Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:25])[NH:7][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.C(B(CC)[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)C>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)=[CH:3][C:4]([C:26]([F:27])([F:28])[F:29])=[CH:5][C:6]=4[N:7]=3)[C@H:12]([CH3:25])[CH2:13]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Reactant: CCB(CC)c1cccnc1
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cccnc3)c2[nH]1

Procedure:
4-Bromo-2-[(2R)-4-(3,5-dichloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (204 mg, 0.4 mmol, Example 149b) and 3-diethylboranyl-pyridine, (118 mg, 0.8 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 510 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH:9]([CH2:12][NH2:13])[C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1[C:11]2[CH2:10][CH:9]([CH2:12][NH:13][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][OH:24])[C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCC1Cc2ccccc2Cc2ccccc21
Reactant: O=C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(CCCCO)NCC1Cc2ccccc2Cc2ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine, γmaxCHCl3 3390, 3300 cm-1, (52.3 g, 0.234 mole), is combined with δ-valerolactone (35 g, 0.35 mole). The mixture is heated for 2 hr. at 150° C (oil bath temperature). After partial cooling, ethanol (250 ml) is added followed by a solution of potassium carbonate (50 g, 0.36 mole) in water (150 ml). The two-phase mixture is stirred at 60° C overnight. The ethanol is removed under reduced pressure and the residual mixture extracted with chloroform. The chloroform solution is washed with water, dried and taken to dryness. The residue is crystallized from benzene (750 ml) -ether (ca 800 ml) affording N-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)methyl]-5-hydroxyvaleramide, m.p. 96° - 98° C, γ maxCHCl3 3630, 3445, 3350, 1663 cm-1.
Reaction SMILES: C([N:8]([CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.N#N.[H][H]>[Pd].CC(C)=O>[NH2:8][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1
Reactant: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CC(C)=O
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Yield: 93.1 %

Procedure:
(S)-5-((dibenzylamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.95 g, 2 mmol) and 0.5 g of 10 wt % Pd—C were added to 20 mL acetone and the air was replaced with N2. The reaction stirred under 5 Mpa hydrogen at room temperature (25° C.) for 5 hours. Filtered and the solvent was evaporated to provide 0.55 g of white solid in 93% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][O:6][C:7]([C:9]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC)=O)=C(C)[NH:13][C:14]=1[CH3:15])=[O:8].C(O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][O:6][C:7](=[O:8])/[CH:9]=[C:14](\[NH2:13])/[CH3:15]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2cccc(Cl)c2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: c1ccncc1
Product: C/C(N)=C/C(=O)OCc1cccc(Cl)c1
Yield: 70 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 3-chlorobenzyl ester in 120 ml of pyridine gave 2,6 dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3-chlorobenzyl ester of melting point 142° C (from ethanol).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[N:19][CH:20]=1)[CH3:14].[CH2:22]=[O:23]>C1COCC1.CCOC(C)=O>[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[N:19][CH:20]=1)[CH3:14]
Reactant: CCc1ccc(C)nc1
Reactant: C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCc1ccc(CCO)nc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled solution (−10° C.) of diisopropylamine (2.31 mL, 16.5 mL) in THF (45 mL) is added dropwise (2.5M) n-butyllithium (6.6 mL, 16.5 mmol), let stir 10 min. then cooled to −78° C. To this mixture is added dropwise a solution of 5-ethyl-2-methylpyridine (1.98 mL, 15 mmol) in THF (3 mL) and let stir for 10 min at −78° C. To the reaction mixture is added paraformaldehyde (1.13 g, 37.5 mmol), the cold bath removed and stirring continued for 1 hr. Quenched reaction with H2O, diluted with EtOAc and the organic layer washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 0.5% ammonia/5% methanol/dichloromethane) to give the title compound as a pale yellow oil. MS (EI) 151 (M)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[C:27]([O:29]CC)=[O:28])=[O:20])=[CH:13][C:12]=1[N+:32]([O-:34])=[O:33])([CH3:3])[CH3:2]>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[C:27]([OH:29])=[O:28])=[O:20])=[CH:13][C:12]=1[N+:32]([O-:34])=[O:33])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccccc2C(C)C)c([N+](=O)[O-])c1
