Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1I.C1COCC1>C(Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(I)c(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 100 °C
Reaction time: 42 h
Yield: 96.5 %

Procedure:
A mixture of potassium carbonate (1.48 g, 10.7 mmol), phenylboronic acid (645 mg, 5.29 mmol), 3-chloro-4-iodonitro benzene (1.00 g, 3.53 mmol), and THF (31 ml) was degassed with nitrogen in a sealable tube for 10 min. The dichloromethane adduct of 1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (351 mg, 0.429 mmol) was added to the reaction mixture and the pressure tube was sealed. The reaction mixture was stirred at 100° C. for 42 h. The mixture was cooled to 23° C., diluted with DCM (40 ml), and filtered. The filtrate was concentrated. The residue was purified by FCC (3-50% EtOAc/hexanes) to yield the titled compound (796 mg, 97%). 1H NMR (600 MHz, DMSO-d6): 8.42-8.41 (m, 1H), 8.26 (dd, J=8.5, 2.2, Hz 1H), 7.72 (d, J=8.5 Hz, 1H), 7.55-7.48 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25].CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: COc1ccc(N)cc1OC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc(Nc2ncc3c(n2)CCN(C(=O)c2cccnc2)C3)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3,4-dimethoxyaniline (0.015 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature, EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 53% yield (0.019 g, 0.049 mmol).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]#[N:26]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]#[N:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol), K2CO3 (8.5 g, 61.6 mmol) and 2-chloroacetonitrile (5.5 g, 73 mmol) in acetonitrile (250 ml) was heated at reflux for 24 hours. The insolubles were filtered off and rinsed with methylene chloride (DCM). During concentration of the solvents on the rotary evaporator, crystals appeared. The crystals were collected and weighed 5.79 g. The product in the mother liquor was further purified by flash chromatography over a silica gel column (SiO2, 70 g; eluted with DCM, and 1% CH3OH in DCM). The second crop of product thus obtained weighed 5.2 g. The total yield was 10.9 g. The sample was recrystallized once more form ethanol, m.p. 130°-132° C.
Reaction SMILES: [CH:1]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[N+:2]([O-:4])=[O:3].[CH2:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CO>[N+:2]([C:1]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:4])=[O:3]
Reactant: C=C(C(=O)OCC)C(=O)OCC
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Solvent: CO
Product: CCOC(=O)C(CC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])C(=O)OCC

Procedure:
Carefully controlled reaction conditions are required because the addition of a nucleophile (nitro- or halonitroalkyl ion) to a methylenemalonate ester gives the salt of an alkylmalonate which is itself capable of undergoing further nucleophilic reactions. Nitroform, a strong acid, reacts with diethyl methylenemalonate in aqueous methanol at ambient temperature, without a base as catalyst, to produce diethyl 2,2,2-trinitroethylmalonate. The same conditions may also be used to produce dimethyl 2,2,2-trinitroethylmalonate. The reaction of 1,1-dinitroethane with methylenemalonates does not take place under these conditions, presumably because the nitro compound is not sufficiently ionized. However, the addition of triethylamine to an ether solution of 1,1-dinitroethane and dimethyl methlenemalonate at 0° C. resulted in a 72% yield of dimethyl 2,2-dinitropropylmalonate. In the same manner, diethyl 2,2-dinitropropylmalonate may be prepared. Finally, the addition fluorodinitromethane to methylenemalonates in ether solution in the presence of catalytic amounts of pyridine produces good yields of dimethyl and diethyl 2-fluoro-2,2-dinitroethylmalonates.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[C:14](=[O:18])[NH:15][CH2:16][CH:17]=[C:12]2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]#[CH:28]>S1(CCCC1)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:28][C:27]#[CH:26])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[C:14](=[O:18])[NH:15][CH2:16][CH:17]=[C:12]2[N:11]=1
Reactant: C#CCBr
Reactant: COc1cc(O)ccc1C1=NC2=CCNC(=O)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: C#CCOc1ccc(C2=NC3=CCNC(=O)C3=N2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g of 2-(2-methoxy-4-hydroxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one was suspended in 30 ml of sulfolane, 1.41 g of potassium carbonate were added, and the mixture was stirred at room temperature. After 15 minutes and again after one hour, 0.9 ml of propargyl bromide was added, and the mixture was then stirred for another 1.25 hours. The solvent was substantially evaporated in vacuo, and the residue was stirred with methylene chloride. After the precipitate had been filtered off and washed with water, the product contained in the organic phase was purified on a silica gel column (eluant: methylene chloride/ethanol 1:0 to 1:0.03). The product crystallized with half a mol of ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-])=[CH:17][C:16]=2[N:15]=[CH:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:27].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:27])[C:16]=2[N:15]=[CH:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCn1cnc2c(N)nc3ccccc3c21
Reaction time: 0.5 h

