Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][NH:3]1.Br[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27](C(OC(C)(C)C)=O)[N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]=[C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([C:19]([F:20])([F:22])[F:21])[CH:5]=[CH:4][N:3]1[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[NH:27][N:26]=1
Reactant: N#Cc1cc(C#N)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(C#N)cc(Oc2c(C(F)(F)F)ccn(Cc3n[nH]c4ncccc34)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}isophthalonitrile (0.076 g, 0.249 mmol), tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.078 g, 0.249 mmol) and potassium carbonate (0.034 g, 0.249 mmol) were combined and diluted with dimethylformamide (1 mL) and stirred at room temperature. After 16 hours, water (10 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting solid was dissolved in TFA. After 30 minutes, the solution was concentrated. The resulting solid was suspended in methanol and filtered to afford the title compound as a solid. 1H NMR (DMSO-d6) δ 8.52 (d, J=4.6 Hz, 1H), 8.17-8.17 (m, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.06 (d, J=7.1 Hz, 1H), 7.98 (m, 2H), 7.18 (dd, J=8.2 Hz, J=4.7 Hz, 1H), 6.65 (d, J=7.3 Hz, 1H), 5.52 (s, 2H). HRMS (M+1)=437.0981.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[NH:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[N+:24]([O-])([OH:26])=[O:25].O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[NH:8][C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:10]([N+:24]([O-:26])=[O:25])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
In 13 ml of acetic anhydride was suspended 5.0 g of 3,4-diethoxycarbonyl-6-phenyl-2-pyridone; and the suspension was cooled to -10° C. Fuming nitric acid (1.32 ml; 2.0 eq.) was added dropwise over 1 hour, and the mixture was stirred for 45 minutes as it is. After 40 ml of water was added, the mixture was stirred at room temperature and left standing overnight. The resulting crystals were collected by filtration and dried. Yield: 4.61 g (80.7%). The crystals were recrystallized from ethanol, to give pale yellow needles.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([Cl:15])=[C:8]([CH3:14])[CH:9]=[C:10]([N+:11]([O-])=O)[C:4]=2[O:3]1.[H][H]>C1COCC1.[Pd]>[NH2:11][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[C:7]([Cl:15])=[C:8]([CH3:14])[CH:9]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Cl)CC(C)O2
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)c2c(c1Cl)CC(C)O2

Procedure:
51.0 g of 3C was dissolved in 600 ml of THF. The solution was divided in half, and each half was hydrogenated (40-50 psig hydrogen pressure) in the presence of 1 g of palladium-on-charcoal catalyst. The final combined reaction mixtures were filtered, the filtrates were combined, dried (MgSO4) and evaporated to dryness, to give 7-amino-2,3-dihydro-2,5-dimethyl-4-chlorobenzofuran (3D).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[CH2:6][CH2:7]Cl)[CH3:2].[NH2-].[Na+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1([CH3:9])[CH2:7][CH2:6]1)=[O:10])[CH3:2]
Reactant: CCOC(=O)C(C)CCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C1(C)CC1
Yield: 47.6 %

Procedure:
Cannon and coworkers (J. Am. Chem. Soc., 1959, 81, pages 1660-1666) disclose the reaction of α-methyl-γ-chlorobutyric acid ethyl ester with sodamide under strictly anhydrous conditions in benzene to provide 1-methylcyclopropane carboxylic acid ethyl ester in a yield of 47.6%. Schwarze and coworkers, U.S. Pat. No. 4,520,209, disclose the reaction of methyl 4-chloro-2-methylbutyrate in methanol with an excess of sodium methylate at a reaction temperature of 90° C. or higher. Although, an 87% yield was claimed by Schwarze et al., wiped film distillation or extraction was required to the separate methyl 1-methylcyclopropanecarboxylate from the sodium chloride by-product. Schwarze and coworkers disclose a boiling point for methyl 1-methylcyclopropanecarboxylate of 136° C. German Patent Publication DE 3026094 discloses the conversion of 4-chloro-2-methylbutyrate to 1-methylcyclopropaneamide via sodium methoxide/ammonia in an autoclave at 145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]1=[O:15].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:14][CH2:13][C@@H:11]1[O:10][C:9](=[O:15])[N:8]([CH2:7][CH2:6][O:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=2[O:2][CH3:1])[CH2:12]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1OCCN1C[C@H](CO)OC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1OCCN1C[C@H](COS(C)(=O)=O)OC1=O

