Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[O:26][CH3:27].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C)C=O>[Br:18][C:19]1[C:20]([O:26][CH3:27])=[CH:21][C:22]([Cl:25])=[C:23]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:11][CH:10]=2)=[O:9])[CH:24]=1
Reactant: COc1cc(Cl)ccc1Br
Reactant: CCc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-ethyl benzoic acid (AQ) (0.50 g, 3.33 mmol) in dry dichloromethane (20 mL) was added dropwise oxalyl chloride (0.32 mL, 3.68 mmol) followed by N,N-dimethylformamide (0.1 mL). After being stirred for 2 h at room temperature, the reaction mixture was evaporated and the residue was dissolved in dry dichloromethane (20 mL) at room temperature under agron. After cooling to −5° C., 1-bromo-4-chloro-2-methoxybenzene (0.6 g, 2.78 mmol) was added. Then AlCl3 (0.43 g, 3.33 mmol) was added portionwise and the reaction temperature was kept between −5° C. and 0° C. After being stirred at room temperature for four hours, the reaction mixture was poured onto ice water and extracted with dichloromethane (80 mL). The combined organic layers were washed with 1 M HCl (10 mL), water (10 mL) and brine (10 mL), and then dried over anhydrous Na2SO4 Concentration under reduced pressure gave AR as a white solid. Yield: 0.5 g (52.3%). 1H-NMR (CDCl3, 400 MHz): δ 7.75 (d, J=8.4 Hz, 2H), 7.60 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 6.98 (s, 1H), 3.99 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:35]2[C:36]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:37][CH:38]=[CH:39][C:34]=2[CH3:33]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3Cl)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][NH:30][CH:31]=2)=[CH:23][CH:22]=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:30]2[CH:31]=[C:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)[N:28]=[CH:29]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1ccc(-c2c[nH]cn2)cc1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-n2cnc(-c3ccc(OC)cc3)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 79.9 %

Procedure:
A mixture of 1.200 g (4.49 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester and 0.861 g (4.94 mmol) of 4-(4-methoxy-phenyl)-1H-imidazole in 15 ml of tetrahydrofuran are refluxed for 5 hours. After cooling, the reaction mixture is distributed between ethyl acetate and water, the organic phase separated and washed with brine, dried over Na2SO4 and concentrated to dryness. The residue is purified by flash chromatography on silica (20 μm particle size) with ethyl acetate/hexane 2:3, yielding 1.511 g of 5-[4-(4-methoxy-phenyl)-imidazol-1-yl]-2-nitro-4-trifluoromethyl-benzoic acid methyl ester as a yellow powder. 1H-NMR (DMSO-d6, 400 MHz): 3.80 s, 3H; 3.95 s, 3H; 7.00 d, J=10.4 Hz, 2H; 7.78 d, J=10.4 Hz, 2H; 7.95 s, 1H; 8.00 s, 1H; 8.28 s, 1H; 8.72 s, 1H.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9]>[Bi](Cl)(Cl)Cl>[CH2:1]([O:5][CH:6]([O:10][CH2:1][CH:2]=[CH:3][CH3:4])[CH2:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4]
Reactant: CCCC=O
Reactant: C/C=C/C=O
Agent: Cl[Bi](Cl)Cl
Product: CC=CCOC(CCC)OCC=CC
Yield: 178.5 %

Procedure:
The general procedure of Example 2 was repeated except that 72 g (1 mole) of n-butanal and 2 mg of bismuth chloride were used instead of 70 g of crotonaldehyde and 3 mg of stannous chloride dihydrate, respectively to give 177.0 g of n-butanal dicrotyl acetal (R1 =an n-propyl group, R2 =a hydrogen atom and R3 =a crotyl group] (boiling point: 116° C./25 mmHg) (yield: 89.4%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26]([OH:28])=O)[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[O:61]1[CH:65]=[CH:64][CH:63]=[C:62]1[CH2:66][CH2:67][NH2:68]>CN(C)C=O.C(OCC)C.O>[O:61]1[CH:65]=[CH:64][CH:63]=[C:62]1[CH2:66][CH2:67][NH:68][C:26](=[O:28])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH3:29]
Reactant: NCCc1ccco1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1ccco1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 69.9 %