Procedure:
15.87 g (44.52 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]quinoline-5-oxide was dissolved in 400 ml of methylene chloride and 200 ml of concentrated aqueous ammonia (29%) was added thereto under ice-cooling. A solution of p-toluenesulfonyl chloride (9.34 g, 48.98 mmol) in 50 ml of methylene was further added thereto and the mixture was stirred for 30 minutes, then rasing up to room temperature stirred for 2 hours. After the reaction solution was separated, the organic phase was washed with brine and dried (Na2SO4). The solvent was distilled off and the residue was triturated with chloroform, then collected by filtration to obtain 7.10 g (19.97 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]-quinoline-4-amine shown below as a faint yellowish white solid. ##STR55## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3440, 3380, 3110, 2980, 1710, 1650, 1530, 1260, 1160, 760.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:23](=[O:25])[CH3:24])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=2)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CO.C(Cl)Cl>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([CH2:38][N:35]3[CH2:36][CH2:37][O:32][CH2:33][CH2:34]3)=[CH:44][CH:43]=2)[CH:3]=[C:4]([N:22]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:23](=[O:25])[CH3:24])[C:5]=1[CH3:21])=[O:8]
Reactant: CC(=O)N(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 44.3 %

Procedure:
A solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(N-(tetrahydro-2H-pyran-4-yl)acetamido)benzamide (50 mg, 0.10 mmol), (4-(morpholinomethyl)phenyl)boronic acid (41 mg, 0.13 mmol), sodium carbonate (27 mg, 0.25 mmol) in 3 ml of dioxane was degassed with argon for 20 min, Pd(PPh3) (12 mg, 0.0012 mmol) was added to the mixture and heated to 100° C. for overnight. The reaction was cooled to room temperature and diluted with water, before extraction with 10% MeOH in DCM, the organic layers were dried over Na2SO4, concentrated and the resulting crude product purified by silica gel (100-200) chromatography to obtain the title compound (26 mg, 23%).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH3:5][CH:6]([CH2:10][C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([OH:9])=O>CO>[CH2:12]([CH:11]1[O:16][C:7](=[O:9])[CH:6]([CH3:5])[CH2:10]1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)CC(=O)CC(C)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC1CC(C)C(=O)O1
Temperature: -2.5 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A cold solution (−5 to 8° C.) of sodium borohydride (0.6 g) in 2N-sodiumhydroxide (1.5 mL) was added dropwise very slowly to a stirred solution of 2,6-dimethyl-4-oxo-heptanoic acid (3) (1.0 g) in methanol (20 mL) and stirring was continued overnight. Methanol was evaporated and more water (3-4 mL) was added to the residue and the mixture was once again cooled to −5 to 0° C. and then acidified with cold dilute hydrochloric acid and then extracted with ether (3×50 mL). The combined extracts were washed with brine, dried (Na2SO4) and then concentrated to give a crude liquid which was loaded on silica gel column and the column was eluted with an increasing amount of hexane/ethyl acetate (100:0 to 95:5). The fractions were monitored on TLC plate and then the desired fractions were combined and solvent was removed under vacuum to afford 4-isobutyl-2-methyl-4-butanolide (trans:cis=68:32 on NMR basis) of formula (1) in 76% yield as a colourless oil with coconut flavour; Rf=0.80 (10% ethylacetate in hexane); IR (film) λmax 2962, 1772, 1558, 1457, 1362, 1173, 1135, 1004, 1024, 926 cm−1; 1H NMR δ4.63-4.55 (dqd, 0.32H, cis-5-CH), 4.46-4.38 (dtd, 0.68H, trans-5-CH), 2.73-2.62 (m, 1H, 3-CH), 2.55-2.47 (m, 1H, 7-CH), 2.09-2.04 and 1.84-1.78 (2 m, 2H, 4-CH2), 1.67-1.61 and 1.50-1.41 (2 m, 2H, 6-CH2), 1.36-1.26 and 1.27-1.25 (2d, 3H, 10-CH3), 0.96-0.95 and 0.94-0.93 (2d, 6H, 8-CH3 & 9-CH3) (FIG. 3); 13C NMR δ179.42 (d, C-2), 76.55 (d, C-5), 44.43 (d, C-3), 37.69 (s, C-4), 35.69 (d, C-7), 33.77 (s, C-6), 21.92 (d, C-10), 15.65, 14.89 (2s, C-8 and C-9) (FIG. 4); GC of compound 1 appeared at tr=30.24 and tr=30.44 also confirms the presence of isomers (FIG. 5); EIMS m/z 156 [M]+ (1.3), 99 (100%), 84 (5.4), 71 (28.5), 56 (14.7), 42 (12.8) (FIG. 6).