Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-])=O)[CH:28]=2)[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:37].[CH:38](O)=O>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]3[NH:33][CH:38]=[N:34][C:29]=3[CH:28]=2)[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:37]
Reactant: O=CO
Reactant: Nc1ccc(CC(NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)C(=O)N2CCc3ccsc3CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCc3ccsc3CC2)cc1Cl

Procedure:
Prepared from 4-amino-N-[1-((4-amino-3-nitro-phenyl)methyl)-2-(5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-6-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[I-].[PH4+].[CH3:13][CH:14]1OC(C)OC(C)O1>I>[CH3:1][C:2]1[NH:3][C:4]([CH2:13][CH3:14])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC1OC(C)OC(C)O1
Agent: I
Agent: [I-]
Agent: [PH4+]
Product: CCc1[nH]c(C)c(C(C)=O)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2,4-dimethyl-3-acetyl-pyrrole (548 mg) in 10 ml of aqueous hydriodic acid containing a little solid phosphonium iodide was cooled in an ice-salt bath. Paraldehyde (0.35 ml) was added and the solution was stirred for 41/2 hrs. without further cooling. The solution was then added to 100 ml of ice water to precipitate the light brown product (385 mg, 58%), m.p. 153°-160° C. For analysis, it was sublimed in vacuo then recrystallized from ether (thimble) as grey needles, m.p. 163° C. after changing to plates at 140°. Anal. Calc. for C10H15O: C; 72.69, H, 9.15; N, 8.48. Found: C, 72.67; H, 8.88; N, 8.69.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:15][C:14]2[C:13]3[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:12]=3[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+].CCO>C1COCC1.O>[Br:20][C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:15][C:14]=3[C:13]=2[CH:16]=1
Reactant: CCOC(=O)c1cc2c(s1)-c1cc(Br)ccc1OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(s1)-c1cc(Br)ccc1OCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid ethyl ester (4.24 g; 12 mmol) in THF (40 ml) at room temperature was added a solution of NaOH (0.96 g; 24 mmol) in water (20 ml) followed by EtOH (20 ml). The reaction mixture was stirred at room temperature for 4 h (now a clear solution) upon which time it was quenched with 2M HCl (20 ml) and diluted with water (50 ml). The resulting solid was collected by filtration, washed with water and dried to give 9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid as a white solid (3.64 g; 93%). δH (400 MHz, d6-DMSO) 3.22 (t, J=5.2, 2H), 4.31 (t, J=5.2, 2H), 7.02 (d, J=8.4, 1H), 7.43 (dd, J=8.4 and 2.4, 1H), 7.62 (s, 1H), 7.78 (d, J=2.4, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N(CC)CC)C.C(OC(=O)C)(=O)C>O>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:10]([OH:12])=[O:11])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)C(=Cc1ccc([N+](=O)[O-])cc1)c1cccc(C(F)(F)F)c1
Yield: 80 %

Procedure:
A solution of (3-trifluoromethyl-phenyl)-acetic acid (7.5 g, 36.7 mmol), 4-nitro-benzaldehyde (5.55 g, 36.7 mmol), triethylamine (4.8 g, 47.8 mmol), and acetic anhydride (14.3 g, 140 mmol) was refluxed for 6 hours. The reaction mixture was poured in acidified water (sulfuric acid, pH 1) and extracted with ethyl acetetate. The organic layer was evaporated and the residue was stirred with sodium bicarbonate solution. The precipitate was sucked off and the filtrate extracted with ethyl acetate. The water was acidified with hydrochloric acid and the resulting oil extracted with ethyl acetate to give 9.9 g of the desired product (80% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)CC(=O)C>[ClH:1].[ClH:1].[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:24]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=2)=[C:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][N:8]([C:11]4[N:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[CH2:7][CH2:6]3)[CH2:27][CH2:26]2)=[CH:32][CH:33]=1
Reactant: ClCCCN1CCN(c2ncccn2)CC1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cl
Product: Fc1ccc(C(=C2CCN(CCCN3CCN(c4ncccn4)CC3)CC2)c2ccc(F)cc2)cc1

Procedure:
A mixture of 0.89 g of 1-(3-chloropropyl)-4-(2-pyrimidinyl)piperazine, 0.80 g of 4-[bis(4-fluorophenyl)methylene]piperidine and 0.51 g of potassium carbonate in 30 ml of 4-methyl-2-pentanone is brought to reflux for 48 hours in the presence of a trace of potassium iodide. The solvent is evaporated off and the residue is taken up in dichloromethane. The solution is washed with water. It is concentrated. The residue obtained is purified on a silica column using a mixture of dichloromethane and methanol (80:20 V/V) as eluent.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.Cl.[NH2:22][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24].CN(C=O)C>C1COCC1>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:22][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a cold (−15° C.) solution of Boc-Ala-OH (1.034 g, 5.47 mmol) and NMM (901 μl, 8.20 mmols) in THF (15 ml) was added ECF (538 μl, 5.63 mmols) under N2 atmosphere and vigorously stirred. After 2 min of stirring, a solution of methyl alaninate hydrochloride (840 mg, 6.01 mmols) in a mixture of solvents THF:DMF (4 mL: 3 mL) was added to the reaction mixture followed by NMM (1.5 ml, 13.67 mmols) and stirred. After 10 min the mixture was warmed to 25° C. and stirred for further 8 h. THF was removed under reduced pressure and the resulting viscous solution was diluted with water (10 mL) and thoroughly extracted with ethyl acetate. The combined organic extracts were washed with saturated citric acid (10 mL), saturated NaHCO3 (10 mL) and dried over by Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by silica gel flash column chromatograph (EtOAc:Hexane—3:17) to give the desired product as a solid (m.p. 107-108° C.) in good yields (1.48 g, 98.6%). (TLC:EtOAc:Hexanes 7:3—Rf—0.55).
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:38]=[C:37]4[CH2:39][NH:40][CH2:41][CH2:42][C:36]4=[N:35][C:34]=3[NH:43][CH:44]([CH3:46])[CH3:45])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.C=O>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:38]=[C:37]4[CH2:39][N:40]([CH3:2])[CH2:41][CH2:42][C:36]4=[N:35][C:34]=3[NH:43][CH:44]([CH3:45])[CH3:46])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CNCC2
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CN(C)CC2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (6.9 mg, 0.033 mmol) was added to a solution of DIPEA (6 μL, 0.033 mmol), (5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone TFA salt (8.9 mg, 0.016 mmol) and formaldehyde (1.5 μL, 0.016 mmol) in MeOH (160 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (2.2 mg, 24.1%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.81-1.94 (m, 2H), 1.96-2.05 (m, 2H), 2.85 (t, J=11.5 Hz, 2H), 3.00 (d, J=6.3 Hz, 2H), 3.07 (s, 3H), 3.44-3.53 (m, 4H), 3.71-3.82 (m, 1H), 4.14-4.23 (m, 2H), 4.28-4.37 (m, 1H), 7.28 (dd, J=10.6, 8.8 Hz, 1H), 7.61 (ddd, J=8.8, 4.1, 2.8 Hz, 1H), 7.75 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 446.3.
