Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH2:21])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2CCc3cccc(N)c32)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCc3cccc(NC(=O)c4ccccc4)c32)cc1
Yield: 82 %

Procedure:
To a solution of 19(0.1 g, 0.26 mmol), benzoyl chloride (0.09 ml, 0.78 mmol) in pyridine (1 ml) was stirred at 100-110° C. for 16H. The reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layer was dried over anhydrous MgSO4 and evaporated to give residue that was chromatographed over silica gel (EtOAc: n-hexane=1:2) to afford 20, yield 82%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][N:15]=1>C(#N)C>[I:20][C:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:15][CH:16]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Ic1ccc(N2CCNCC2)nc1
Yield: 59.5 %

Procedure:
To a solution of piperazine (215 mg, 2.5 mmol) and potassium carbonate (890 mg, 6.45 mmol) in acetonitrile (5 mL) was added 2-chloro-5-iodopyridine (300 mg, 1.25 mmol) (prepared in Example 2(a)). The mixture was heated at reflux for 26 h and allowed to cool. It was then filtered and the solvents removed under reduced pressure. Column chromatograpgy of the residue on silica gel (dichloromethane:methanol:ammonia solution 100:5:1) gave 1-(5-iodopyridin-2-yl)-piperazine as a yellow solid (215 mg, 60%). δH (300 MHz DMSO-d6) 2.76 (4H, m, piperazinyl ), 3.40 (4H, m, piperazinyl ), 6.72 (1H, d, J=9.0), 7.77 (1H, dd, J=2.4 and 9.0), 8.25 (1H, d, J=2.4), ESMS 290 (MH+)
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.[OH-].[Na+].O>[N+:10]([C:7]1[CH:6]=[C:3]([C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 480 g of 2-chloro-5-nitro-benzaldehyde in 3.2 litres of ethanol is treated dropwise under a nitrogen atmosphere at 30°-40° C with stirring within 4 hours with a solution of 320 g of thiophenol in 120 g of sodium hydroxide, 2 litres of ethanol and 440 ml of water. The mixture is stirred for a further 30 minutes at 60° C, then cooled to 0° C and filtered. There is obtained crude crystalline 3-nitro-6-(phenylthio)-benzaldehyde of melting point 96°-100° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([NH:20][C@H:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=O)=[O:19]>C(OC(C)C)(C)C>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([NH:20][C@@H:21]1[C:27](=[O:28])[O:29][C:24](=[O:26])[CH2:23][CH2:22]1)=[O:19]
Reactant: O=C(O)CC[C@H](NC(=O)c1ccc2ccccc2c1)C(=O)O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: O=C1CC[C@H](NC(=O)c2ccc3ccccc3c2)C(=O)O1

Procedure:
30.6 g (0.3 moles) of acetic anhydride with 60 ml of isopropyl ether are added to 30.1 g (0.1 moles) of 2-naphthoyl glutamic acid. The mixture is heated under reflux (73°-77° C.) for 2 hours. It is cooled, filtered, washed with a little ether to remove residual acetic anhydride and dried. 24.8 g are thus obtained. Yield 88%.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:20]>>[ClH:20].[CH2:1]([O:8][CH:9]1[CH2:10][NH:11][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)C1
Agent: Cl
Product: c1ccc(COC2CNC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
tert-butyl 3-(benzyloxy)azetidine-1-carboxylate 23 (1.0 gm) was taken into a round bottomed flask and was added methanolic-HCl (15 mL, 20%) and was stirred for 1 h at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed under vacuum to get a white solid as a crude product. The crude product was washed with ethyl acetate repeatedly and then dried well to obtain compound 24 as a white solid (92%) and was used further without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH:40]([O:44][CH3:45])[CH2:41][NH:42][CH3:43]>>[CH3:38][O:39][CH:40]([O:44][CH3:45])[CH2:41][N:42]([CH3:43])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CNCC(OC)OC
Product: COC(CN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1)OC

