:10]4[CH:16]=[CH:15][CH:14]=[C:11]4[CH2:12]3)=[O:30])=[CH:32][CH:33]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)c1ccc2c(c1)NCc1cccn1C2
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(C3CCCCC3)cc1)Cc1cccn1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid methyl ester of Step B (9.9 mmol) in 1,2-dichloroethane (25 mL) was added 4-cyclohexyl benzoyl chloride (1.1 equiv.) and triethylamine (2.5 equiv.) and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue chromatographed on silica gel eluting with 5% ethyl acetate in petroleum ether to provide the title compound as a white crystalline solid, m.p. 174–176° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[C:3]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3ccsc3)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 80 °C

Procedure:
5-Bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, (0.35 g, Example 1c)), thiophene-3-boronic acid (0.053 g), barium hydroxide octahydrate (0.15 g) and tetrakis(triphenylphosphine)palladium (0) (0.0097 g) in ethylene glycol dimethyl ether (6 ml) and water (1 ml) were combined in a sealed vial and stirred with heating at 80° C. for 18 hours. After cooling, the reaction mixture was absorbed onto silica and purified by flash silica chromatography eluting with 25% ethyl acetate in isohexane to give an oil. The oil was triturated with isohexane, filtered and dried under vacuum to give the title compound as a beige solid (0.020 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[C:11]([OH:29])[C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([CH2:38][CH2:39]O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[C:11]([O:29][CH2:39][CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:10]=1[CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Reactant: OCCc1ccccc1
Product: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1OCCc1ccccc1

Procedure:
4-(4-benzyloxy-3-ethyl-2-phenethyloxyphenoxy)-5-methyl-7-nitroindane was prepared in a similar manner to those described in Example 2 using 3-benzyloxy-2-ethyl-6-(5-methyl-7-nitroindan-4-yloxy)phenol instead of ethyl N-[7-(3-ethyl-2-hydroxy-4-trifluoromethanesulfonyloxyphenoxy)-6-methylindan-4-yl]malonamate and using 2-phenylethanol instead of 4-fluorobenzylalcohol.
Reaction SMILES: [CH:1]([O:14][C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][C:35](=[O:38])[CH2:36][Cl:37])=[N:31][CH:30]=1)[CH:24]([S:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=1)[C:23]2=[O:48])=[O:19])=[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.ClC1C=CC=C(C(OO)=[O:57])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([O:14][C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26](=[O:57])[CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][C:35](=[O:38])[CH2:36][Cl:37])=[N:31][CH:30]=1)[CH:24]([S:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=1)[C:23]2=[O:48])=[O:19])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CC(=O)OC(c1ccccc1)c1ccccc1)NC1=C(c2cnc(NC(=O)CCl)s2)CSC2C(Sc3ccc(Cl)c(Cl)c3)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CC(=O)OC(c1ccccc1)c1ccccc1)NC1=C(c2cnc(NC(=O)CCl)s2)CS(=O)C2C(Sc3ccc(Cl)c(Cl)c3)C(=O)N12
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A solution of 2-benzhydryloxycarbonyl-3-(2-chloroacetamido-thiazol-5-yl)-7-(3,4-dichlorophenylthio)-acetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2 g) in methylene chloride (50 cc) is cooled to 0° C. and treated with an 85% strength solution of meta-chloroperbenzoic acid (0.45 g) in methylene chloride (10 cc). After 30 minutes at a temperature of between 0° and 5° C., the reaction mixture is diluted with methylene chloride (100 cc) and a saturated sodium bicarbonate solution (100 cc) is added. The solid which precipitates is filtered off and taken up in methylene chloride (200 cc). The decanted organic phase is added to this solution, after having been washed with water (100 cc) and then with a saturated sodium chloride solution (100 cc) and dried over sodium sulphate, and the mixture is then concentrated under reduced pressure to a residual volume of 10 cc. The solid is filtered off and washed with ethyl acetate (20 cc) and then with ethyl ether (20 cc). 2-Benzhydryloxycarbonyl-3-(2-chloroacetamido-thiazol-5-yl)-7-(3,4-dichlorophenylthio)-acetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (1.48 g) is obtained in the form of a cream solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:4]
Reactant: C1CSCCN1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCSCC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To an ice-cold solution of chloroacetyl chloride (2.87 g, 25 mmol) in 15 mL of methylene chloride was added thiomorpholine (2.50 g, 24 mmol) and triethylamine (4.9 g, 48 mmol) slowly. The reaction mixture was stirred at 5° C. for 30 minutes, then warmed to room temperature and stirred for 18 hours. After quenching with water (20 mL) at 5° C., additional methylene chloride (200 mL) was added. The organic layer was separated, washed with saturated aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered, and the filtrate was concentrated at reduced pressure. The concentrated residue was dried in vacuo to give 1.83 g (42.0%) of 4-(2-chloroacetyl) thiomorpholine as a brown liquid. 1HNMR (300 MHz / CDCl3):δ 2.62 (t, 2H, J=5.03 Hz), 2.68 (t, 2H, J=4.93Hz), 3.75 (t, 2H, J=5.04 Hz), 3.85 (t, 2H, J=5.04 Hz), 4.04 (s, 2H); mass spectrum, m/z =180.2 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1)=O.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].C(OC(=O)C)(=O)C>CCOC(C)=O>[C:19]([O:22][CH2:1][S:2][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc(-c2ccc(S(C)=O)cc2)cs1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(-c2ccc(SCOC(C)=O)cc2)cs1
Temperature: 25 °C
Yield: 47 %