Procedure:
Using dichloromethane solution of the compound of formula 2 prepared in Example 2 80.1 g (0.3 mol), triethylamine 45.5 g (0.45 mol) and methanesulfonyl chloride 37.8 g (0.33 mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@@H:9]([NH2:17])[C@H:8]([O:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])O.[Na+].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[C@@H:9]([NH:17][C:29](=[O:31])[CH3:30])[C@H:8]([O:18][CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@H](OS(C)(=O)=O)C1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 190 mg of 20 and EtOAc (1.6 mL) in a 10 mL round-bottom flask equipped with a magnetic stirrer and an inert gas supply was added was added at RT aqueous 1 M sodium hydrogen carbonate (1.6 mL). To the resulting mixture was added 62 μl of acetic anhydride and the 2-phase mixture was stirred for 1 h at RT. The mixture was diluted with 2.0 mL of EtOAc, the organic phase was separated, dried (Na2SO4), filtered and the filter cake was washed with total 3.0 mL EtOAc. The filtrate was evaporated at 40° C./200-10 mbar to afford 192 mg of 22 as off white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9](=[O:11])[CH2:10][C:3]=12.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=[C:10]3[C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[Cl:1])[NH:8][C:9]3=[O:11])=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=C1Cc2c(Cl)ccnc2N1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2nccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A reaction mixture of 4-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (85 mg, 0.5 mmol), 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (125 mg, 0.5 mmol), 0.1 mL of piperidine and 10 mL of ethanol was stirred at room temperature overnight. The yellow precipitate was filtered after cooled with an ice bath, washed with cold ethanol and dried to give 185 mg (92%) of 5-(4-chloro-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][NH:10][CH3:11]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([N:10]([CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(Br)n1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cccc(Br)n1

Procedure:
Heat a stirred mixture of 2,6-dibromopyridine (15; g, 63; mmol) and dimethylamine (40% aqueous solution, 21.4; mL, 190; mmol, 3; equiv) in ethanol (75; mL) for 3; days at 70° C. Evaporate the yellow solution to a reduced volume and dilute with ethyl acetate (100; mL). Wash with water (40; mL), brine (40; mL) and dry over sodium sulfate. Decant the liquid and evaporate to give pale yellow oil (13.8; g). Distill using a Kügelrohr apparatus to give the title product as a colorless liquid (12.4; g, b.p.=100-140° C. at 0.1 mbar). MS (m/z): 201, 203; (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[S:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:18].[K+].[K+]>S(=O)(=O)(O)O>[F:16][C:2]([F:15])([F:1])[S:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:18])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 65 °C
Yield: 114.5 %

Procedure:
A suspension of 4-(trifluoromethanesulfonyloxy)benzaldehyde (5.2 g, 20.5 mmol, described in JACS, 1987, 109, 5478) and potassium dichromate (2.5 g) in sulfuric acid (30%, 47 mL) was heated at 65° C. for 1 h. The mixture was allowed to cool to ambient temperature and then poured on ice. The formed precipitate was filtered off and washed with several portions of water. The crude product was recrystallized from water/ethanol (1:1) affording 2.63 g (47% yield) of the title compound: mp 178-180° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, 2 H), 7.64 (d, 2 H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]C=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3=NC=CC=C3CC2)=[N:27]C(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3=[N:27][CH:17]=[CH:16][CH:15]=[C:14]3[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCc3cccnc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCc3cccnc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 8.47, 7.61, 7.18, 5.30, 3.05, 2.81, 2.78, 1.98, 1.33-1.19; (MS/CI) calcd for C16H19N4Br+H 348.3, found 347.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].Br[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=1)[C:16]#[N:17]>>[NH2:6][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:9]=[CH:8][CH:7]=1
Reactant: C#Cc1cccc(N)c1
Reactant: N#Cc1cncc(Br)c1
Product: N#Cc1cncc(C#Cc2cccc(N)c2)c1
Yield: 37.6 %