Procedure:
A room temperature solution of 0.30 g (0.76 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.11 g (0.81 mmol) of 1-hydroxybenzotriazole hydrate in 10 mL of anhydrous N,N-dimethylformamide under N2 atmosphere was treated with 0.16 g (0.83 mmol 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride in one portion. The reaction was stirred for 1.75 hours at room temperature and treated with 0.09 g (0.93 mmol) of triethylamine and 0.13 g (0.88 mmol) of 2-furanethaneamine hydrochloride. The reaction was stirred for 21 hours at room temperature, then partitioned between saturated aqueous NaHCO3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed with aqueous 1M citric acid (3×15 mL), water (2×15 mL), saturated aqueous NaHCO3 (15 mL), water (15 mL), and saturated aqueous NaCl (15 mL), dried over Na2SO4, and concentrated in vacuo. The residue was passed through a plug of SiO2 (70×230 mesh, 50% ethyl acetate-hexane eluant, 15 mL medium sintered glass funnel) to give a clear glass. The residue was dissolved in diethyl ether (3 mL), methanol (5 mL), and water (2 mL), and concentrated in vacuo until a solid formed. The mixture was treated with water, filtered, and dried to give 0.26 g (70%) of the desired product as a white solid, mp 87°-97° C.; 1H NMR (CDCl3) δ1.5-2.0 (17H, m), 2.67-2.74 (2H, m), 3.29 (1H, d, J 15 Hz), 3.46-3.49 (3H, m), 4.82 (1H, br s), 5.16 (1H, br s), 5.95 (1H, d, J 3 Hz), 6.25 (1H, dd, J 3 Hz and J 2 Hz), 6.37 (1H, br s), 6.97 (1H, d, J 2 Hz), 7.1-7.3 (3H, m), 7.36 (1H, d, J 8 Hz), 7.59 (1H, d, J 8 Hz), 8.18 (1H, br s).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14]OS(C)(=O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C-:22]#[N:23].[Na+]>CS(C)=O.O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][C:22]#[N:23])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 140 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240) (7 g, 21.73 mmol) in dimethyl sulfoxide (200 mL) were added KI (0.361 g, 2.17 mmol) and NaCN (1.6 g, 32.6 mmol). The reaction mixture was then stirred at 140° C. for 6 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (2×300 mL) and the organic layer was washed with water and brine. It was then dried over Na2SO4 and concentrated. The crude product was purified by 100-200 silica column chromatography using 5% ethyl acetate in hexane as the eluent to give [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241) (3.3 g, 60%) as a colorless thick liquid.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]2[CH2:10][N:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:20][Li].O.Cl.[OH-].[Na+]>C1COCC1.O>[CH:1]1([CH2:6][C@H:7]([CH2:10][NH:9][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([OH:19])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Li]O
Reactant: O=C1[C@H](CC2CCCC2)CN1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](CNOCc1ccccc1)CC1CCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 106.9 %