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and (2,2-dimethoxy-ethyl)-methylamine according to conditions described in general procedure C. Mp: 135-136° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.59-1.61 (m, 6 H), 2.82 (s, 3 H), 3.01-3.08 (m, 2 H), 3.27-3.30 (m, 10 H), 3.60 (s, 1 H), 6.25-6.40 (bd, 1 H), 6.93-6.98 (m, 1 H), 7.16 (d, J=8.5 Hz, 1 H), 7.40 (d, J=9.0 Hz, 1 H), 7.45 (s, 1 H), 7.54-7.59 (m, 3 H), 7.80 (s, 1 H), 7.96-7.99 (m, 1 H), 8.27 (d, J=4.4 Hz, 1 H), 10.41 (s, 1 H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Br[C:43]1[CH:44]=[CH:45][C:46](=[O:53])[N:47]([CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:48]=1>CN(C)C=O>[CH:50]1([CH2:49][N:47]2[C:46](=[O:53])[CH:45]=[CH:44][C:43]([C:22]3[CH:21]=[CH:20][C:19]([C@@H:17]([N:13]4[CH2:12][CH2:11][C@:10]([CH2:9][C:8]([OH:7])([CH3:40])[CH3:41])([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:15][C:14]4=[O:16])[CH3:18])=[CH:24][CH:23]=3)=[CH:48]2)[CH2:52][CH2:51]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Br)cn1CC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CC3CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2 M aqueous Na2CO3 solution (0.84 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.40 g) and 5-bromo-1-cyclopropylmethyl-1H-pyridin -2-one (0.24 g) in dimethyl-formamide (4 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (34 mg) was added. The mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol 99:1->95:5) to afford the title compound that was crystallized with little ethyl acetate. Yield: 0.19 g (46% of theory); Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][C@H:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]3[O:46][CH2:45][CH2:44][N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:42]=3[CH:52]=2)[C@@H:33]([C:53]2[CH:58]=[CH:57][C:56]([CH2:59][O:60][CH2:61][C@@H:62]([CH3:66])[CH2:63][O:64][CH3:65])=[CH:55][CH:54]=2)[C@H:32]([CH2:67][N:68]=[N+]=[N-])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.O1CCCC1.O.N>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][C@H:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]3[O:46][CH2:45][CH2:44][N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:42]=3[CH:52]=2)[C@@H:33]([C:53]2[CH:58]=[CH:57][C:56]([CH2:59][O:60][CH2:61][C@@H:62]([CH3:66])[CH2:63][O:64][CH3:65])=[CH:55][CH:54]=2)[C@H:32]([CH2:67][NH2:68])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN=[N+]=[N-])[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 8 h

Procedure:
7.128 mmol of triphenylphosphine are added to a solution of 5.940 mmol of (3S,4R,5R)-3-azidomethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester in 20 ml of methanol, 20 ml of tetrahydrofuran, 5 ml of water and 3.56 ml of concentrated aqueous ammonia (25%) at room temperature. After overnight stirring, the reaction mixture is partitioned between tert-butyl methyl ether and 5:1 water/saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted with tert-butyl methyl ether—the combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf=0.42 (dichloromethane-methanol-25% ammonia conc. 200:20:1); Rt=4.64 (gradient I).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([OH:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C@H:26]([OH:28])[CH3:27])=[CH:23][CH:24]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: C[C@@H](O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 22.3 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.086 g, 0.32 mmol) was reacted with (R)-1-(4-aminophenyl)propan-2-ol (0.058 g, 0.38 mmol) to afford the title compound (0.027 g, 22%) as a light yellow solid. MW=378.89. 1H NMR (DMSO-d6, 500 MHz) δ 8.06 (s, 1H), 7.91-7.88 (m, 1H), 7.76-7.72 (m, 1H), 7.46-7.38 (m, 2H), 7.23-7.14 (m, 5H), 4.53 (d, J=4.5 Hz, 1H), 3.86-3.78 (m, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.71-2.65 (m, 1H), 2.58-2.52 (m, 1H), 2.08 (quin, J=7.5 Hz, 2H), 1.05 (d, J=6.5 Hz, 3H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: C([C:8]1([CH2:18][C:19]([OH:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)(OC(C)(C)C)=O.Cl.[CH3:23]O>>[CH3:23][O:21][C:19](=[O:20])[CH2:18][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1
Reactant: CC(C)(C)OC(=O)C1(CC(=O)O)NCCc2ccccc21
Reactant: CO
Agent: Cl
Product: COC(=O)CC1NCCc2ccccc21
Reaction time: 8 h
Yield: 100 %

Procedure:
To Boc-tetrahydoisoquinoline-1-acetic acid (100.4 g, 520.0 mmol), in MeOH (200 mL), was added 400 mL of 2.3 M HCl in methanol. The mixture was stirred overnight and then concentrated to dryness. The resulting residue was dissolved in EtOAc, washed with saturated sodium bicarbonate, brine, dried (Na2SO4), and concentrated to dryness; affording 109.5 g (100%) of the ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]#N)=[C:7]([CH2:12][CH3:13])[C:6]=2[CH:14]=1.[OH-:15].[K+].[OH2:17]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:17])=[O:15])=[C:7]([CH2:12][CH3:13])[C:6]=2[CH:14]=1
Reactant: O
Reactant: [OH-]
Reactant: CCc1c(C#N)oc2ccc(Br)cc12
Agent: [K+]
Solvent: CCO
Product: CCc1c(C(=O)O)oc2ccc(Br)cc12

Procedure:
A mixture of 5-bromo-3-ethylbenzofuran-2-carbonitrile (2.00 g), potassium hydroxide (1.00 g), water (10 ml) and ethanol (0.5 ml) was heated under reflux for 48 hours and then the solvent was evaporated. The residue was dissolved in water and the solution was filtered and acidified with 2N hydrochloric acid. The solid was filtered off, washed with water and dried to give 5-bromo-3-ethylbenzofuran-2-carboxylic acid (2.01 g) which had m.p. 240°-242° after crystallisation from methanol/H2O.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[Br:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:17][C:18]1[CH:19]=[C:20]([O:24][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)[CH:21]=[N:22][CH:23]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cn2nc(Oc3cncc(Br)c3)ccc2n1)C1CC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.7 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) were added 5-bromopyridine-3-ol (1.7 g, 10 mmol) and potassium carbonate (1.7 g, 13 mmol), and the mixture was stirred at 140° C. for 8 hr. After cooling the mixture to room temperature, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and precipitated from ethyl acetate/diisopropyl ether to give the title compound (1.6 g, 85%) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:37]=[CH:36][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:24]4[C:19](=[N:20][CH:21]=[C:22]([O:25][Si](C(C)C)(C(C)C)C(C)C)[CH:23]=4)[NH:18][CH:17]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:37]=[CH:36][C:6]([CH2:7][NH:8][C:9]2[N:10]=[CH:11][C:12]([CH2:15][C:16]3[C:24]4[C:19](=[N:20][CH:21]=[C:22]([OH:25])[CH:23]=4)[NH:18][CH:17]=3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(C)[Si](Oc1cnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)cc4)nc3)c2c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)cc4)nc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To (4-Trifluoromethyl-benzyl)-[5-(5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (85, 0.13 g, 0.23 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (3 mL, 1.0 M in tetrahydrofuran, 3 mmol). The reaction mixture was stirred at room temperature overnight, and then was stirred at 65° C. for 48 hours. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (P-0061, 0.062 g, 66%). MS (ESI) [M+H+]+=399.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:26]=[C:27]=[O:28])[CH:24]=[CH2:25].O>CN(C)C=O>[CH2:23]([NH:26][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:28])[CH:24]=[CH2:25]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C=CCN=C=O
Solvent: CN(C)C=O
Solvent: O
Product: C=CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in N,N-dimethylformamide (5 ml), allyl isocyanate (0.2 ml) was added, and the admixture was stirred at 80° C. for 15 hours with heat. Water was added to the reaction mixture, the admixture was extracted 2 times with ethyl acetate, and the organic layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 61 mg of the title compound (yield: 96%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C(OC(=O)C=C)(=O)C=C.C(Cl)(=O)C(C)(C)C.C(Cl)(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1.C(Cl)(=O)C.[CH3:37][C:38](C)(C)[C:39]([CH2:41][C:42](C)(C)C(Cl)=O)=O>>[C:1]([O:4][C:5](=[O:7])[C:6]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)(=[O:3])[C:2]1[CH:42]=[CH:41][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)C(=O)CC(C)(C)C(=O)Cl
Agent: C=CC(=O)OC(=O)C=C
Agent: CC(C)(C)C(=O)Cl
Solvent: CC(=O)Cl
Product: O=C(OC(=O)c1ccccc1)c1ccccc1