Procedure:
Prepare according to the general procedure outlined in EXAMPLE 30 using 3-ethynylaniline (1.0 g, 8.5 mmol) and 5-bromonicotinonitrile (1.56 g, 8.54 mmol) to give the title compound (0.7 g, 38%).
Reaction SMILES: C(N([P:6](N(CC)CC)[C:7]1[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[CH:9][CH:8]=1)CC)C.[CH:25]1[CH:30]=[C:29]2[CH:31]=[CH:32][C:33]([OH:46])=[C:34]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][C:36]=3[OH:45])[C:28]2=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH:38]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=2[C:35]2[C:34]3[C:33]([O:46][P:6]([C:7]4[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:10]=[CH:9][CH:8]=4)[O:45][C:36]=2[CH:37]=1)=[CH:32][CH:31]=[C:29]1[C:28]=3[CH:27]=[CH:26][CH:25]=[CH:30]1
Reactant: CCN(CC)P(c1cccc(NC(=O)C(C)(C)C)n1)N(CC)CC
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(-p2oc3ccc4ccccc4c3c3c(ccc4ccccc43)o2)n1

Procedure:
N-(6-(bis(diethylamino)phosphino)pyridin-2-yl)pivalamide (0.292 g, 0.60 mmol, 1 eq) was dissolved in toluene (12 ml). (S)-BINOL (0.172 g, 0.60 mmol, 1 eq) was subsequently added and the reaction mixture was refluxed for 3 hours. The solvent was removed under reduced pressure. The title compound could be obtained in the form of a white solid (0.276 g, 0.56 mmol, 93%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:15]([O:19][C:20]([C:22]1[CH:32]=[C:31]([OH:33])[C:25]2[CH2:26][CH:27]([CH2:29][OH:30])[O:28][C:24]=2[CH:23]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([C:22]1[CH:32]=[C:31]([O:33][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:25]2[CH2:26][CH:27]([CH2:29][OH:30])[O:28][C:24]=2[CH:23]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
Benzyl bromide (1.8 mL, 15.2 mmol) and Cs2CO3 (4.89 g, 15.0 mmol) were added to a solution of 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (4.0 g, 15.0 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with H2O (60 mL) and extracted EtOAc (2×60 mL). The organic layers were washed with H2O (2×100 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 30-40% EtOAc in hexanes to give a pale yellow oil (4.43 g, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.34-7.45 (m, 5 H) 7.19 (s, 1 H) 7.09 (s, 1 H) 5.13 (s, 2 H) 4.96-5.03 (m, 1 H) 3.85 (ddd, J=12.00, 6.95, 3.28 Hz, 1 H) 3.74 (dt, J=12.13, 6.06 Hz, 1 H) 3.27 (dd, J=16.42, 9.60 Hz, 1 H) 3.01 (dd, J=16.42, 7.07 Hz, 1 H) 1.58 (s, 9 H); LCMS for C21H24O5 m/z 357.00 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:12]=1>>[CH3:32][O:31][C:21]1[CH:20]=[C:19]([NH:18][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])[CH:16]=[C:15]([CH3:17])[N:14]=2)[CH:24]=[CH:23][C:22]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1
Reactant: N#Cc1cccc(O)c1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(Oc3cccc(C#N)c3)n2)ccc1-n1cnc(C)c1
Yield: 75 %

Procedure:
The title compound was prepared in analogous manners as described in example 9) from 3-hydroxy-benzonitrile and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 75% yield as a pale-brown solid. MS ISP (m/e): 413.4 (100) [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([OH:14])[CH3:13])=[CH:8][CH:7]=1.CS[CH:17](SC)[CH2:18][N+:19]([O-:21])=[O:20]>>[OH:14][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]2[O:10][C:9]([CH2:11][N:12]([OH:14])[CH3:13])=[CH:8][CH:7]=2)=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:8]=1)[CH3:13]
Reactant: CSC(C[N+](=O)[O-])SC
Reactant: CN(O)Cc1ccc(CSCCN)o1
Product: CN(O)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCSCc2ccc(CN(C)O)o2)o1
Yield: 45.6 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N-hydroxy-N-methyl-2-furanmethanamine base (1.48 g) and 1,1-bis-(methylthio)-2-nitroethane (0.57 g) was heated at 98°-100° for 3 hr. The oily residue was chromatographed (silica/acetone) and the appropriate eluate evaporated to give the title compound (0.78 g) as an amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:12])[C:7]2[C:5](=[CH:4][C:3]([Cl:9])=[C:2]([Br:1])[CH:8]=2)[NH:6][CH:20]=1)=[O:16])[CH3:19]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(Cl)c(Br)cc2c1=O
Yield: 88 %