Procedure:
A mixture of (3R)-3-(cyclopentylmethyl)-1-[(phenylmethyl)oxy]-2-azetidinone (20 g, 77.1 mmol) and LiOH.H2O (32.4 g, 0.77 mol) in THF/water (500 mL/170 mL) was stirred at room temperature for 36 h. To the reaction mixture was added 6M HCl (130 mL), and then 1 N NaOH was added until a neutral pH was obtained. The layers were separated, and the aqueous layer was extracted once with EtOAc. The combined organics were dried (MgSO4) and concentrated to provide (2R)-3-cyclopentyl-2-({[(phenylmethyl)oxy]amino}methyl)propanoic acid (22.85 g, >100%) as a clear, colorless oil. LCMS: (M+H)+: 277.9.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:26][CH3:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)(=O)C.O.[OH-].[Li+]>CO.O>[C:32]([O:31][C:29]([NH:28][C:6]([CH2:26][CH3:27])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1)[CH2:5][OH:4])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCC(CCc1ccc(OCCCCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CO)(CCc1ccc(OCCCCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 116 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-ethyl-4-(4-(4-phenylbutyloxy)phenyl)butyl acetate (3.4 g) in methanol (50 ml) was added a solution of lithium hydroxide monohydrate (0.33 g) in water (10 ml) and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give the subject compound (3.6 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.Cl[CH2:18][C:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([NH:30][C:31](=[O:47])[C:32]3[C:37]([F:38])=[CH:36][CH:35]=[C:34]([NH:39][S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41])[C:33]=3[F:46])[CH:28]=2)[NH:23][CH:22]=1)=[O:20]>CCO>[F:46][C:33]1[C:34]([NH:39][S:40]([CH2:43][CH2:44][CH3:45])(=[O:41])=[O:42])=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[C:31]([NH:30][C:27]1[CH:28]=[C:29]2[C:21]([C:19](=[O:20])[CH2:18][N:13]3[CH2:14][CH2:15][CH2:16][CH:11]([F:10])[CH2:12]3)=[CH:22][NH:23][C:24]2=[N:25][CH:26]=1)=[O:47]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Reactant: FC1CCCNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CN4CCCC(F)C4)c3c2)c1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
Hunig's base (0.0196 mL, 0.106 mmol) and 3-fluoropiperidine (0.0148 g, 0.106 mmol) were added to N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.0106 mmol) in EtOH (0.2 mL), which was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified via column chromatography (5% to 10% MeOH/DCM) to provide 2,6-difluoro-N-(3-(2-(3-fluoropiperidin-1-yl)acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (3 mg, 52.6%). 1H NMR (400 MHz, CD3OD) δ 8.90-8.92 (m, 1H), 8.62-8.63 (m, 1H), 8.60 (s, 1H), 7.63-7.69 (m, 1H), 7.13-7.16 (m, 1H), 4.60-4.80 (m, 1H), 3.76 (s, 2H), 3.08-3.15 (m, 2H), 2.86-2.94 (m, 1H), 2.59-2.79 (m, 4H), 2.50-2.55 (m, 1H), 1.80-1.93 (m, 4H), 1.57-1.71 (m, 2H), 1.04-1.08 (m, 3H); m/z (APCI-pos) M+1=538.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH:19]1([CH2:22][N:23]([CH2:29][CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:22][CH:19]1[CH2:21][CH2:20]1)[CH2:29][CH3:30])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CCN(CCCCN)CC1CC1
Product: CCN(CCCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12)CC1CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine, N1-(cyclopropylmethyl)-N1-ethylbutane-1,4-diamine (Step 1), the title compound is obtained; MS (Found M+1=412).
Reaction SMILES: [H-].[Na+].C(OC(N[C:11]1[S:15][C:14]([C:16]([N:18]([CH3:30])[CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:17])=[C:13]([CH3:31])[CH:12]=1)=O)(C)(C)C.CI>CN(C)C=O.C(OCC)(=O)C>[C:24]([O:23][C:22]([N:21]([CH3:29])[CH2:20][CH2:19][N:18]([CH3:30])[C:16]([C:14]1[S:15][C:11]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][C:13]=1[CH3:31])=[O:17])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(CNC(=O)OC(C)(C)C)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 198.9 %

Procedure:
Sodium hydride (50 mg, 55%, 1.14 mmol) was added to a solution of the compound (407 mg, 0.952 mmol) obtained in Example 89b in N,N-dimethylformamide (3 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.119 mL, 1.90 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed successively with water (×3) and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, v/v) to give the title compound (418 mg; yield, 99%) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:17]1)=[O:13].C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[C:1]([NH:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:17]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(=O)NCC1CCCN(Cc2ccc(Cl)cc2)C1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccccc1)NCC1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A chloroform (0.4 mL) solution of benzoyl chloride (0.060 mmol) was added to a chloroform (1.0 mL) solution of 3-[(glycylamino)methyl]-1-(4-chlorobenzyl)piperidine (0.050 mmol) and triethylamine (0.070 mmol). The resulting reaction mixture was shaken at room temperature for 2.5 hours, and an (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was then added to the obtained mixture. The resulting mixture was shaken at room temperature for 12 hours and filtered, and the resin was washed with dichloromethane (0.5 mL). The filtrate and washings were combined, and dichloromethane (4 mL) was added. The obtained mixture was washed with an 2 M aqueous solution of NaOH (0.5 mL) and concentrated to thereby afford 3-[(N-benzoylglycyl)amino]methyl-1-(4-chlorobenzyl)piperidine (Compd. No. 434) -(14.7 mg, 74%). The purity was determined by RPLC/MS (91%). ESI/MS m/e 400 (M++H, C22H26ClN3O2).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5](O)[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.[N+:20]([C:23]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=1N)([O-:22])=[O:21]>[Cu](F)F.C(#N)C>[N+:20]([C:23]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:24]=1[O:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:12])[CH3:11])([O-:22])=[O:21]
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC1(C)CCCC(C)(C)N1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 69.3 %

Procedure:
The procedure of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 7.84 g (76 mmol) of tert-butyl nitrite, 25 mg (0.25 mmol) of copper(II) fluoride, 120 mL of acetonitrile and 10.3 g (50 mmol) of 2-nitro-4-trifluoromethylaniline at 65° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 6.0 g of light yellow crystals melting at 54-55° C., a 68.9% yield based on nitroxyl. The structure is confirmed by 1Hnmr, mass spectroscopy and elemental analyses.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:11](=[O:14])[CH2:12]Br)[CH:9]=[CH:10][C:4]=2[C:3]=1[CH3:15].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:11](=[O:14])[CH2:12][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)[CH:9]=[CH:10][C:4]=2[C:3]=1[CH3:15]
Reactant: c1c[nH]cn1
Reactant: Cc1c(Br)sc2cc(C(=O)CBr)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1c(Br)sc2cc(C(=O)Cn3ccnc3)ccc12
Yield: 32.9 %