Procedure:
N-{4-[4-(Methylsulfinyl)phenyl]-1,3-thiazol-2-yl}acetamide (1.5 g), sodium acetate (1.54 g), and acetic anhydride (30 ml) were combined under N2 atmosphere. The reaction mixture was refluxed for 2 hours. After cooled to r.t., the mixture was diluted in AcOEt. The organic solution was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual solid was washed with ethyl ether/n-hexane to give ({4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl)thio)methyl acetate (811.2 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]#[C:26][CH3:27].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:23][CH:26]([CH2:25][C:24]([O:29][CH2:30][CH3:31])=[O:28])[CH2:27][N:22]=1)[NH:6]2
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Yield: 64 %

Procedure:
A solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (1.62 g), ethyl but-2-ynoate (1.2 mL) and tributylphosphine (1.1 mL) in a mixed solvent of tetrahydrofuran (30 mL)-toluene (20 mL) was stirred at room temperature for 4 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90-35:65). The obtained crystals were crystallized from ethyl acetate-hexane to give the title compound (1.35 g, yield: 64%) as pale-yellow crystals.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[C:9]1([C:15]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]=2[NH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:16]=2[NH:17][C:2]2[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCCCC1=O
Reactant: Nc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCC=C1Nc1c(-c2ccccc2)cccc1-c1ccccc1
Yield: 116.7 %

Procedure:
Follow a procedure similar to that of Preparation 2 except use 1,2-cyclohexanedione (1.0099 g, 9.0065 mmol); 2,6-diphenylaniline (2.2258 g, 9.0731 mmol); toluene (22 mL); p-toluenesulfonic acid monohydrate (0.0859 g, 0.4516 mmol); reflux reaction mixture for 2.3 hours; to isolate 3.5678 g of a brown thick oil. Purify the thick oil be chromatography using a Biotage SNAP 50 g KP-Sil column, loading the thick oil with small amount of 4% ethyl acetate/96% hexanes and 100% ethyl acetate and eluting with a gradient of 4-8% ethyl acetate in hexanes to afford after isolation 1.1388 g (37.2%) of the 2-((1,1′:3′,1″-terphenyl)-2′-ylamino)-2-cyclohexen-1-one as a yellow thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.OO.[ClH:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:17])=[CH:4][C:3]=1[N:9]=[C:10]1[NH:11][CH2:12][CH2:13][NH:14]1
Reactant: Cc1ccc(N=C2NCCN2)c(Cl)c1
Reactant: Cl
Agent: OO
Product: Cc1cc(Cl)c(N=C2NCCN2)cc1Cl
Temperature: 45 °C
Yield: 6.35 %

Procedure:
6.08 gm (0.029 mol) of 2-(2-chloro-4-methyl-phenylimino)-imidazolidine were dissolved in 50 ml of concentrated hydrochloric acid, 200 mgm of ferric chloride were added to the solution, and the mixture was heated to 45° C. while vigorously stirring. 3 ml of 30% hydrogen peroxide were now slowly added dropwise, during which time the temperature of the reaction mixture rose to a maximum of 70° C. As soon as the temperature dropped to 40° C. again, the reaction had gone to completion. The reaction mixture was now admixed with ice, and the aqueous mixture was extracted with ether; the ether extracts were discarded. The aqueous phase was fractionally extracted at stepwisely increasing pH-values (alkalization with 2N NaOH), and the uniform fractions were combined, dried over magnesium sulfate and filtered. The ether was evaporated from the filtrate in vacuo, and the residue was dried, yielding 0.45 gm (6.35% of theory) of 2-(2,5-dichloro-4-methyl-phenylimino)-imidazolidine, m.p. 190°-191° C., Rf -value 0.6 in the mobile phase 50 parts benzene, 40 parts dioxane, 5 parts ethanol, 5 parts concentrated ammonium hydroxide; carrier: silicagel G; detector: potassium iodoplatinate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23]>O>[CH3:1][C:2]1[C:7]([N+:22]([O-:24])=[O:23])=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Temperature: 25 °C

Procedure:
A stirred suspension of 1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (10.0 g, 0.046 moles) in water (10 ml) is cooled in an ice bath. Concentrated sulfuric acid (25 ml) is added, followed after 15 minutes by the dropwise addition of concentrated nitric acid (12 ml). The ice bath is removed and the mixture allowed to warm to room temperature. After 48 hours the mixture is poured over crushed ice, stirred, and made strongly basic by the addition of concentrated ammonium hydroxide. The precipitated product is filtered off, rinsed with water and dried. Recrystallization from acetonitrile gave the product (8.7 g), mp 197°-199° C.
Reaction SMILES: C1[C@H](N)[C@@H]([O:8][C@@H]2O[C@@H](CN)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N.[NH2:34][C@H:35]([C:43](N)=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41].C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N>>[NH2:34][C@H:35]([C:43]([OH:44])=[O:8])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41]
Reactant: N=C(N)NCCC[C@H](N)C(N)=O
Reactant: NC[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@@H](O)[C@H](O)[C@H]1O
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Product: N=C(N)NCCC[C@H](N)C(=O)O

Procedure:
R4K was characterized as a free base and consisted, according to HPLC, of essentially one product, the kanamycin A derivative. The 1H NMR (400 MHz, D2O) spectrum revealed the presence of the characteristic groups of the protons of arginine amide moieties at chemical shifts of (δ) 3.38 (Hα), 3.21 (Hβ) and 1.64 ppm (Hγ,δ) All the characteristic kanamycin proton signals, in particular the anomeric hydrogens (as doublets at 4.99 and 5.15 ppm), were observed. Integration afforded 1:4 ratio of antibiotic to arginine components. A 13C NMR (100,609 MHz 10% D2O) spectrum of R4K revealed carbon resonances of the C-arginine amide moieties and the kanamycin moiety. The presence of antibiotic anomeric carbon signals at δ 101.77 and 101.07 ppm, the amide carbons at 181.13, 180.81, 180.38, 179.76 ppm and the guanidino carbons at 159.47 ppm 5 confirmed the structure of the aminoglycoside-arginine conjugate. FABHRMS of R4K revealed a mass peak of 1109.7 Da (calculated molecular weight of R4K: 1109.25 Da). A second peak of 1067.4 Da (−42.3 from mass peak) was attributed to a loss of aminoamino carbon fragment during ionization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.C(N(CC)CC)C.[I-].C([NH3+])(C)(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)CCCCCBr
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCCCCSc1ccc(Cl)cc1