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:6])[C:3]([OH:5])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.O[CH:31]([C:34]1[CH:50]=[C:49]2[N:37]([CH2:38][C:39]3[C:40]2=[N:41][C:42]2[C:47]([CH:48]=3)=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36](=[O:51])[C:35]=1[CH3:52])[CH2:32][CH3:33]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:52][C:35]1[C:36](=[O:51])[N:37]2[C:49](=[CH:50][C:34]=1[CH:31]([O:4][C:3](=[O:5])[C:2]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:1])[CH3:6])[CH2:32][CH3:33])[C:40]1=[N:41][C:42]3[C:47]([CH:48]=[C:39]1[CH2:38]2)=[CH:46][CH:45]=[CH:44][CH:43]=3
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(OC(=O)C(C)(C)NC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture containing 2-methyl-2-[N-[(1,1-dimethylethoxy)carbonyl]amino]propionic acid (406 mg, 2.0 mmol) and dicyclohexylcarbodiimide (432 mg, 2.0 mmol) in CH2Cl2 (3 mL) under an argon atmosphere were added (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (153 mg, 0.5 mmol) and 4-dimethylaminopyridine (25 mg). The resulting mixture was allowed to stir at room temperature for 4 d and then was poured into CH2Cl2, washed successively with 5% aqueous NaHCO3, 0.5N HCl and H2O, and dried over sodium sulfate. Removal of the solvent in vacuo and purification of the residue by column chromatography (silica gel) eluting with a solvent gradient of 1.5-5% MeOH/CH2Cl2 afforded the title compound as an off-white solid. 1H NMR (CDCl3) d 8.33 (s, 1H), 8.20 (d, J=8.9 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.80 (m, 1H), 7.62 (m, 1H), 7.33 (s, 1H), 5.92 (dd, J=7.5, 6.3 Hz, 1H), 5.25 (s, 2H), 5.10 (br s, 1H), 2.38 (s, 3H), 2.08-1.82 (m, 2H), 1.56 (s, 3H), 1.55 (s, 3H), 1.41 (s, 9H), 0.99 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>C1C=CC=CC=1>[C:32]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:35])[CH2:33][CH3:34]
Reactant: CCOC(=O)CCCNC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)CC)C(c1ccccc1)c1ccccc1
Yield: 92.6 %

Procedure:
Analogously to Example 19, 9.0 g of ethyl 4-benzhydrylaminobutyrate and 4.3 g of diisopropylethylamine in 100 ml of benzene are reacted with 3.1 g of propionyl chloride. The reaction product is recrystallized from ethyl acetate/ligroin (1:1) to obtain 9.9 g (92.5% of theory) of ethyl N-propionyl-4-benzhydrylaminobutyrate (M.P. 83° to 85°).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3].[CH2:23](I)[CH3:24].[OH-].[K+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:23]([O:1][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:15])=[O:14])[CH3:3])[CH3:24]
Reactant: CCI
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)O)cccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCOC(C)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
11.9 g (37.8 mmol) of 4-(1-hydroxyethyl)-1-tosyl indole in 150 ml of methylene chloride was mixed at room temperature under argon with 13.3 g (85 mmol) of ethyl iodide, 6.7 g of tetrabutylammonium hydrogen sulfate and 6.7 g (119.3 mmol) of pulverized potassium hydroxide one after the other. The solution was stirred for 2 hours. After filtration over silica gel, the solution was again mixed with equal amounts of ethyl iodide, tetrabutylammonium hydrogen sulfate and potassium hydrogen oxide. The reaction mixture was stirred for 2 hours at room temperature, washed with 200 ml of water and the organic phase dried, filtered and concentrated. Subsequent chromatography on silica gel with cyclohexane/ethyl acetate (8:2) yielded 8.5 g of 4-(1-ethoxyethyl)-1-tosyl indole as oil.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([Br:17])=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5](Br)[CH:4]=2.[CH2:19]([Mg]Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([Br:17])=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:4]=2
Reactant: CCCCCCCC[Mg]Br
Reactant: Fc1c(F)c2cc(Br)ccc2c2ccc(Br)cc12
Product: CCCCCCCCc1ccc2c(c1)c(F)c(F)c1cc(Br)ccc12
Yield: 51.8 %

