Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:13])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[O:23][CH3:24].N1CCCCC1>C(O)C.O.Cl>[OH:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[C:3]2/[C:4](=[O:13])[N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[N:6]=[C:2]/2[CH3:1])=[CH:17][C:16]=1[O:23][CH3:24]
Reactant: CC1=NN(c2ccccn2)C(=O)C1
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: COc1cc(/C=C2/C(=O)N(c3ccccn3)N=C2C)ccc1O
Temperature: 0 °C

Procedure:
1.4 g (7.99 mmol) of 5-methyl-2-(2-pyridinyl)-2,4-dihydro-3H-pyrazol-3-one and 1.84 g (11.98 mmol) of 4-hydroxy-3-methoxybenzaldehyde are stirred under reflux with the addition of 3 ml of piperidine in absolute ethanol for 2 hours. The mixture is then diluted with water and slowly rendered neutral with 2N hydrochloric acid. After cooling in the ice bath, the orange precipitate which settles out is filtered off, washed with water and dried under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)[CH:21]=[O:22].C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]([C:20]2[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:18]([O:17][CH3:16])[CH:19]=2)[OH:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2cccc(OCc3ccccc3)c2)c1
Yield: 82.1 %

Procedure:
1-Benzyloxy-3-bromobenzene (10.56 g, 40.13 mmol), 3,5-dimethoxybenzaldehyde (7.34 g, 44.14 mmol), and n-butyl lithium (17.66 ml, 44.14 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (3-Benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as an oil (11.54 g, 82%): 1HNMR (CDCl3) 7.43-7.21 (m, 6H, Ar), 7.04-6.85 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.72 (d, J=3 Hz, 1H, CHOH), 5.04 (s, 2H, CH2), 3.76 (s, 6H, 2OCH3), 2.21 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.C([Li])CCC.F[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].Cl>O1CCCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:1][C:2]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=2)=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCOC(=O)c1cn(C)nc1N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C)nc1Nc1ccc(F)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 3-amino-1-methylpyrazole-4-carboxylate (Helv. Chim. Acta (1959) 42 349)(17 g) in dry tetrahydrofuran (250 ml) was stirred under nitrogen at -10° C. n-Butyl lithium (75 ml of 1.84 molar solution in hexane) was added at -10° to -15° C. The mixture was stirred at -15° C. for 10 minutes and a solution of 2,5-difluoronitrobenzene (16 g) in dry tetrahydrofuran (50 ml) was added at -15° to -10° C. The solution was warmed to room temperature and stirred for 1 hour. The ink-blue solution was poured into 500 ml of a 1:1 mixture of hydrochloric acid (2M) and ice-brine, extracted with chloroform (3×250 ml), washed with water (2×250 ml), dried with magnesium sulphate and evaporated to dryness. The brick-red residue was crystallised from ethanol (800 ml) to give the title compound having a m.p. of 162° C.
Reaction SMILES: [N:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([P:18]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[OH:17])=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[C:26]([O:25][P:18]([CH:16]([OH:17])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[NH2:1])=[CH:11][CH:12]=1)([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])([CH3:27])([CH3:28])[CH3:29]
Reactant: COC(=O)C(=Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Yield: 92 %

Procedure:
A solution of 7 (1.25 g, 2.85 mmol) in MeOH (50 mL) was hydrogenated in a Parr apparatus over 10% Pd.C (200 mg) under 40 psi H2. The hydrogen was replenished after 10 minutes. The reaction was terminated after 3 hours, and catalyst removed by filtration. Evaporation of solvent yielded 8 as a clear, colorless syrup, 1.17 g (100% crude yield). Silica gel chromatography [CHCl3 :MeOH(25:1)] provided pure 8 (92%).
Reaction SMILES: [CH:1](I)(C)C.NC1[CH2:11][CH2:10][CH:9]([N:12](C)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])CC1.[CH:21]([N:24]([CH:27]([CH3:29])[CH3:28])CC)([CH3:23])[CH3:22]>C1COCC1>[CH:27]([NH:24][CH:21]1[CH2:22][CH2:11][CH:10]([CH2:9][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:1][CH2:23]1)([CH3:28])[CH3:29]
Reactant: CC(C)I
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N)CC1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)NC1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
Isopropyl iodide (2 equivalents) was added dropwise to a suspension of tert-butyl N-[4-aminocyclohexyl]-methylcarbamate (1 equivalent) and diisopropylethyl amine (3 equivalents) in THF. The resulting mixture was stirred for 1 day. TLC analysis showed some starting amine. Additional isopropyl iodide (1 equivalent) and diisopropylethyl amine (3 equivalents) were added to the reaction mixture and heated at 40° C. for 1 day. The reaction mixture was concentrated and chromatrographed to give tert-butyl N-[4-(isopropylamino)cyclohexyl]methylcarbamate: 22% yield, 271 (ESMS, MH+); 1H NMR (CDCl3) δ 4.65 (broad, 1H), 2.91 (m, 3H), 2.42 (m, 1H), 1.80 (ABm, 4H), 1.38 (s, 9H), 0.98 (d, 6H, J=6.3 Hz), 1.32-0.85 (m, 5H).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[N+]=[N-])=[CH2:3].[Cl:7][CH2:8][C:9](=[O:34])[C@:10]1([OH:33])[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@:24]([F:30])([C@@H:25]([OH:29])[CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:31])[CH:20]=[CH:21]2)[CH2:16][CH2:15]3)[CH2:12][C@H:11]1[OH:32]>CCOCC.CO>[Cl:7][CH2:8][C:9](=[O:34])[C@:10]1([OH:33])[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@:24]([F:30])([C@@H:25]([OH:29])[CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:31])[CH:20]=[CH:21]2)[CH2:16][CH2:15]3)[CH2:12][C@H:11]1[O:32][CH2:3][C:2]([CH3:4])=[CH2:1]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: C=C(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Temperature: 0 °C

Procedure:
A solution of 2-methyl-3-diazo-1-propene in 150 ml of ether (prepared from 0.1 mole of N-(2-methyl-2-propenyl)-ethyl carbamate by the method of J. L. Brewbaker and H. Hart, J. Am. Chem., Soc., 91, 711 (1969)) is diluted with 50 ml of methanol and cooled to 0°C. A total of 7 g of 21-chloro-9-fluoro-11β,16α,17-trihydroxypregna-1,4diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on an 80 g -silica gel column. Elution with chloroform gives TLC pure material which crystallizes from acetone-hexane to give 5.4 g of 21-chloro-9-fluoro-11β,17 -dihydroxy-16α-[(2-methyl-2-propenyl)oxy]pregna-1,4-diene-3,20-dione, melting point 238°-240°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:35])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1>>[ClH:1].[CH:17]([NH:16][C:14]1[N:13]([CH3:20])[C:12]2[CH:21]=[CH:22][C:9]([N:8]([CH3:23])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH3:35])=[C:29]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:30]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1)([CH3:19])[CH3:18]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NC(C)C)n4C)n2)cc1S(N)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (60 mg, 0.18 mmol) and 5-amino-2-methyl-benzenesulfonamide (34 mg, 0.18 mmol) as a white solid (42 mg, 45%). 1H NMR (300 MHz, d6-DMSO) δ 9.85 (s, 1H), 8.67 (s, 1H), 8.51 (s, 1H), 7.87 (d, J=6.3 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 7.18-7.27 (m, 3H), 5.73 (d, J=6.0 Hz, 1H), 4.11 (m, 1H), 3.68 (s, 3H), 3.48 (s, 3H), 1.32 (d, J=6.3 Hz 6H) ppm. MS (ESI) m/z=481 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: c1ccc2ccccc2c1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc2ccccc2c1
Yield: 59.3 %

Procedure:
To 900 ml of dichloromethane contained in a 3 liter, 3-neck flask equipped with a mechanical stirrer, drying tube and thermometer and surrounded by an ice water bath was added 290.0 g (2.26 moles) naphthalene. To the stirred suspension was added 145.2 g (1.44 moles) of succinic anhydride. A total of 400 g of aluminum chloride was then added in small increments over the next 41/2 hours while stirring and cooling in an ice water bath. The resulting amber brown-yellow reaction mixture was stirred at room temperature overnight. Next morning it was poured on crushed ice and acidified with conc. hydrochloric acid. The aqueous portion was decanted and the organic layer was filtered to collect white solids. The solids were washed with dichloromethane containing 20% hexanes and slurried in 700 ml of boiling ethyl acetate. After cooling in a cold water bath, the solids were collected by filtration and washed with fresh ethyl acetate. Then the solids were recrystallized from 500 ml of glacial acetic acid and dried under vacuum to give 195.0 g (59.4% yield) of 4-(2naphthyl)-4-oxobutyric acid as an off-white solid. M.P. 171°-175° C.; M/e 229; λmax 282 nm (7,260) in ethanol.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:9][OH:10]>>[CH2:1]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC=O
Reactant: NO
Agent: Cl
Product: CCCCCCN(O)CCCCCC
Yield: 67.5 %

Procedure:
Following the general procedure of Example 2, hexanal (5.0 g, 50 mmol) is reacted with only one half equivalent of hydroxylamine hydrochloride (1.9 g, 28 mmol) to give 3.4 g of crude N,N-di-n-hexylhydroxylamine as a white solid which 90 1H NMR confirmed to be essentially only one compound. Purification of the crude product as described in Example 2 gives 2.0 g of the title compound as a white solid melting at 67° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25]O)[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:51]=[N+:52]=[N-:53].[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:51]=[N+:52]=[N-:53])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N(C(=O)OCc2ccccc2)c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](N(C(=O)OCc2ccccc2)c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Temperature: 25 °C

Procedure:
To a solution 3.36 g of (3R)-3-{benzyloxycarbonyl-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (10.8 mmol) and 2.05 ml of triethylamine (10.8 mmol) in 40 ml of dichloromethane, was added at 0° C. 0.805 ml of methanesulfonyl chloride (10.8 mmol). The reaction was stirred at rt. and monitored by TLC. The reaction was diluted with water and washed with water and brine. The org. layer was dried over Mg sulfate, filtered and the filtrate evaporated The solid residue was dissolved in 10 ml of DMF and 1.38 g sodium azide (10.8 mmol) was added and the mixture stirred under inert gas at 80° C. for 20 hrs. The DMF was evaporated, the residue dissolved in ethyl acetate, washed with water and brine, dried over Mg sulfate, filtered and evaporated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:16]=[C:15]([O:17][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=[C:13]([O:18][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:12]=1
Reactant: COC(=O)CN(CC(=O)OC)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OC)CC(=O)OC)c1
Reaction time: 48 h
Yield: 52.8 %

Procedure:
A mixture of 0.50 g (1.86 mmol) of N-[(3,5-Dihydroxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 0.81 ml (3.9 mmol) of 1-bromodecane and 0.77 g (5.57 mmol) of potassium carbonate in 15 ml of acetone was stirred at reflux for 24 hours. An additional 0.8 ml of 1-bromodecane was added and reflux was continued for 48 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated at reduced pressure to an oil which was purifiedby HPLC using 15% ethyl acetate-hexane to give 0.54 g (52% yield) of N-(2-methoxy-2-oxoethyl)-N-[3,5-bis-(decyloxy)phenyl]glycine methyl ester as an oil. The nmr and mass spectra of this product were identical to those obtained using the procedure of Example 5.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.N1C2C(=NC=CC=2)N([N:20]2[C:24](/[CH:25]=[C:26]3\[C:27](=[O:36])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[C:23]([CH3:37])[C:22]([C:38]([O-])=[O:39])=[C:21]2[CH3:41])N=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:36])/[C:26]/2=[CH:25]\[C:24]1[NH:20][C:21]([CH3:41])=[C:22]([C:38]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]2)=[O:39])[C:23]=1[CH3:37]
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Reactant: NC1CCC(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)O)CC1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
4-Amino-cyclohexanecarboxylic acid (84 mg, 0.573 mmol) was added to a solution of A4 (200 mg, 0.478 mmol) and DIEA (0.125 mL, 0.717 mmol) in 15 mL of DMF. The mixture was stirred at r.t. LC-MS was used to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was triturated with ACN for several times to provide 4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-cyclohexanecarboxylic acid (180 mg, 88.5%).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:22]([CH2:24][NH2:25])[OH:23].O>N1C=CC=CC=1>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:23][CH2:22][CH2:24][NH2:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: NCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
Triphenylchloromethane (1.00 g, 3.58 mmol) (Wako Pure Chemical Industries, Ltd.) and ethanolamine hydrochloride (1.00 g, 10.3 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in pyridine (4 mL), and the solution was stirred at room temperature for 3 days. Water (200 mL) was poured into the reaction solution, and the precipitates were suction-filtered. The solid matters were suspended in diethyl ether, and 3 (N) hydrochloric acid (Wako Pure Chemical Industries, Ltd.) was added thereto, followed by stirring at room temperature for 15 minutes. The insoluble matters were suction-filtered. The insoluble matters were dissolved in a mixed solution of ethyl acetate (Wako Pure Chemical Industries, Ltd.) and a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.), and the mixture was shaken, followed by the separation of the organic layer. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and then suction-filtered and concentrated under reduced pressure, to thereby obtain the title compound (0.31 g, 28% yield).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=O)=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.Cl.[NH2:22][OH:23].[OH-].[Na+].Cl>O.C(O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=[N:22][OH:23])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: CC(C=O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C=NO)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
To a solution of 0.288 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propanal in 4 ml. of ethanol is added a solution of 0.12 g. of hydroxylamine hydrochloride and 0.11 g. of sodium hydroxide in 0.4 ml. of water. The mixture is refluxed briefly, then acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed, dried and evaporated to yield a crude product which is chromatographed on silica gel, eluting with chloroform:methanol (19:1) to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propanal oxime.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11](=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.CS(C)=O>O>[CH3:21][C:22]1[N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11](=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=2)[CH:24]=[CH:25][N:26]=1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCC(=O)CCC(=O)c1ccc(-n2ccnc2C)cc1
Temperature: 180 °C
Yield: 27.1 %

Procedure:
Ethyl 7-(4-fluorophenyl)-4,7-dioxoheptanoate (2.00 g, 7.1 mmol) and 2-methyl-1H-imidazole (7.0 g, 86 mmol) were taken up into DMSO (4 mL). The mixture was heated to 180° C. under microwave for 72 min. Water (100 mL) was added and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (DCM to DCM:MeOH=25:1) to afford the title compound as a dark brown solid (660 mg, yield 25%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[C:19]2[O:20][C:21]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([OH:34])=O)=[CH:27][C:22]=3[S:23](=[O:26])(=[O:25])[CH2:24][C:18]=2[CH:17]=[C:16]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:15]=1.[CH:41]1([NH2:44])[CH2:43][CH2:42]1>CN(C=O)C>[ClH:13].[CH:41]1([NH:44][C:32]([C:28]2[CH:29]=[C:30]([CH3:31])[C:21]3[O:20][C:19]4[C:14]([Cl:13])=[CH:15][C:16]([N:35]5[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]5)=[CH:17][C:18]=4[CH2:24][S:23](=[O:25])(=[O:26])[C:22]=3[CH:27]=2)=[O:34])[CH2:43][CH2:42]1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NC2CC2)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Product: Cl
Reaction time: 2 h

Procedure:
1,1′-Carbonyldiimidazole (0.172 g, 11 mmol) was added at 25° C., to a stirred solution of compound of Example 18 (0.3 g, 7 mmol) in dry DMF (10 mL) under nitrogen atmosphere. The reaction mixture was stirred for 2 h, and cyclopropyl amine (0.06 mL, 8.4 mmol) was added. The reaction mixture was stirred at 25° C. for 2 h. Solvent was partially removed and the reaction mixture was diluted with water (50 mL), The solid separated was filtered, washed with water and dried. The product was converted to its hydrochloride salt using methanolic-HCl to obtain the title compound. Yield: 0.15 g (42.5%); 1H NMR (DMSO-d6, 300 MHz): δ 0.56 (s, 2H, CH2), 0.66 (d, 2H, CH2), 2.61 (s, 3H, CH3), 2.82 (bs, 1H, CH), 3.20-3.36 (m, 8H, 4CH2), 5.11 (s, 2H, CH2), 7.14 (d, 1H, Ar), 7.66 (d, 1H, Ar), 8.01 (s, 1H, Ar), 8.13 (s, 1H, Ar), 8.67 (s, 1H, NH); MS: m/e (ES+) 462 (M+1, freebase).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Br[CH2:16]CCC.C(Cl)Cl>O>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH3:1])[CH:7]=1)[CH2:10][CH2:11][CH3:16]
Reactant: CCCOc1ccc([N+](=O)[O-])c(C)c1
Reactant: CCCCBr
Solvent: ClCCl
Solvent: O
Product: CCCCOc1ccc([N+](=O)[O-])c(C)c1
Yield: 99 %

Procedure:
This compound was prepared in a similar manner to that for 404b except 1-bromobutane was deployed for the alkyl ether adduct and the partition step during workup utilized DCM (150 mL) and water (150 mL) to provide a yellow oil (2.0 g, 99%): TLC Rf 0.70 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (d, 1H, J=8.88 Hz), 6.79-6.76 (m, 2H), 4.03-4.01 (t, 2H, J=6.48 Hz), 2.63 (s, 3H), 1.80-1.78 (quin, 2H, J=7.44 Hz), 1.53-1.47 (sex, 2H, J=7.44 Hz), 1.0-0.97 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, CDCl3) δ 162.7, 141.9, 137.1, 127.6, 117.9, 112.2, 68.3, 31.0, 21.8, 19.1, 13.8. Elemental analysis calculated for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.25; H, 7.09; N, 6.69.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:51][NH:52][O:53][CH3:54]>ClCCl>[CH3:54][O:53][N:52]([CH3:51])[C:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[N:19][CH:18]=1)=[O:22]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid (13.8 g, 44.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (12.8 g, 67.2 mmol) and hydroxybenzotriazole (7.2 g, 53.7 mmol) in dichloromethane (200 mL) was added triethylamine (25 mL, 179.2 mmol). The mixture was stirred at room temperature for 1 hour, and then N,O-dimethylhydroxylamine (5 g, 53.7 mmol) was added. The reaction mixture was stirred for another 3 hours. LCMS showed the reaction was completed. The reaction mixture was directly washed with water (100 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate (11.2 g, 67%) as a white solid. MS (ES+) C16H25N5O4 requires: 351, found: 296 [M-56+H]+.