Procedure:
A mixture of 2-bromo-6-bromoacetyl-3-methylbenzo[b]thiophene (1.74 g.), imidazole (0.34 g.) and sodium carbonate (1.50 g.) in acetone (20 ml.) was heated under reflux for 2 hours and then evaporated. Water (50 ml.) was added to the residue and the mixture was extracted several times with ethyl acetate. The combined extracts were dried (Na2SO4) and evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallized from isopropanol/petrol (b.p. 60°-80°) to give 2-bromo-6-(1-imidazolyl)acetyl-3-methylbenzo[b]thiophene (0.55 g.), m.p. 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(Sc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of ester from step 3 and LiOH (2N, 3 eq) in MeOH (0.2M) was stirred at reflux for 2 h, cooled to rt and acidified to pH 3 with HCl 10%. The mixture was extracted with ether and the solvent evaporated. The residue was purified by stirring vigorously in hexane followed by filtration to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH:1]1([CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([N:20]3[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]3)=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(NCCCC1CC1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (28% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.89, 7.73, 7.65, 7.58, 7.38, 6.99, 4.08-3.67, 3.54-3.46, 3.39-3.31, 1.77-1.66, 1.34-1.23, 0.72-0.62, 0.45-0.36, 0.06-0.04. MS (ES+) m/z 462.2 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[C:4]([C:12]([OH:14])=[O:13])=[CH:5][N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].[F:16][CH:17]([F:27])[C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CO>[F:16][CH:17]([F:27])[C:18]1[CH:23]=[C:22]([C:2]2[C:3](=[O:15])[C:4]([C:12]([OH:14])=[O:13])=[CH:5][N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=2[CH3:8])[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(C(F)F)c1
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)O)cn1C(C)C
Temperature: 75 °C

Procedure:
A mixture of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 3c, 3.00 g, 8.32 mmol, based on 76% purity), 3-(difluoromethyl)-phenylboronic acid (2.30 g, 13 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (690 mg, 0.94 mmol) and 2 M aqueous K2CO3 solution (10 mL, 20 mmol) in acetonitrile (20 mL) is heated for 2 h at 75° C. The reaction mixture is diluted with methanol and purified by preparative reversed phase HPLC (XBridge, gradient of acetonitrile in water, 0.3% NH4OH, 30° C.). Yield: 1.46 g (55% of theory); ESI mass spectrum: [M+H]+=322; Retention time HPLC: 0.92 min (Z018_S04).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@@H:12]([N:25]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1[O:37][CH3:38])(=O)C1C=CC=CC=1.[Na].[Cl-].[NH4+]>CO>[CH3:38][O:37][C@@H:11]1[C@H:10]([OH:9])[C@@H:14]([CH2:15][OH:16])[O:13][C@H:12]1[N:25]1[CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(C(F)(F)F)c(=O)[nH]c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C(F)(F)F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.5 %

Procedure:
3',5'-Di-O-benzoyl-2'-O-methyl-5-trifluoromethyluridine (10.6 g, 20 mmoles) was dissolved in dry methanol (250 ml). Sodium metal (0.7 g, 30 mmoles) was added and the resulting solution was stirred at room temperature for 17 hours. Ammonium chloride (1.6 g, 31 mmoles) was added and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel (100 g) column eluting with a gradient of 0 to 10% methanol in CH2Cl2 to afford 6.1 g (94%) 2'-O-methyl-5-trifluoromethyluridine as a white solid, mp 192°-194°. 1H NMR (DMSO-d6): δ3.43 (s, 3H, OCH3), 3.5-3.8 (m, 2H, H-5'), 3.8-4.0 (m, 2H, H-3',4'), 4.12 (m, 1H, H-2'), 5.18 (d, J=7 Hz, 1H, 3' -OH), 5.40 (br t, 1H, 5'-OH), 5.78 (d, J=2.5 Hz, 1H-1'), 8.92 (s, 1H, H-6), 11.80 (br s, 1H, N-H). Anal. Calcd for C11H13F3N2O6 (326.23): C, 40.49; H, 3.99; N, 8.59. Found: C, 40.42; H, 4.17; N, 8.32.