Procedure:
In analogy to Example 2, from 4.1 g of 9,10-difluoro-2,7-dibromo-phenanthrene and 10 mmol of octylmagnesium bromide. The catalyst used is 0.2 mmol of 1,3-bis(diphenylphosphine)butanenickel(ll) chloride. Chromatography gives 2.1 g of 9,10-difluoro-2-bromo-7-octyl-phenanthrene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=2[C:28]([NH:30][CH2:31][CH3:32])=[O:29])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=2[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CC)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide to yield a yellow solid (6.3%). LCMS: m/z=525.19 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.11 (s, 1H), 7.49 (s, 1H), 7.35 (d, 1H, J=7.3 Hz), 7.24 (m, 3H), 7.14 (d, 1H, J=8.6 Hz), 7.02 (s, 1H), 3.70 (m, 2H), 3.43 (m, 2H), 2.26 (m, 2H), 2.06 (s, 2H), 1.32 (s, 6H), 1.28 (m, 3H), 1.18 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2]>C(O)C>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Solvent: CCO
Product: CCOc1cc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
Prepared analogously to Example 40 by catalytic hydrogenation of benzyl 2-ethoxy-4-[N-(α-acetoxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate in ethanol.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:22][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][C:27]=1[O:35][CH3:36])[CH3:24].[F:37][C:38]1[CH:46]=[CH:45][C:44](/[C:47](/[NH:50]O)=[N:48]/[H])=[C:43]2[C:39]=1[C:40]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:41][NH:42]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:37][C:38]1[CH:46]=[CH:45][C:44]([C:47]2[N:50]=[C:32]([C:29]3[CH:30]=[N:31][C:26]([O:25][CH:23]([CH3:22])[CH3:24])=[C:27]([O:35][CH3:36])[CH:28]=3)[O:34][N:48]=2)=[C:43]2[C:39]=1[C:40]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:41][NH:42]2
Reactant: COc1cc(C(=O)O)cnc1OC(C)C
Reactant: [H]/N=C(\NO)c1ccc(F)c2c(CCC(=O)OCC)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(OC)c4)n3)ccc(F)c12
Reaction time: 2 h
Yield: 64.8 %

Procedure:
HOBT (161 mg) and EDCI (203 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinecarboxylic acid (110 mg) in THF (4 mL). The resulting solution was stirred for 2 hours. Ethyl 3-{4-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D45) (199 mg) in THF (4 mL) was added, and the reaction mixture was stirred at RT overnight. TBAF (780 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 2.5 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (10% EtOAc in hexane) to afford ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D50) (158 mg) as a white solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.47 (6H, d), 2.76 (2H, t), 3.24 (2H, t), 4.01 (3H, s), 4.15 (2H, q), 5.55 (1H, m), 6.91 (1H, dd), 7.14 (1H, d), 7.76 (1H, d), 8.06 (1H, dd), 8.64 (1H, d), 9.69 (1H, br s). MS (ES): C24H25FN4O5 requires 468; found 469.2 (M+H+).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=C3C(=CC=2)NC(=O)CC3)CCNCC1.[C:41]([O:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1)(=[O:43])[CH3:42]>CN(C=O)C.O.C(N(CC)CC)C>[C:41]([O:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]4)[CH2:3][CH2:4]2)=[O:50])=[CH:47][CH:46]=1)(=[O:43])[CH3:42]
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril monohydrobromide in 10 ml of DMF was added 296 mg of sodium hydrogencarbonate and stirred at room temperature for 30 minutes to convert the compound to 6-piperazinyl-3,4-dihydrocarbostyril, to which was added 0.62 ml of triethylamine. Then, a solution of 605 mg of 4-acetyloxybenzoyl chloride in 5 ml of DMF was slowly added dropwise to the mixture. After completion of addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed serially with saturated aqueous sodium hydrogencarbonate solution and with water and then dried over anhydrous sodium sulfate. Chloroform was distilled off to give 6-[4-(4-acetyloxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril.