Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH:22]=[CH:23][C:24]#[N:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S([CH2:35][N+:36]#[C-])(=O)=O)=CC=1.O.[CH2:40](OCC)C>CS(C)=O>[Si:3]([O:20][CH2:21][C:22]1[C:23]([C:35]#[N:36])=[CH:24][NH:25][CH:40]=1)([C:16]([CH3:18])([CH3:19])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)[Si](OCC=CC#N)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](OCc1c[nH]cc1C#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60%, 0.12 g) in diethyl ether (5 mL) were added a solution of 4-(tert-butyldiphenylsilanyloxy)-buta-2-ennitrile (0.81 g) and p-toluensulfonylmethylisocyanide (0.49 g) in diethyl ether (5 mL) and dimethylsulfoxide (5 mL). After stirring at room temperature for 5 hours, to this reaction mixture was added water and this reaction mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=60/40-39/61) to give the title compound (0.50 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:23])([F:22])[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19](O)=[O:20])=[CH:13]2.[NH3:24]>C1COCC1.CN(C)C=O>[F:7][C:8]([F:23])([F:22])[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([NH2:24])=[O:20])=[CH:13]2
Reactant: N
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.63 ml, 30.6 mmol) was added dropwise at 0° C. within 45 min. to a suspension of 5-trifluoromethoxy-1H-indole-2-carboxylic acid (5 g, 20.4 mmol) in THF (20 ml) and N,N-dimethyl formamide (0.5 ml). Stirring was continued at 0-5° C. for 30 min. and thereafter for 3 h at room temperature. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 75 ml of a 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo yielding 5-trifluoromethoxy-1H-indole-2-carboxylic acid amide as off white solid. Yield 5 g (100%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH:17]2[CH2:19][CH2:18]2)[N:11]=1.Cl.N>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH:17]3[CH2:19][CH2:18]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(C2CC2)nc(Cl)n1
Reactant: Nc1cccc(F)c1
Agent: Cl
Agent: N
Solvent: CCO
Product: Cc1cc(C2CC2)nc(Nc2cccc(F)c2)n1
Temperature: 25 °C