Procedure:
As seen below, benzoyl chloride, acetyl chloride and pivaloyl chloride were tested for use in the present invention. The best results were obtained with benzoyl chloride, which provided a yield of the acrylic anhydride of 77.2%. Acetyl chloride gave a less preferred product mixture that comprised 50% mixed anhydride, 25% acetic anhydride and 25% acrylic anhydride; the pivaloyl chloride reaction also gave a less preferred product mixture that comprised 50% mixed anhydride, 30% pivaloyl anhydride and 20% acrylic anhydride, based on gas chromatographic analysis. Benzoyl chloride is also more preferred than acetyl chloride and trimethyacetyl (pivaloyl) chloride, because the benzoyl chloride reaction yields benzoic anhydride which has a much greater boiling point than acrylic anhydride, facilitating the separation of the acrylic anhydride.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@H:12]([OH:17])[C@@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([O:20][C@@H:21]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([O:28][C@H:29]3[O:34][C@@H:33]([CH2:35][NH2:36])[C@@H:32]([OH:37])[C@H:31]([OH:38])[C@H:30]3[NH2:39])[C@H:22]2[OH:40])[C@@H:3]([OH:41])[C@@H:2]1[NH2:42].[NH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48].CO[C:52](=[NH:54])[NH2:53].CSC(=N)N>O>[CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@H:12]([OH:17])[C@@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([O:20][C@@H:21]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([O:28][C@H:29]3[O:34][C@@H:33]([CH2:35][NH2:36])[C@@H:32]([OH:37])[C@H:31]([OH:38])[C@H:30]3[NH2:39])[C@H:22]2[OH:40])[C@@H:3]([OH:41])[C@@H:2]1[NH2:42].[NH:43]([CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:52]([NH2:54])=[NH:53]
Reactant: COC(=N)N
Reactant: NCCCC(=O)O
Agent: CSC(=N)N
Agent: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@@H]3O[C@H](CN)[C@H](O)[C@@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O
Solvent: O
Product: N=C(N)NCCCC(=O)O

Procedure:
For guanylation, the neomycin B/γ-amino butyric acid conjugate obtained in Example 9a above is treated with O-methyl isourea or S-methyl isothiourea in water at basic pH for 34 days, resulting in guanylation of the terminal amino groups. The product is purified by ion exchange chromatography, yielding the neomycin B/γ-guanidino butyric acid conjugate 17.
Reaction SMILES: CC(C)[C@@H](N1CC2C(=CC=C(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)C=2)C1=O)C(O)=O.[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=4)=[O:56])=[CH:50][CH:49]=3)=[CH:45][CH:46]=2)[CH2:41][N:40]1[CH2:68][CH2:69][CH2:70][C:71]([O:73]C)=[O:72]>>[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48]3[CH:49]=[CH:50][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:66])([F:65])[F:67])[CH:59]=4)=[O:56])=[CH:52][CH:53]=3)=[CH:45][CH:46]=2)[CH2:41][N:40]1[CH2:68][CH2:69][CH2:70][C:71]([OH:73])=[O:72]
Reactant: COC(=O)CCCN1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Product: O=C(O)CCCN1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Yield: 89 %

Procedure:
The compound of example 376 was prepared analogous to the compound of example 361 by hydrolysis of the compound of example 375.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.S(O)(O)(=O)=O.[CH3:18][C@H:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:27][C@@H:19]([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](N)Cc1ccccc1
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN[C@@H](C)Cc2ccccc2)cc1OC
Reaction time: 16 h
Yield: 65.7 %

Procedure:
A solution of 3,4-dimethoxybenzaldehyde (1.06 g, 6.4 mmol), (S)-1-methyl-2-phenylethylamine sulfate (1.18 g, 6.4 mmol) and triethylamine (0.89 ml, 6.4 mmol) in 1,2-dichloroethane (50 ml) was stirred at room temperature under argon for 15 min. Sodium triacetoxyborohydride (2.97 g, 14 mmol) was added over 5 min. then stirring was continued for a further 16 h. The reaction mixture was diluted with MDC (50 ml) then washed with saturated aqueous K2CO3. The aqueous phase was extracted with MDC and the combined organics washed with brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0–100% EtOAc-pentane) to afford the title compound as a colourless oil (1.20 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)([Cl:16])=O.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 26 °C

Procedure:
A mixture containing 1200 g. (5.95 moles) of 4-chloro-2-nitrobenzoic acid, 5000 ml. (69 moles) of thionyl chloride and 40 ml. of N,N-dimethylformamide was stirred 4 hours while the temperature was maintained at 26° C. When the evolution of hydrogen chloride subsided, the temperature was raised to 65° C. and stirring was continued an additional hour. After removing excess thionyl chloride by vacuum distillation, the residue was dissolved in 1 l. of 1,2-dichloroethane and the solution was evaporated under reduced pressure. The residue which was essentially free of thionyl chloride was dissolved in 5 l. of 1,2-dichloroethane and the solution was twice treated with decolorizing carbon and filtered to give a final solution of 4-chloro-2-nitrobenzoyl chloride in 1,2-dichloroethane which was used directly in the next step.