Procedure:
To a solution of 6-bromohexanoic acid methyl ester (2.1 g, 10 mmol), triethylamine (1.6 mL, 11 mmol) and tert-butylammonium iodide (200 mg, 0.54 mmol) in freshly distilled THF (30 mL) was added 4-chlorothiophenol (1.45 g, 10 mmol) under an atmosphere of argon. The mixture was stirred at reflux for 2 hours after which it was concentrated under reduced pressure. The oil was dissolved in ethyl acetate (100 mL) and then washed successively with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL) and brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an yellow oil that was purified by flash chromatography (1:9 diethyl ether:40-60° C. petroleum ether). The title compound was obtained as a colourless oil (2.5 g, 93%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:20]([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][CH:22]=2)=[N:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]([N:25]1[C:21]([C:20]2[C:15]([CH2:14][O:1][C:2]3[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=3)=[N:16][CH:17]=[CH:18][N:19]=2)=[CH:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1nccc1-c1nccnc1CCl
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2nccnc2-c2ccnn2C(C)C)cn1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (110 mg, 0.60 mmol, 1.2 eq.), 2-(chloromethyl)-3-(1-isopropyl-1H-pyrazol-5-yl)pyrazine hydrochloride (crude above, 0.5 mmol, 1 eq.), and K2CO3 (207 mg, 1.50 mmol, 3 eq.) in DMF (15.0 mL) was heated at 100° C. for 30 min. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-methoxyisonicotinaldehyde (12.0 mg, 68%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.05 (s, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.06 (s, 1H), 6.49 (d, J=1.9 Hz, 1H), 5.32 (s, 2H), 4.68 (sep, J=6.6 Hz, 1H), 3.89 (s, 2H), 1.48 (d, J=6.6 Hz, 6H). LRMS (M+H+) ink 354.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([C:30]#[N:31])=[C:20]([OH:32])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.C(O)(=[O:40])C>C(O)C.O>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]([C:30](=[O:40])[NH2:31])=[C:20]([OH:32])[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(C#N)cc3-c3ccccc3)cc2)CCC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(C(N)=O)cc3-c3ccccc3)cc2)CCC1
Temperature: 50 °C
Yield: 72 %

Procedure:
To a suspension of tert-butyl(1-(4-(5-cyano-6-hydroxy-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (14.6 g, 3.58 g, 0.033 mol) in ethanol (112 ml) and water (112 ml) at room temperature was added sodium hydroxide solution (6M, 54.4 ml) and hydrogenperoxide (30%, 21.9 ml). The resulting mixture was heated at 50° C. for 16 h. After cooled down to 0° C., the mixture was added acetic acid to adjust pH=4. The resulting precipitate was filtered and the filter cake was dried to give the title compound as white solid (10.8 g, 72%). LCMS (Method A): RT=5.88 min, M+1=460. 1H NMR (500 MHz, DMSO-d6): 9.65 (1H, br), 8.10 (1H, s), 7.25-7.05 (7H, m), 6.98 (2H, m), 2.45-2.25 (4H, m), 2.0-1.95 (1H, m), 1.79-1.75 (1H, m), 1.3-1.0 (91-1, br).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([OH:25])[CH:27]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(O)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Hydroxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.10 (t, 1H), 6.66 (m,2H), 6.45 (d, 1H), 5.39 (s, 2H), 3.74 (m, 4H), 3.33 (br, 2H), 3.24 (br, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=403.1, found 403.0.