Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40])[C@@H:3]1[OH:45].N1C=CC=CC=1.[C:52](Cl)(=[O:57])[CH2:53][CH2:54][CH2:55][CH3:56]>C(Cl)(Cl)Cl>[CH3:56][CH2:55][CH2:54][CH2:53][C:52]([O:36][CH2:35][C:33]([C@:11]1([OH:37])[CH2:12][C:13]2[C:18](=[C:17]([OH:19])[C:16]3[C:20](=[O:21])[C:22]4[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:23]=4[C:24](=[O:25])[C:15]=3[C:14]=2[OH:32])[C@@H:9]([O:8][CH:6]2[O:7][CH:2]([CH3:1])[CH:3]([OH:45])[CH:4]([NH:38][C:39]([C:41]([F:44])([F:42])[F:43])=[O:40])[CH2:5]2)[CH2:10]1)=[O:34])=[O:57]
Reactant: CCCCC(=O)Cl
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](OC2CC(NC(=O)C(F)(F)F)C(O)C(C)O2)C1)C(=O)c1c(OC)cccc1C3=O

Procedure:
A solution containing 5.0 mg. of N-trifluoroacetyladriamycin dissolved in 0.5 ml. of anhydrous pyridine was treated with 18 microliters of valeroyl chloride, which was added in small portions over a two-day period. The reaction was monitored by thin layer chromatography and when the presence of N-trifluoroacetyladriamycin could no longer be observed, the reaction mixture was diluted with 10 ml. of chloroform. The chloroform solution was extracted three times with pH 4 gaseous buffer and once with pH 7 buffer. The dried chloroform solution was then evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel G with chloroform:methanol:water (120:20:1 by volume) as the solvent system. The major orange-colored band was removed and washed free of silica gel with a mixture of methanol and ethyl acetate. Upon evaporation of the methanol and ethyl acetate, 2.19 mg. of N-trifluoroacetyladriamycin-14-valerate was obtained. This material was idential by spectral and chromatographic comparison with samples of N-trifluoroacetyladriamycin-14-valerate prepared by the earlier described methods.
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][CH:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH3:31]>CN(C)C=O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([CH2:31][C:30](=[O:32])[CH2:29][CH2:28][CH:27]([CH3:33])[CH3:26])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1
Reactant: CC(=O)CCC(C)C
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
An oily suspension (50% by weight; 0.5 g) of sodium hydride is added in small portions at a temperature in the region of -5° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (1.6 g) in anhydrous dimethylformamide (20 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of -5° C. A solution of 5-methyl-2-hexanone (1.2 g) in anhydrous dimethylformamide (5 cc) is then added and stirring is continued for 5 hours at a temperature in the region of 20° C. The reaction mixture is then poured into distilled water (200 cc) and extracted with dichloromethane (3×100 cc). The organic phases are combined, washed with distilled water (5×20 cc) and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oily residue obtained is purified by chromatography on silica gel (15 g) contained in a column 1.5 cm in diameter [eluent: dichloromethane/methanol (99:1 by volume)]. Elution is first performed with 30 cc of solvent: the corresponding eluate is discarded; elution is then performed with 100 cc of solvent: the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is recrystallized in ethyl acetate; 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (1.3 g), m.p. 150° C., is thereby obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[S:29](=[O:37])(=[O:36])[N:28]=1>C(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[S:29](=[O:36])(=[O:37])[N:28]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: NCCCCOn1cc(CN2CCCCC2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S1(=O)N=C(NCCCCOn2cc(CN3CCCCC3)cn2)c2ccccc21
Reaction time: 3 h
Yield: 29.4 %

Procedure:
3.5 g of 4-(4-piperidinomethylpyrazol-1-yloxy)butylamine and 1.4 g of triethylamine are dissolved in 50 ml of methylene chloride. A solution of 2.8 g of 3-chlorobenzoisothiazole 1,1-dioxide in 15 ml of methylene chloride is then added dropwise. After standing for 3 hours at room temperature, the reaction mixture is washed with water, the organic phase is evaporated down and the residue is chromatographed over neutral Al2O3 (activity level III), using methylene chloride as the mobile phase. 1.7 g of the title compound are obtained, the product being crystallized from ether.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]3([C:44](O)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)[CH:25]=1.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]3([C:44]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)[CH:25]=1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)NS(C)(=O)=O)CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (60.4 mg, 0.31 mmol) is added to a stirred ice cold solution of 4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid [150 mg, 0.3 mmol, Example 80(a)], methanesulfonamide (30 mg, 0.31 mmol) and 4-dimethylaminopyridine (38.5 mg, 0.3 mmol) in dry DCM under nitrogen and the reaction mixture is stirred overnight, while warming to room temperature. The mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate, washed with 0.1 N HCl, brine and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluting with ethyl acetate/heptane to afford N-[4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carbonyl]-methanesulfonamide [65 mg, Example 80(b)] . LCMS: RT=2.54 minutes; MS: 579, 581 (M+H); 1H NMR (300 MHz, CDCl3): □8 (1H, s), 7.85 (1H, d, J=3.5 Hz), 7.45 (3H, m), 7.2 (2H, s), 6.4 (1H, s), 5.38 (1H, b), 4 (3H, s), 3.65-3.9 (6H, m), 3.2 (3H, s), 3.08 (2H, t, J=3.5 Hz), 2.45 (2H, b), 2.18 (2H, m). IC50<1 nM
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=1[F:26]>>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])=[CH:19][C:18]=1[F:26]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Br)c(F)c1

Procedure:
1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17, 1.25 g, 6 mmol) was reacted with 4-bromo-3-fluorobenzoic acid (1.1 g, 5.0 mmol) in an analogous manner to that described in Method 16 to give the title compound, which was used without further purification; Mass Spectrum: (M+H+-Boc) 311.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[S:4]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10](OC)=[C:9]([O:16]C)[CH:8]=1)(=[O:6])=[O:5])[CH3:2].B(Br)(Br)Br.[OH2:24].Cl>ClCCl>[CH2:1]([N:3]([CH2:18][CH3:19])[S:4]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([OH:16])[C:8]=1[OH:24])(=[O:6])=[O:5])[CH3:2]
Reactant: O
Reactant: CCN(CC)S(=O)(=O)c1cc(Cl)c(OC)c(OC)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cc(Cl)cc(O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing 0.7 g of N,N-diethyl-5-chloro-3,4-dimethoxybenzenesulfonamide in 10 ml of dichloromethane 9.0 ml of 1 molar BBr3 in dichloromethane was added. The solution was stirred overnight at room temperature. Water and hydrochloric acid were added and the mixture was extracted with dichloromethane. The solvent was evaporated. Yield 0.3 g (47%), m.p. 62°-64° C.
Reaction SMILES: [C:1]1([C:7]23[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17](=[O:25])(=[O:24])[CH2:16][C:10]4([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[CH:8]2[O:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[H][H]>[Pd].C(Cl)Cl>[OH:9][C@@H:8]1[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:16][S:17](=[O:25])(=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S1(=O)CC2(CCCCC2)C2OC2(c2ccccc2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@H](c2ccccc2)c2ccccc21
Yield: 40.1 %

Procedure:
A mixture of 0.5 g (1.4 mmoles) of 58, 20 ml of ethanol,10 ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg (60%) as a white solid, mp99-100° C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][C:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)=[C:53]([CH3:62])[O:52][N:51]=1>CN(C=O)C>[CH3:49][C:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)=[C:53]([CH3:62])[O:52][N:51]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Cc1noc(C)c1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(3,5-dimethyl-isoxazol-4-yl)-phenylamine (0.012 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 61% yield: LCMS (ESI) m/z 377 (MH+).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:19]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O>ClCCl>[N:1]([CH2:4][C@@H:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)[NH2:19])=[N+:2]=[N-:3]
Reactant: CCCC(C)COc1ccc([C@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)COc1ccc([C@@H](N)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of t-butyl (1R)-2-azido-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (14.2 g, 39.2 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (18.1 mL, 235 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residue was transferred to a separatory funnel containing saturated aqueous K2CO3 solution. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford (1R)-2-azido-1-(4-(2-methylpentyloxy)phenyl)ethanamine (9 g, 88% yield) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.6 Hz, 2 H), 3.96 (t, J=6.4 Hz, 1H), 3.80 (dd, J=9.1, 5.5 Hz, 1H), 3.71 (dd, J=9.2, 6.7 Hz, 1H), 3.29-3.39 (m, 2H), 2.59-2.75 (m, 2H), 1.86 (dq, J=12.8, 6.5 Hz, 1H), 1.25-1.48 (m, 3H), 1.12-1.22 (m, 1H), 0.95 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.1 Hz, 3H); HRMS (ESI) m/e 263.1860 [(M+H)+, calcd for C14H23N4O 263.1872].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21](O)=[O:22])(=[O:15])=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1.C(N(C(C)C)CC)(C)C>ClCCl>[N:7]1([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:20]([CH:24]=2)[C:21]([NH:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:22])(=[O:15])=[O:14])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalyl chloride (0.06 ml, 0.66 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 5-(4-morpholinylsulfonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 66; 250 mg, 0.66 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h. The organic phase was evaporated in vacuo to give the crude acyl chloride as a yellow solid. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (62.3 mg, 0.66 mmol) and diisopropylethylamine (0.12 ml, 0.66 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times and saturated brine (10 ml) two times, dried over sodium sulfate, and evaporated in vacuo to give the crude product as a orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12](=[O:17])[C:9]=2[NH:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O.O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:10]1[CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:18])[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12](=[O:17])[C:9]1=2)[CH3:31]
Reactant: CCOC(=O)c1c[nH]c2c(=O)ccccc2c1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1cc(C(=O)OCC)c(=O)c2ccccc(=O)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-3-carboxylic acid ethyl ester (1 g, described in example 2), potassium carbonate (1 g) and ethyl bromoacetate (1 g) in dimethylformamide (DMF, 50 ml) was stirred at 25° C. for 5 hr. The reaction mixture was diluted with water and extracted with chloroform. The chloroform extract was evaporated to dryness. The residue was purified by chromatography on silica gel using chloroform-methanol (99:1) as the eluant. The appropriate fractions were pooled and crystallized from acetone to give the title compound; mp 152°-154° C.; nmr (CDCl3) δ1.3 (t, 6H), 4.3 (m, 4H), 4.85 (s, 2H), 7.0 (m, 3H), 8.2 (m, 2H); ir (CHCl3) 1740, 1730, 1690, 1630 cm-1 ; uv λ max (MeOH) 349 nm (ε12,625), 235 (18,760), 212 (25,070); Anal Calcd for C17H17NO6 : C, 61.63% H, 5.17% N, 4.23% Found: C, 61.67% H, 5.23% N, 4.25%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>ClCCl>[Br:31][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccccc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
To a 100-mL round-bottomed flask was added 2-methoxybenzyl alcohol (1.33 mL, 9.99 mmol, Aldrich, St. Louis, Mo.), triphenylphosphine (2.62 g, 9.99 mmol, Aldrich, St. Louis, Mo.) and carbon tetrabromide (0.969 mL, 9.99 mmol, Aldrich, St. Louis, Mo.) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 4 h and then the solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% EtOAc in hexanes to give 1-(bromomethyl)-2-methoxybenzene (1.78 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][C:18](OS(C)(=O)=O)([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2].CS(Cl)(=O)=O.[N:38]1C=CC=CC=1>N.C(O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][C:18]([NH2:38])([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: c1ccncc1
Reactant: CCOC(=O)CC1(OS(C)(=O)=O)CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC1(N)CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Reaction time: 2 h

