Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]=1[C:9]1[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=1.[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[C:19]=1[CH:20]=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:2][C:3]2[CH2:8][CH2:7][O:6][CH2:5][C:4]=2[C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=2)[C:19]=1[CH:20]=[O:21]
Reactant: O=Cc1c(O)cccc1O
Reactant: CC(C)n1nccc1C1=C(CBr)CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nccc1C1=C(COc2cccc(O)c2C=O)CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (110 mg, 0.38 mmol) and 2,6-dihydroxybenzaldehyde (100 mg, 0.76 mmol) in DMF (6 mL) was added K2CO3 (110 mg, 0.76 mmol). After stirred at room temperature for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc. Organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=1:1) to give 2-hydroxy-6-((5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methoxy)benzaldehyde (90 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 11.89 (s, 1H), 10.33 (s, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.33 (t, J=8.8 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H), 4.40 (dd, J=12.8, 6.4 Hz, 1H), 4.35 (s, 2H), 4.18 (s, 2H), 3.97 (t, J=5.2 Hz, 2H), 2.44 (s, 2H), 1.40 (d, J=6.4 Hz, 6H); MS (ESI) m/z 343.3 [M+H]+.
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14](Cl)[N:13]=1.Cl.[I:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C(N(CC)CC)C>C(O)C>[I:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:14]1[N:13]=[C:12]([Cl:11])[N:20]=[C:19]2[C:15]=1[NH:16][CH:17]=[N:18]2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1cccc(I)c1
Agent: Cl
Agent: Nc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1nc(NCc2cccc(I)c2)c2[nH]cnc2n1

Procedure:
N6 -(3-iodobenzyl)-2-substituted adenosine derivatives can be synthesized from the corresponding adenine derivative. 2,6-Dichloropurine reacted with 3-iodobenzylamine hydrochloride in the presence of triethylamine in ethanol at room temperature provides N6 -(3-iodobenzyl)-2-chloroadenine, which can be silylated before coupling to yield the silylated derivative. The glycosidic bond is formed upon treatment of the 1'-O-acetyl riboside derivative N-methyl 1-O-acetyl-2,3-dibenzoyl-β-D-ribofuronamide with the aforesaid 9-silylated adenine derivative in the presence of TMSOTf as a Lewis acid catalyst. Condensation of N-methyl 1-O-methyl-2,3-dibenzoyl-β-D-ribofuronamide with the aforesaid 9-silylated adenine derivative produces ribose ring-opened product. Benzoyl groups of 2-chloro-N6 -(3-iodobenzyl)-9-[5-(methylamido)-2,3-di-O-benzoyl-β-D-ribofuranosyl]-adenine are deprotected with NH3 /MeOH to produce 2-chloro-N6 -(3-iodobenzyl)-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine, which reacted with various nucleophiles such as methylamine/THF and sodium thiomethoxide/DME yield compounds N6 -(3-iodobenzyl)-2-methylamino-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine and N6 -(3-iodobenzyl)-2-methylthio-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine. The benzoyl groups of 2-chloro-N6 -(3-iodobenzyl)-9-[2,3,5-tri-O-benzoyl-β-D-ribofuranosyl]-adenine can be similarly deprotected to produce the riboside derivative 2-chloro-N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine.
Reaction SMILES: [CH2:1]([C:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][C:20](=[O:26])[NH:21]2>>[CH2:1]([C:8]1([OH:15])[CH2:13][CH2:12][N:11]([C:14]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[NH:19][C:20](=[O:26])[NH:21]3)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2ncnc(Cl)c2[nH]1
Reactant: CN1CCC(O)(Cc2ccccc2)CC1
Product: O=c1[nH]c2ncnc(N3CCC(O)(Cc4ccccc4)CC3)c2[nH]1