Reaction SMILES: C([O-])(=O)C.[Tl+3].C([O-])(=O)C.C([O-])(=O)C.[F:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:26])[C:22]([O:24]C)=[O:23])[CH:18]=[CH:17][C:16]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C.CCCCCC>[F:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:26])[C:22]([OH:24])=[O:23])[CH:18]=[CH:17][C:16]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Agent: CC(=O)[O-]
Agent: [Tl+3]
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
Following the procedure of Example 2, the enol ether of the formula ##STR9## is reacted with thallium (III) acetate in an aqueous acetic acid/hexane mixture at 25° to 50° C. until methyl 2-(2-fluoro-4-biphenylyl)propionate is formed. This ester is isolated from the reaction mixture and hydrolyzed to 2-(2-fluoro-4-biphenylyl)propionic acid (generic name, flurbiprofen) by the described procedure.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]=O.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>ClCCl.C(OCC)(=O)C>[CH2:13]([O:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:20][CH2:21][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=O
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOP(=O)(COC(COCc1ccccc1)COCc1ccccc1)OCC
Temperature: 140 °C

Procedure:
Dry HCl gas was bubbled through an ice-cooled solution of 1,3-dibenzyloxypropan-2-ol (25 g, 0.092 mol) and paraformaldehyde (2.75 g, 0.092 mol) in dry dichloromethane (100 ml) for 1 hour. The resulting solution was dried (MgSO4) and evaporated to dryness to leave an oil. Triethyl phosphite (15.7 ml, 0.092 mol) was added and the resulting mixture stirred and heated at 140° C. for 16 hours. The liquid obtained was dissolved in ethyl acetate and washed with sodium bicarbonate solution. The organic phase was washed with brine, dried (MgSO4) and evaporated to give a mobile oil, which was chromotographed in silica (hexane/ethyl acetate 50:50 as eluant) to give the title compound as a colourless, mobile oil (19.7 g, 51). IR: νmax (film) 3055, 3020, 2900, 2860, 1490, 1470, 1450, 1390, 1305, 1255, 1095, 1050, 1030, 970, 820, 770, 735, 700 cm-1. 1H NMR: δH (CDCl3) 1.3 (6H, t, J=7 Hz, P-(OCH2CH3)2), 3.6 (4H, d, 2×CH2OCH2Ph),3.8-4.05 (1H, m, CH), 4.05 (2H, d, J=9 Hz, OCH2P), 4.0-4.3 (4H, m, P-(OCH2CH3)2), 4.55 (4H, s, 2×OCH2Ph), 7.38 (10H, s, 2×Ph). C22H31PO6 requires: C, 62.54; H, 7.42. Found: C, 62.75, H, 7.61. m/z: C22H31PO6 requires 422.1858; observed (M+) 422.1864.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:12][C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[C:9](=[O:25])[C:8]=2[CH:26]=1.O>CCOCC.O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:13]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[CH:12][C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[C:9]([CH3:1])([OH:25])[C:8]=2[CH:26]=1
Reactant: CN1CCN(c2cc3ccccc3c(=O)c3cc(Br)ccc23)CC1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C2=Cc3ccccc3C(C)(O)c3cc(Br)ccc32)CC1
Reaction time: 3 h

Procedure:
Methyllithium, 35 ml. of a 1.6 M solution in ether, was added dropwise to a stirred solution of the product from Step C (18 g., 0.047 mole) in ether (200 ml) and tetrahydrofuran (60 ml) cooled in an ice bath and under nitrogen. Stirring was continued at room temperature for 3 hours. The mixture was cooled in ice and hydrolyzed by the dropwise addition of water. After dilution with ether and water, the layers were separated and the aqueous phase was re-extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. The mixture of 3-bromo-5-methyl-10-(4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-ol and 3-bromo-5-methyl-11-(4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-ol was obtained as a residual dark yellow glass; yield, 18 g, (96%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]1=[O:17].[C:18](=[O:21])([O-])[O-:19].[Na+].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>O>[CH:24]1[C:28]2[CH:2]([CH2:3][O:19][C:18]([NH:1][C@H:2]3[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C:3]3=[O:17])=[O:21])[C:8]3[C:25](=[CH:26][CH:5]=[CH:6][CH:7]=3)[C:24]=2[CH:28]=[CH:26][CH:25]=1