Procedure:
1 g of ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)-4-methanesulfonyloxypiperidine-4-acetate (obtainable from the 4-hydroxy compound (see Example 13) with methanesulfonyl chloride/pyridine) is dissolved in a 2% NH3 solution in 10 ml of a 1:1 mixture of ethanol and THF, and the solution is left to stand at 20° for 2 hours. The solution is concentrated by evaporation and subjected to conventional work-up to give ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)-4-aminopiperidine-4-acetate, FAB 387.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH3:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=O>C(O)C>[CH3:5][C:6]12[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]1=[N:4][CH2:1][CH:2]=[CH:3]2
Reactant: CC1C(=O)CCc2ccccc21
Reactant: C#CCN
Solvent: CCO
Product: CC12C=CCN=C1CCc1ccccc12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Propargylamine (0.21 mL) is added to a microwave oven suited vessel charged with a stir bar, 1-methyl-2-tetralone (0.50 mL), NaAuCl4*2H2O (27 mg), and ethanol (3 mL) (caution: a very exothermic reaction may evolve afterwards→keep an ice bath at hand). The resulting mixture is stirred under microwave irradiation at 100° C. for 10 min. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 25:75→0:100) to afford the title compound as an oil. Yield: 0.29 g (50% of theory); LC (method 1): tR=1.78 min; Mass spectrum (ESI+): m/z=198 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:43][NH:44][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48]>C1COCC1.C(N(CC)CC)C>[CH3:48][N:47]([CH3:49])[CH2:46][CH2:45][N:44]([CH3:43])[C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CNCCN(C)C
Reactant: O=C(O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCN(C)C(=O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of (4-(((benzyloxy)carbonyl)amino)-phenyl)acetic acid (6 g) in THF (100 ml) were added WSC (4 G), HOBt (3 g), and N,N,N-trimethylethylenediamine (2.1 g) sequentially. Triethylamine (3 ml) was added to the reaction mixture. After stirring at room temperature overnight, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from IPE/ethyl acetate to obtain the titled compound (7 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=2[O:8][CH:7]=1.C(OCC)C>CS(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH:7]=[C:6]([CH2:5][C:1]#[N:2])[C:10]=2[CH:11]=1
Reactant: Fc1ccc2occ(CCl)c2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CCc1coc2ccc(F)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Lithium aluminium hydride (15 g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmosphere followed by dropwise addition of a solution of methyl 5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). The temperature increased to 55° C. during the addition. After stirring for 2 h the reaction was quenched succesively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL). Further tetrahydrofuran (500 mL) was added and the mixture stirred for 1 h. The mixture was filtered and the precipitate extracted with a mixture of methylene chloride (1 L) and ethanol (0.5 L). The combined organic phases were concentrated in vacuo giving an oil which was applied to silica gel flash chromatography (eluent: methylene chloride/25% aq. NH3 99:1). The resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g) crystallised on standing. A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated succesively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g). A suspension of sodium cyanide (10 g) in dimethylsulfoxide (150 mL) was heated to 80° C. followed by quick addition of a solution of 3-chloromethyl-5-fluorobenzofuran (10 g) in dimethylsulfoxide (50 mL). The mixture was kept at 80° C. for ½ h and then poured onto ice. Standard work-up with diethyl ether gave a dark crystalline material, 5-fluorobenzofuran-3-ylacetonitrile (8.8 g).