Solvent: O
Product: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)N2CCCCC2C(=O)O)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared by the procedures described in Example 226, substituting the ethyl ester from Example 225 with the ethyl ester from Example 242, giving a light-yellow solid. 1H NMR (CDCl3, 300 MHz) δ 1.18 (d, J=6.9 Hz, 6H), 1.40-1.89 (m, 5H), 2.34 (br d, J=11.7 Hz, 1H), 3.31-3.51 (m, 1H), 3.44 (septet, J=6.9 Hz, 1H), 4.01 (d, J=11.7 Hz, 1H), 5.42 (br s, 1H), 6.70 (d, J=7.8 Hz, 1H), 6.99 (br d, J=15.6 Hz, 1H), 7.29 (td, J=2.7, 6.9 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.45-7.58 (m, 3H), 7.64 (d, J=15.6 Hz, 1H), 8.43 (s, 1H). MS (ESI+) (M+H)+ at m/z 455. Anal. Calcd for C24H26N2O5S.0.08 H2O: C, 63.22; H, 5.78; N, 6.14. Found: C, 63.21; H, 5.65; N, 6.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10]O)[CH:6]=[CH:5][N:4]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:13][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CCO)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(CCBr)ccn1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 2-(2-methoxypyridin-4-yl)ethanol (commercially available) (700 mg, 4.57 mmol,), CBr4 (2.27 g, 6.85 mmol) and triphenylphosphine (1.8 g, 6.85 mmol) in 75 mL toluene was stirred at RT for 64 h. The mixture was filtered over a silica-plug and washed with toluene. The filtrate concentrated under vacuum to yield the crude product. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield, after evaporation of the product containing fraction, 624 mg (63%) of the title compound as colourless liquid. MS (m/e): 216.2 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:16]=1[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[CH2:3][C:4]([O-:6])=[O:5].CO.[OH-].[Na+].C(O)(=O)C>O.O1CCCC1>[CH3:1][N:2]([CH2:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:16]=1[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CN(CC(=O)[O-])Cc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(CC(=O)O)Cc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Yield: 73.7 %

Procedure:
0.22 g (0.543 mmol) of 2-(methyl((3-((3-(trifluoromethyl)phenyl) ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl)amino)acetate were dissolved in 6 ml of a mixture consisting of methanol and tetrahydrofurane with magnetic stirring and then 0.543 ml (0.543 mmol) of a 1M NaOH aqueous solution were added. The mixture was stirred at r.t. for 16 h. 0.163 ml (0.163 mmol) of a 1M NaOH aqueous solution were added. The mixture was stirred at r.t. for a further 24 h before being treated with a solution of 0.04 ml (0.705 mmol) of acetic acid in 10 ml of water. The mixture was stirred at r.t. for 30 min. The solid formed was isolated by filtration, washed with 5 ml of water and dried in a vacuum bell jar in order to obtain 0.155 g (yield=73%) of 2-(methyl((3-((3-(trifluoromethyl)phenyl) ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino) acetic acid as a beige solid. LC-MS: m/z=388 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.74 (d, J=6.7 Hz, 1H), 8.10 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.74-7.64 (m, 2H), 7.49-7.39 (m, 1H), 7.13 (t, J=6.4 Hz, 1H), 4.02 (s, 2H), 3.59 (s, 1H), 3.33 (s, 2H), 2.41 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]#[CH:25].C(OCC)(=O)C.CCCCCC>CC(C)=O>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[N:10]([CH2:25][C:24]#[CH:23])[C:9]1=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCBr
Reactant: CC1(C)NC(=O)N(Cc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C#CCN1C(=O)N(Cc2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a stirred solution of 3-benzyl-5,5-dimethylhydantoin (9.5 g, 43.6 mmole) in acetone (100 mL) at room temperature were added potassium carbonate (8.4 g, 60.9 mmole) and propargyl bromide (7.1 g of 80 % in toluene, 47.7 mmole). The reaction mixture was refluxed for 16 hr; cooled to room temperature and the solid was filtered off by suction-filtration. The filtrate was concentrated and the resultant residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate. After evaporation, a yellow crude oil was obtained. A pure product, 5.5 g (yield=50%) of 3-benzyl-1-propargyl-5,5-dimethylhydantoin as a yellow oil, was obtained by column chromatography on silica gel eluting with ethyl acetate:hexane (1:1 ).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH2:1]([S:8]([CH2:9][CH:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CCC(CSCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: O=C(O)CCC(CS(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a cooled mixture (-78° C.) of 2-[(benzylsulfanyl)methyl]pentanedioic acid (5.2 g, 19.4 mmol) in dichloromethane (100 ml) was added 3-chloroperbenzoic acid (85%, 3.9 g, 19.4 mmol) with stirring. The reaction mixture was allowed to stir for 1 hour at -78° C., then allowed to warm to room temperature. If starting material was still present according to analysis by TLC, the reaction was cooled again to -780° C. and additional 3-chloroperbenzoic acid (2-4 mmol depending on the intensity of the starting material spot) added and the reaction mixture allowed to warm at room temperature. This was repeated until no more starting material was detected by TLC. The dichloromethane was removed under reduced pressure and the resulting residue was purified by column chromatography to yield 3.8 g (69%) of white solid.
Reaction SMILES: Cl.Br[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCCCCC.[CH2:27]([Sn:31](Cl)([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30].O>C1COCC1>[CH2:36]([Sn:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH2:37][CH2:38][CH3:39]
Reactant: Brc1c(COC2CCNCC2)ccc2ccccc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(COC2CCNCC2)ccc2ccccc12
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of 1 (0.5 g, 1.6 mmole) in dry THF (50 ml) was cooled to -70° C. under argon. This was followed by the addition of 2.5 M solution of n-butylithiumin hexane (0.8 ml, 2.1 mmole) and tributyltin chloride (1.7 g, 5 mmole) and the reaction mixture was stirred for 30 min at -70° C. and then for 1 hr at room temperature. The rations mixture was then added to 50 ml of water and extracted with methylene chloride. The methylene chloride fractions were washed with saturated solution of NaHCO3, H2O, brine, dried with anhydrous MgSO4 and evaporated in vacuo to give 64 as light semi-solid. A single component was detected by TLC (ammonium hydroxide/methanol/ethyl acetate/hexane; 1:1:8:2) Rf, 0.5; NMR (CDCl3) d 0.8-1.5 (m, 27H, 3× n-butyl); d 4.6 (s, --CH--O-ring); d 7.8-8.0 (m, 6H, naphthyl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(O[N:51]1N=N[C:53]2[CH:54]=CC=C[C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:51][CH2:52][CH2:53][CH3:54])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCN
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCC(C)CC4)CC3)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and propylamine (6.78 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.6 mg, 55%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[NH:15][CH3:16])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.CCOC(C)=O.[Cl:25][C:26]1[CH:31]=[C:30](CCl)[CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:17])[NH:15][CH3:16])[CH2:12][CH2:13]2)[CH:29]=[CH:28][N:27]=1
Reactant: CNC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCc1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1-Boc-4-(N-methylcarbamoyl)piperazine was treated with 8 M HCl/EtOAc to afford a salt, then the salt (1.0 equiv) was mixed with 2-chloro-4-(chloromethyl)pyridine (1.0 equiv) (Preparation B-11) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜90% yield).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]([N:8]([CH:15]([OH:30])[C@H:16]1[O:22][C@:20]([CH2:23][CH2:24][CH2:25][CH3:26])([OH:21])[C@H:19]([OH:27])[C@@H:18]([OH:28])[C@@H:17]1[OH:29])[C:9](=[O:14])[NH:10][CH2:11][CH2:12][Cl:13])([CH3:7])[CH3:6]>C(O)(=O)C>[CH:5]([N:8]([CH:15]([OH:30])[C@H:16]1[O:22][C@:20]([CH2:23][CH2:24][CH2:25][CH3:26])([OH:21])[C@H:19]([OH:27])[C@@H:18]([OH:28])[C@@H:17]1[OH:29])[C:9](=[O:14])[N:10]([CH2:11][CH2:12][Cl:13])[N:1]=[O:3])([CH3:6])[CH3:7]