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)CN1CCCC[C@H](N)C1=O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C1=O
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (3S)-3-amino-2-oxoperhydroazepine-1-acetate (7 g) in THF (50 me) was added to a solution of sodium carbonate (3 g) in water (30 ml). A solution of N-(9-fluorenylmethoxycarbonyloxy)succimimide (9.7 g) in THF (100 ml) was then added dropwise over 30 minutes with stirring. The reaction mixture was stired at ambient temperature for a further 30 minutes. Water (200 ml) was added and the reaction mixture extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (100 ml), dried (MgSO4) and evaporated. The residue was purified by MPLC on silica, eluting initially with dichloromethane and gradually increasing to 15% ethyl acetate/dichloromethane to give tert-butyl (3S)-3-(9-fluorenylmethoxycarbonylamino)-2-oxoperhydroazepine-1-acetate (10.9 g) as a clear oil; NMR (d6-DMSO): 1.45 (s, 9H), 1.5-2.15 (m, 6H), 3.1-3.25 (m, 1H), 3.6-3.75 (m, 1H), 4.0-4.5 (m, 5H), 6.25 (d, 1H), 7.25-7.45 (m, 4H), 7.6 (d, 2H), 7.75 (d, 2H); mass spectroscopy, m/e (ES+) 465.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][C:15](OC(C)=O)=O>>[CH3:14][C:15]1[NH:13][S:10](=[O:12])(=[O:11])[C:3]2[CH:4]=[C:5]([Br:9])[CH:6]=[C:7]([Br:8])[C:2]=2[N:1]=1
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Reactant: CC(=O)OC(C)=O
Product: CC1=Nc2c(Br)cc(Br)cc2S(=O)(=O)N1

Procedure:
A stirred solution of 2-amino-3,5-dibromobenzenesulfonamide (see compound 125) (660 mg; 2 mmol) was refluxed in Ac2O (25 ml; 265 mmol) over night. The reaction mixture was poured onto ice and filtered. The isolated solid was washed with Et2O. M.p. 287–289° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])(=O)C.[NH4+:17]>C(O)C>[NH2:17][CH:4]([CH2:3][CH:2]([CH3:12])[CH3:1])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)CC(N)CC(C)C
Temperature: 80 °C
Reaction time: 15 h
Yield: 34.8 %

Procedure:
Ru(OCOCH3)2((R)-dm-binap)(5.5 mg, 0.058 mmol), ethyl 5-methyl-3-oxo-hexanoate (500 mg, 2.903 mmol), ammonium acetate (224 mg, 2.903 mmol) and ethanol (2.5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo and the residue was purified by column chromatography on silica gel (eluent:hexane ethyl acetate/triethylamine=50/50/5) to give ethyl (−)-3-amino-5-methylhexanoate (175 mg) as a colorless oil in 35.0% yield. The resulting ethyl (−)-3-amino-5-methylhexanoate was converted into ethyl 3-(4-nitrobenzoylamino)-5-methylhexanoate, and the enantiomeric excess of the product was found to be 97.3% ee by HPLC analysis using a CHIRALCEL OD-H column.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13]CC)=[O:12])[C:2]=1[C:16]([O:18]CC)=[O:17].[OH-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[C:2]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1cc2ccccc2nc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2ccccc2nc1C(=O)O

Procedure:
To a solution of diethyl 2,3-quinolinedicarboxylate (0.162 mol) in ethanol (150 ml) is added a solution of sodium hydroxide (0.50 mol) in water (400 ml). The mixture is heated at reflux for 5 hours, and the ethanol then removed by distillation at atmospheric pressure. The solution is cooled in an ice bath, diluted with water (100 ml), and acidified with concentrated hydrochloric acid, added in small increments. The precipitate is filtered, washed with water, and air dried to afford the desired 2,3-quinolinedicarboxylic acid as the trihydrate; mp 271°-277° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:29]#[C:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:29]([C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: C#CCCCC