Procedure:
4-Benzyl-1-methyl-piperidin-4-ol was reacted with 6-chloro-7,9-dihydro-purin-8-one under conditions analogous to those set out in Example 3A to give the title compound LC/MS: (LCT) Rt 5.68 [M+H]+326.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[C:9]([Cl:30])[CH:8]=1.[CH3:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=[C:34]([O:47][CH2:48][C:49]2([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]2)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[Cl:30][C:9]1[CH:8]=[C:7]([C:37]2[C:32]([CH3:31])=[CH:33][C:34]([O:47][CH2:48][C:49]3([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]3)=[N:35][CH:36]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: CCOC(=O)C1(COc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cn2)CCC1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(Cl)c3)cn2)CCC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
N,N-dimethylformamide (3.3 mL) was added to 2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (200 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}-methyl)cyclobutanecarboxylate (164 mg) and palladium chloride (dppf) methylene chloride complex (18 mg), and after adding 2N aqueous sodium carbonate solution (0.66 mL) to the mixture, the atmosphere was replaced with nitrogen and the mixture was stirred at 65° C. for 3 hours. To the reaction mixture were added ethyl acetate and water, and the liquids were separated. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 80:20) to obtain ethyl 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}-cyclobutanecarboxylate (214 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([CH3:23])[C:20]([C:24]([OH:26])=O)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1.[N+:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([NH2:39])[CH:34]=[CH:33]2)([O-:29])=[O:28].CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([NH:39][C:24]([C:20]1[C:21]([CH3:23])=[N:22][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=3)=[N:18][CH:19]=1)=[O:26])[CH:34]=[CH:33]2)([O-:29])=[O:28]
Reactant: Nn1ccc2cc([N+](=O)[O-])ccc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 85 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
DIPEA (12.65 mmol) is added a solution of 2-(3-fluoro-phenyl) -4-methyl-pyrimidine-5-carboxylic acid (4.22 mmol), 5-nitro-indole-1-ylamine (4.22 mmol) and HOTT (S-(1-oxido-2-pyridyl)-thio-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (7.6 mmol) in anhydrous DMF (15 mL) and the mixture is heated at 80-90° C. overnight. After evaporation of solvent, the residue is dissolved in EtOAc (150 mL), washed with water (20 mL), 5% sodium sulfate (20 mL), water (mL) and brine (20 mL). The organic layer is dried (Na2SO4), filtered and concentrated. The residue is kept at rt overnight to yield 4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-nitro-indol-1-yl)-amide (730 mg, 44%) as a solid. MS: 392 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.78(s, 3H), 6.88(d, H), 7.38-7.53(m, H), 7.57-7.76(m, 2H), 7.81(d, H), 8.06-8.32(m, 2H), 8.34(d, H), 8.65(d, H), 9.27(s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([O:26][NH2:27])[CH2:23][CH2:24]C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:27]([O:26][CH2:22][CH2:23][CH3:24])[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: CCCCON
Product: CCCOn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 187 and using 6-chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid and O-n-butylhydroxylamine. A colorless powder (280 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15]C2C=CC=CC=2)=O)[CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[O:15])(=[O:30])=[O:31])=[CH:25][CH:24]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(N)cc1

Procedure:
As the starting substances, methyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-aminobenzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-(4-aminobenzenesulfonyl)-N'-(2-methoxycarbonyl-5-chlorophenyl)urea and further to obtain from 470 mg (1.27 mmol) of N-(4-aminobenzenesulfonyl)-N'-(2-carboxy-5-chlorophenyl)urea 270 mg of the above-identified compound (yield 60.5%). Properties: colorless crystal, Melting point: >250° C. (decomposition), PMR (δppm, DMSO-d6):6.39 (2H,s), 6.63 (2H,d), 7.09 (1H,s), 7.22 (2H,d), 7.76 (2H,d), 7.83 (2H,d), 11.51 (1H,s).
Reaction SMILES: [O:1]=[C:2]1[CH:8]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH:8]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: COC(=O)c1ccccc1C=CC1CCCCNC1=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1C=CC1CCCCN=C1OC

Procedure:
The product of Example 85 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C)C=O>[CH2:21]([O:20][C:18]([CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:19])[CH3:22]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (10 g) and potassium carbonate (17 g) in dimethylformamide (100 ml) was added ethyl bromoacetate (15 g) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (ethyl acetate:n-hexane, 1:4, V/V) to give 4-(ethoxycarbonylmethoxy)benzaldehyde (16 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:29]([O:33][C:34](=[O:40])[CH2:35][CH2:36][C:37](O)=[O:38])[CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:29]([O:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([NH:2][C@H:3]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:20][CH:21]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])=[O:38])[CH2:30][CH2:31][CH3:32]
Reactant: N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CCCCOC(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)CCC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A mixture of (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (Intermediate 8-4: 150 mg, 0.360 mmol), 4-butoxy-4-oxobutanoic acid (107 mg, 0.540 mmol, 88% purity), EDCl (104 mg, 0.540 mmol), DIPEA (0.094 ml, 0.540 mmol) and HOAt (73.6 mg, 0.540 mmol) in DMF (2 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-benzyl 3-(4-butoxy-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoate (178.9 mg); HPLC retention time=1.47 minutes (condition B); MS (m+1)=536.42; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-0.94 (m, 3 H) 1.31-1.40 (m, 2 H) 1.56-1.63 (m, 2 H) 2.39-2.42 (m, 2 H) 2.48-2.62 (m, 4 H) 2.84 (A of ABX, Jab=13.6 Hz, Jax=8.1 Hz, 1 H) 2.97 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1 H) 4.07 (t, J=6.7 Hz, 2 H) 4.48-4.56 (m, 1 H) 5.12 (A of AB, J=12.1 Hz, 1 H) 5.18 (B of AB, J=12.1 Hz, 1 H) 6.27 (br d, J=7.7 Hz, 1 H) 7.20 (d, J=8.3 Hz, 1 H) 7.29-7.39 (m, 7 H) 7.42-7.47 (m, 3 H) 7.54-7.55 (m, 1 H).
Reaction SMILES: [Cl:1][C@@H:2]([CH3:22])[CH2:3][C@H:4]([CH3:21])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)#[N:24].N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:17][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][C@@H:4]([CH3:21])[CH2:3][C@@H:2]([Cl:1])[CH3:22])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)=[CH:27][CH:26]=1)#[N:24]
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: N#Cc1ccc(O)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(C(=O)Oc3ccc(C#N)cc3)cc2)cc1
Yield: 60.7 %

Procedure:
Methyl (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)-phenyl]benzoate, which had been obtained from methyl 4(4'-hydroxyphenyl)benzoate and monotosylate of (R,R)-2,4-pentadiol, was chlorinated and hydrolyzed. 0.5 g of the (S,S)-4-[4'-(3"-chloro-1"-methylbutoxy)phenyl]-benzoic acid thus obtained, 0.19 g of 4-cyanophenol, 0.04 g of 4-pyrrolidinopyridine, 0.34 g of dicycylohexylcarbodiimide and 6 ml of methylene chloride were stirred at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The obtained crude product was recrystallized from ethyl alcohol to thereby give 0.4 g of the title compound (m.p.: 103.8° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15].OS(O)(=O)=O>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)C)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(C(C)C)cc1[N+](=O)[O-]

Procedure:
N-(4-Isopropylphenyl)acetamide obtained in step I above was nitrated using nitric acid (1.2 eq)+H2SO4 (1.0 eq) at 0 to 5° C. for 2 hrs. After the completion of the reaction, reaction mixture was added to ice and pH was adjusted to 8, extracted with dichloromethane, which was evaporated to dryness to obtain N-(4-isopropyl-2-nitrophenyl)acetamide.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]3[N:15]4[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:14]4=[CH:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.[H-].[Na+]>>[CH:27]1([CH2:26][N:22]2[CH2:21][CH2:20][CH2:19][N:15]3[C:16]4[CH:17]=[CH:18][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:11][C:12]=4[CH:13]=[C:14]3[C:23]2=[O:24])[CH2:29][CH2:28]1
Reactant: O=C1NCCCn2c1cc1cc(OCCCN3CCCC3)ccc12
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: O=C1c2cc3cc(OCCCN4CCCC4)ccc3n2CCCN1CC1CC1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 17, from 9-(3-pyrrolidin-1-yl-propoxy)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 16), 1-(bromomethyl)cyclopropane and sodium hydride, to give the desired product as a white solid (29%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([CH3:47])[C:41]=1[CH3:48].C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[C:41]([CH3:48])[C:42]=1[CH3:47])=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 69%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH2:5]1[CH2:11][S:8](=[O:10])(=[O:9])[O:7][CH2:6]1.CCCCCC>ClCCl.CCOCC>[CH:1]([NH:4][CH2:6][CH2:5][CH2:11][S:8]([OH:10])(=[O:9])=[O:7])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)N
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 65.8 %

Procedure:
Isopropylamine (2.5 mL, 29 mmol) was added to a solution of 1,3-propane sultone (3.05 g, 25 mmol) in a mixture of dichloromethane/ether (40 mL, 1:1). The mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and hexane (10 mL) was added. The solid material was collected by filtration, rinsed with ether (10 mL), and dried in vacuo. Compound CG was obtained as a fine white powder (2.98 g, 65.6% yield). m.p. 240-43° C. 1H NMR (500 MHz, D2O) δ 1.06 (d, J=6.3 Hz, 6H), 1.86 (qt, J=7.6 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 3.14 (t, J=7.8 Hz, 2H), 3.13-3.21 (m, J=6.6 Hz, 1H). 13C NMR (125 MHz, D2O) δ 18.2, 21.5, 25.8, 43.4, 47.9, 50.8.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:14]1[C:19](=[O:20])[CH:18]=[N:17][C:16]([CH3:21])=[N:15]1)[CH2:11][CH2:12][CH3:13].[NH4+].[Cl-].C(OCC)(=O)C>CCOCC>[CH2:10]([N:14]1[C:19](=[O:20])[CH:18]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:17][C:16]([CH3:21])=[N:15]1)[CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CCCCn1nc(C)ncc1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCN1N=C(C)NC(c2ccc(C)cc2)C1=O
Yield: 86 %

Procedure:
4-Methylphenylmagnesium bromide (1.64 mL, 1.0 M in ether) was added all at once via syringe to a well-stirred solution of 1-n-butyl-3-methyl-1,2,4-triazin-6-one (178 mg, 1.06 mmol) in ether (9.85 mL) under N2 at room temperature. After stirring the resulting mixture overnight, saturated aqueous NH4Cl (10 mL) and ethyl acetate (10 mL) were added, the organic phase was separated, and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (5 g, 4:1 hexanes:ethyl acetate) to afford Compound 22 as a tan solid (236 mg, 86% yield).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[N+:2]=[N-:3].[OH-].[K+].O>CO>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CCCCCN=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Ethyl 6-azidohexanoate (8.59 g, 44.8 mmol) and KOH (13.0 g, 0.231 mol) were dissolved into a mixture of 120 ml of water and 180 ml of MeOH. The solution was stirred at 0° C. for 2 hrs then MeOH was removed in vacuo. The aqueous layer was extracted by CHCl3 (2×100 ml), acidified to pH=1 by 2N aqueous HCl and extracted by Et2O (2×100 ml). The organic layers were combined, washed with water (100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 6-azidohexanoic acid (6.56 g, 93%) was obtained as a colorless oil. 6-Azidohexanoic acid (6.56 g, 41.7 mmol) in 15 ml of toluene was treated with oxalyl chloride (13.2 g, 104 mmol). The mixture was stirred at 50° C. for 10 hrs. After removal of toluene in vacuo, crude 6-azidohexanoic chloride was used for hext reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](N)=[C:4]([O:10][CH3:11])[CH:3]=1.N([O-])=O.[Na+].S(=O)(=O)(O)O.[BrH:21]>C(OCC)(=O)C>[Br:21][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11]
Reactant: Br
Reactant: COc1cc(F)c(C)cc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C)cc1Br
Temperature: 110 °C
Yield: 47 %

Procedure:
A suspension of 4-fluoro-2-methoxy-5-methyl-phenylamine (25.75 g, 0.17 mol) in 180 mL of HBr (48%, 0.9 M) in an ice bath was treated dropwise with an aq solution of sodium nitrite (12.6 g, 0.18 mol, 3.6 M). A brown gas was evolved and the temperature of the reaction was monitored so that the internal temperature did not raise above 10° C. In the meantime, a suspension of CuBr (13.1 g, 0.09 mol) in 6.5 mL of HBr (48%, 13.9 M) was heated to 110° C. Next, the solution at 0° C. was slowly poured (over a period of 20 minutes) into the stirring CuBr suspension. The combined reaction mixture was heated for 2.5 h at 110° C. After cooling to room temperature, the solution was diluted with ethyl acetate and treated with aq sulfuric acid ( 50% v/v). The organic layer was separated and was washed successively with water, sulfuric acid, water, 1.25 M NaOH, water, and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting brown oil was purified via silica gel flash chromatography (5% ethyl acetate in heptane) to afford 1-bromo-4-fluoro-2-methoxy-5-methyl-benzene (17.1 g, 47%) as a clear liquid: Rf 0.70 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.34 (d, J=8.4 Hz, 1H), 6.61 (d, J=10.8 Hz, 1H), 3.85 (s, 3H), 2.18 (d, J=1.8 Hz, 3H); Anal. calcd for C8H8BrFO: C, 43.86. ; H, 3.68; Br, 36.48. Found C, 44.01; H, 3.68; Br, 36.57.