Procedure:
A mixture of 4-bromo-3-chloroaniline (8.3 g) and diethyl ethoxymethylene malonate (8.9 g) was heated at 120°-130° C. for 1.5 hours. The mixture was added to diphenyl ether (140 ml) and refluxed for 30 minutes. The cooled mixture was filtered, the solid was washed with benzene and dried. The solid was recrystallized from DMF to give 6-bromo-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (11.7 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)O)([CH3:4])([CH3:3])[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[N:24]1[C:20](=[O:30])[C:21]2[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:23]1=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of [3-(3-chloro-phenyl)-3-hydroxy-propyl]carbamic acid tert-butyl ester (12 g, 42 mmol), phthalimide (6.2 g, 42 mmol), and PPh3 (14.3 g, 55 mmol) in THF (150 mL) was added DEAD (9.0 mL, 55 mmol) dropwise at about 5° C. After 1 hour, the mixture was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:8) to afford [3-(3-chloro-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-carbamic acid tert-butyl ester. (Yield 15.65 g, 90%). LC-MS: [M+H]+ 415.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:13]2[C:12](=[CH:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=3)[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C>[CH:3]1[C:13]2[C:12](=[CH:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCC=C2c3ccccc3COc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCC=C2c3ccccc3COc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 78 h

Procedure:
Sodium hydroxide (1M, 2.5 ml, 2.5 mmol) was added to a solution of a 4:1 E/Z double-bond isomer mixture of ethyl 3-{4-[3-(6H-dibenzo[b,e]oxepin-11-ylidene)-propoxy]-phenyl}-2-ethoxy-propionate (0.24 g, 0.51 mmol) in ethanol (5 ml) and the mixture stirred at room temperature for 78 h. The resulting mixture was partitioned between 1N hydrochloric acid (20 ml) and dichloromethane (20 ml), and the organic phase collected. The aqueous phase was further extracted with dichloromethane (3×20 ml) and the combined organics washed with brine, dried (Na2SO4) and evaporated to give a pale yellow gum. This was then purified by column chromatography on silica gel (3% methanol in dichloromethane eluent) to give the title compound as an inseparable 4:1 mixture of E and Z double-bond isomers, as a pale yellow glass; 0.186 g (80%).
Reaction SMILES: [C:1]([O:4][CH:5]1[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:6]1[NH2:7])(=[O:3])[CH3:2].[I:25][C:26]1[CH:31]=[C:30]([I:32])[CH:29]=[C:28]([I:33])[C:27]=1[C:34]1[CH:39]=[CH:38][C:37]([C:40](Cl)=[O:41])=[C:36]([N+:43]([O-:45])=[O:44])[CH:35]=1>>[N+:43]([C:36]1[CH:35]=[C:34]([C:27]2[C:28]([I:33])=[CH:29][C:30]([I:32])=[CH:31][C:26]=2[I:25])[CH:39]=[CH:38][C:37]=1[C:40]([C:5]1([O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:6]1[NH2:7])[O:4][C:1](=[O:3])[CH3:2])=[O:41])([O-:45])=[O:44]
Reactant: O=C(Cl)c1ccc(-c2c(I)cc(I)cc2I)cc1[N+](=O)[O-]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1OC(OC(C)=O)(C(=O)c2ccc(-c3c(I)cc(I)cc3I)cc2[N+](=O)[O-])[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7) to yield 2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 38.8 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (50 mg, 0.16 mmol), 3-(trifluoromethyl)benzoic acid (38 mg, 0.20 mol), EDCI (38 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol), and Et3N (20 mg 0.20 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%-5%-10% (NH4OH/MeOH)/CH2Cl2) to give 30 mg of the title product as a white solid. MS found: (M+H)+=484.25