Reactant: Nc1nc(I)nc2c1nc(NCc1ccccc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CCCCC#Cc1nc(N)c2nc(NCc3ccccc3)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-benzylaminoadenosine (11, 230 mg, 0.46 mmol) and 1-hexyn (2.23 mmol). The mixture was purified by column chromatography (EtOAc). Yield 146 mg (0.32 mmol, 70%), mp 141–143÷C; Rƒ 0.26 (5% MeOH in EtOAc); 1H NMR (DMSO-d6) δ 7.64 (t, 1H, J=6.10 Hz, NH), 7.36–7.18 (m, 5H, phenyl), 6.59 (bs, 2H, NH2), 5.92 (d, 1H, J=7.71 Hz, H-1′), 5.77 (t, 1H, J=4.85 Hz, OH-2′), 5.32 (d, 1H, J=6.74 Hz, OH-5′), 5.18 (d, 1H, J=4.18 Hz, OH-3′), 4.64 (q, 1H, J=4.64 Hz, H-2′), 4.58 (t, 2H, J=4.65 Hz, NHCH2), 4.09 (t, 1H, J=4.09 Hz, H-3′), 3.98 (d, 1H, J=1.60 Hz, H-4′), 3.62 (q, 2H, J=2.58 Hz, H-5′), 2.36 (t, 2H, J=6.92 Hz, ≡CCH2), 1.55–134 (m, 4H, CH2CH2), 0.89 (t, 3H, J=7.11 Hz, CH3); MS m/z 453 (M+H)+; Anal. (C23H28N6O4) C, H, N.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:57])([F:56])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:55])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:27]=3)[C@H:20]2[CH3:55])[CH:10]=[C:9]([C:8]([F:7])([F:57])[F:56])[CH:14]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CCOCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
Morpholine (207 μl, 2.369 mmol), methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (INTERMEDIATE 46, 350 mg, 0.474 mmol), and THF (2.4 mL) were stirred at 100° C. for 10 minutes in the microwave reactor, at which time LCMS shows complete conversion to target. The reaction was partitioned between water and ethyl acetate. The organic was then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude isolate was purified by silica gel chromatography, eluting with 25-100% ethyl acetate/hexanes to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ 8.20 (d, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.92 (d, 1H), 7.88 (s, 1H), 7.72 (s, 2H), 7.46 (d, 1H), 7.31 (d, 1H), 5.63 (d, 1H), 4.74 (d, 1H), 4.31 (m, 1H), 4.00 (m, s, 4H), 3.94 (s, 3H), 3.86 (m, 4H), 3.80 (m, 4H), 2.37 (s, 3H), 0.72 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.[CH3:44][N:45]([CH:47]=[O:48])[CH3:46]>>[CH3:44][N:45]([CH3:46])[C:47]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:24])[C:5]1=[O:34])=[O:48]
Reactant: CN(C)C=O
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.057 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (3 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.0055 mL, 0.06 mmol) (40° C. After 2½ h the reaction was cooled, concentrated in vacuo, and the resulting residue was triturated with EtOAc and water, filtered, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.84 (s, 1 H), 2.39-2.47 (m, 4 H), 2.52-2.57 (m, 2 H), 2.71 (s, 6 H), 3.23-3.31 (m, 2 H), 3.44-3.55 (m, 2 H), 3.56-3.62 (m, 4 H), 4.12 (s, 2 H), 4.25 (t, J=6.32 Hz, 2 H), 6.57 (t, J=5.55 Hz, 1 H), 7.09-7.18 (m, 2 H), 7.41 (dd, J=8.70, 5.62 Hz, 2 H), 8.30 (s, 1 H), 8.53 (s, 1 H), 10.40 (t, J=5.90 Hz, 1 H); ES+ MS: 541 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11][C:12](=[O:16])N(C)C)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[F:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:1]([OH:3])=[CH:2][C:12](=[O:16])[S:11]2
Reactant: CC(=O)c1c(F)cccc1SC(=O)N(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(O)c2c(F)cccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Dimethyl-thiocarbamic acid S-(2-acetyl-3-fluoro-phenyl) ester (2.1 g, 8.7 mmol) was dissolved in anhydrous THF (25 mL.) This solution was slowly added to a rapidly stirring solution potassium tert-butoxide (22 mL, 1M, 22 mmol) via cannula. Upon complete addition, the reaction was permitted to stir overnight at ambient temperature. The reaction was concentrated in vacuo and the residue dissolved in water and extracted three times with an equal volume of 5:1 heaxanes:ethyl acetate. The organic portions were discarded and the aqueous phase acidified with 1N HCl to precipitate the product. The product was isolated via filtration and dried to provide the title compound (1.59 g.) 1H NMR (200 MHz, DMSO-d6): δ (ppm)=12.192 (br s, 1H), 7.651-7.546 (m, 1H), 7.421 (d, 1H), 6.036 (s, 1H).