Reactant: O=N[O-]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)NCCCl)C(C)C)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC[C@]1(O)O[C@H](C(O)N(C(=O)N(CCCl)N=O)C(C)C)[C@@H](O)[C@H](O)[C@H]1O
Yield: 62.3 %

Procedure:
Sodium nitrite (0.74 g) was slowly added to a solution of 3-isopropyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (3.43 g, 8.96 mmol), obtained in the above way, in 40% aqueous acetic acid with well stirring at 0° to 5° C. After continuation of stirring for four hours at the same temperature, an ion exchange resin (13 ml, the same type as used in Example 65) was added to the resulting solution, and the mixture was stirred for 30 minutes. The ion exchange resin was filtered off, and the filtrate was vacuum-concentrated at 25° C. and purified by column chromotography (packing: Kiesel gel 60; eluent: chloroform/methanol 10:1). Thus, 2.39 g of 3-isopropyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained; yield 64.8%, m.p. 70°-72 C., [α]D20 +69.8° (C 1.0, methanol).
Reaction SMILES: [H-].[Na+].I[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:12][CH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]1=[O:21]>O1CCCC1>[C:8]([O:7][C:5]([CH2:4][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:13]([Br:12])[C:14]1=[O:21])=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)CI
Reactant: O=C1NCCCCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCCCCC(Br)C1=O

Procedure:
To a vigorously stirred suspension of 0.55 g sodium hydride in 30 ml tetrahydrofuran add over 20 min. a solution of 5.0 g t-butyl iodoacetate and 4.12 g 3-bromoperhydroazocin-2-one [Nagasawa et al., J. Med. Chem., 14 501 (1971)] dissolved in 35 ml tetrahydrofuran. After the addition is completed stir the reaction at room temperature for 1.5 hours then quench by the addition of 5-6 ml of saturated NH4Cl solution. Filter the reaction and concentrate the filtrate. Add ether to the residue, filter and wash the filtrate with H2O and brine. Dry the ether solution and concentrate to obtain 1-t-butoxycarbonylmethyl-3-bromoperhydroazocin-2-one. Prepare an analytical sample by silica gel chromatography. M.p. 107.5-109. Anal. (C13H22BrNO3). Calc: C, 48.75; H, 6.93; N, 4.37. Found: C, 48.78; H, 7.12; N, 4.26.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([NH:70][CH:71]1[CH2:75][CH2:74][NH:73][CH2:72]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:73]1[CH2:74][CH2:75][CH:71]([NH2:70])[CH2:72]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(N)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-tert.-butyloxycarbonylamino-pyrrolidine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:37]=[CH:36][C:23]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:38])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:40][OH:41].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:37]=[CH:36][C:23]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:38])[CH:21]=1)[CH2:9]/[C:10](=[N:40]\[OH:41])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)N[C@H]3CC[C@H](C(=O)O)CC3)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)N[C@H]3CC[C@H](C(=O)O)CC3)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, trans-4-{4-[1-(2-chloro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-benzoylamino}-cyclohexanecarboxylic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 13% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=552.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C1C=CC=CC=1>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:26]1)=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCC(c2ccccc2)CC1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCN1CCC(c2ccccc2)CC1

Procedure:
A mixture of m-nitrobenzaldehyde (0.66 g), 2-(4-phenylpiperidino)ethyl acetoacetate (1.2 g), piperidine (0.1 ml) and benzene (20 ml) was refluxed overnight, during which time the water produced was removed azeotropically. The solvent was then distilled off and the residue was chromatographed on silica gel (50 g) [ethyl acetate-hexane (1:1, v/v)] to give 2-(4-phenylpiperidino)-ethyl 2-(3-nitrobenzylidene)acetoacetate as an oil. Yield 0.80 g (45.7%).