Procedure:
A solution of 5.5 g (50 mmol) of 3-fluoroaniline and 9.3 g (55 mmol) of 2-chloro-4-methyl-6-cyclopropylpyrimidine in 100 ml of ethanol is adjusted to pH 1 with 5 ml of concentrated hydrochloric acid, with stirring, and is then heated under reflux for 18 hours. After the brown emulsion has been cooled to room temperature, it is rendered alkaline with 10 ml of 30% ammonia, poured onto 100 ml of ice-water and extracted twice with 150 ml of diethyl ether each time. The combined extracts are washed with 50 ml of water, dried over sodium sulfate and filtered, and the solvent is evaporated. The yellowish crystals which remain are purified by recrystallisation from diisopropyl ether/petroleum ether (b.p. 50°-70° C.). The white crystals melt at 87°-89° C.; yield: 8.3 g (34 mmol; 68% of the theoretical yield).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[O:18][CH3:17])[OH:22])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: COc1ccccc1C(=O)O
Product: COc1ccccc1C(O)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2-methoxybenzoic acid
Reaction SMILES: [CH3:1][NH:2][CH3:3].[H-].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([CH2:13]Cl)[CH:10]=[C:9]([Cl:15])[C:8]=1[C:16]1[NH:17][C:18]2[C:24]3[CH:25]=[CH:26][N:27]=[CH:28][C:23]=3[NH:22][C:21]3[N:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]=2[N:33]=1>CN(C)C=O.CO>[Cl:6][C:7]1[CH:12]=[C:11]([CH2:13][N:2]([CH3:3])[CH3:1])[CH:10]=[C:9]([Cl:15])[C:8]=1[C:16]1[NH:17][C:18]2[C:24]3[CH:25]=[CH:26][N:27]=[CH:28][C:23]=3[NH:22][C:21]3[N:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]=2[N:33]=1
Reactant: CNC
Reactant: ClCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of dimethylamine (23 μL, 2.0 M in tetrahydrofuran) was dissolved in N,N-dimethylformamide (0.5 mL) and cooled to 0° C. Sodium hydride (1.1 mg, 0.05 mmol) was added and the mixture was stirred for 15 minutes. 2-[2,6-dichloro-4-(chloromethyl)phenyl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine (10.0 mg, 0.02 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with methanol and purified on preparative LCMS at pH 10 to give the desired product (3.2 mg, 31%). LC/MS: 437 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[CH:27]=1>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:32][C:28]4[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=4)[C:25]([OH:34])=[O:24])[CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3ccccc32)s1
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4ccc(Cl)s4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 19 (part C) starting with 1.48 mmol (4.48 mmol) of 1-(5-chloro-thiophen-2-ylmethyl)-3-piperidin-4-yl-1H-indole and 1.0 g (8.8 mmol) of 3-bromomethyl-benzoic acid methyl ester. The crude mixture was purified by flash chromatography over silica gel affording 0.29 g (14% of yield) of the pure acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[C:3]=1[NH:12][C:13](=O)[C:14]#[C:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1.O>CN(C)C=O>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:13]2[NH:12][C:3]3[C:4](=[O:11])[NH:5][C:6](=[O:10])[N:7]([CH2:8][CH3:9])[C:2]=3[N:1]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CCn1c(N)c(NC(=O)C#Cc2ccc(OC)c(OC)c2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)[nH]c(=O)c2[nH]c(C#Cc3ccc(OC)c(OC)c3)nc21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
To a stirred solution of 3-(3,4-dimethoxyphenyl)propynoic acid (6-amino-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) amide (2.27 g, 6.3 mmol) in 12 ml of dry dimethylformamide was added phosphorous pentaoxyde (5 g, 17 mmol). The mixture was stirred at 100° C. for 10 min and cooled to room temperature. The product was recipitated by adding water (100 ml), filtered under reduced pressure, washed thoroughly with water and dryed at 70° C., light yellow yielding 8-(3,4-dimethoxyphenylethynyl)-3-ethyl-3,7-dihydro-purine-2,6-dione (1.6 g, 74%).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.C(OCC)(=O)C>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([S:38]([C:35]5[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=5)(=[O:40])=[O:39])[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (27.6 mg, 0.085 mmol, 1.0 equivalent, prepared as described in Example 55, Part B) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial. Triethylamine (43 mg, 0.425 mmol, 5.0 equivalents) was added followed by 4-(trifluoromethyl)benzene-1-sulfonyl chloride (27 mg, 0.11 mmol, 1.3 equivalents) as a solution in dichloromethane (0.1 mL). The reaction was stirred for 15 minutes. The mixture was loaded directly onto a 4 g silica gel column and with 0:100 to 50:50 ethyl acetate:heptanes (flow rate=18 mL/minute) over 20 minutes to give the title compound as a white solid (25 mg, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J=1.4 Hz, 1H), 7.92 (d, J=1.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 5.53-5.25 (m, 1H), 4.17 (td, J=9.4, 3.0 Hz, 1H), 4.12-4.00 (m, 1H), 3.97 (d, J=13.4 Hz, 1H), 3.79 (d, J=3.5 Hz, 2H), 2.99-2.55 (m, 5H), 2.14-1.92 (m, 2H), 0.95 (ddt, J=12.1, 7.0, 2.0 Hz, 4H); MS (ESI+) m/z expected 497.1; found: 497.0 (M+H)+; [α]D24.1=0.19 (c=0.12, CH3OH).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:15][N:16]=1)=[CH:8]2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][C:18]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:20])=[CH:15][N:16]=1)=[CH:8]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: CN(c1cccc2cc(-c3ncc(CC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3ncc(CC(=O)N4CCOCC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)acetic acid (0.38 g), morpholine (0.16 g), 1H-1,2,3-benzotriazol-1-ol (0.18 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide-hydrochloride (0.26 g) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. A solution of the obtained crystals in tetrahydrofuran was treated with activated carbon and concentrated to give the title compound (0.37 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate. melting point 199-200° C.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[C:11]([F:33])[CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4](C(OCC2C=CC3C(=CC=CC=3)C=2)=O)[CH2:3]1.CCO.CCOC(C)=O.[ClH:57]>O1CCOCC1.[Pd]>[F:33][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([O:8][C@@H:7]3[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]3[F:1])[CH:10]=1)[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][CH:20]=1)[CH:15]=[CH:14]2.[ClH:57]
Reactant: COCCOc1ccn2c(-c3ccc4cc(F)cc(O[C@@H]5CCN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5F)c4n3)cnc2c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOc1ccn2c(-c3ccc4cc(F)cc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1
Reaction time: 48 h

Procedure:
Pd/C (45 mg, 0.042 mmol) 10% wet was added to a solution of (3R,4R)-naphthalen-2-ylmethyl 3-fluoro-4-(6-fluoro-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (270 mg, 0.42 mmol) in a 1:1 mixture of EtOH/EtOAc (10 mL) and 500 uL of 6 N HCl. The mixture was purged with H2, and then allowed to stir under a balloon of hydrogen for 48 hours. The mixture was filtered through GF paper removing the desired product salt as a precipitate, with the palladium catalyst. The combined solids were washed into a beaker with 30 mL of MeOH and the palladium removed by subsequent filtration through GF filter paper. The organic phase was concentrated in vacuo, followed by flash column chromatography (1-20% MeOH/DCM (4% NH4OH). The resulting product was dissolved in chloroform and subject to four equivalents of 4 M HCl in dioxane. The desired product was then isolated as the bis-HCl salt. MS APCI (+) m/z 455.2 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.C12NC(CC1)CCC2>>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: C1CCCNCC1
Agent: C1CC2CCC(C1)N2
Agent: Cl
Product: N#Cc1cc(F)c(N2CCCCCC2)c(F)c1

Procedure:
The title compound was prepared using the procedure described in Example 325A except using 3,4,5-trifluorobenzonitrile and azepane instead of 3,4-difluorobenzonitrile and 8-aza-bicyclo[3.2.1]octane hydrochloride. 1H NMR (DMSO-d6) δ 7.62 (d, 2H), 3.39 (m, 4H), 1.73 (m, 4H), 1.61 (m, 4H); MS (ESI) m/z 237 (M+H)+.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[C:12](Cl)(Cl)=[O:13].[O:16]1CCOC[CH2:17]1>C1(C)C=CC=CC=1>[CH3:17][O:16][C:5]1[CH:4]=[CH:3][CH:2]=[C:7]2[C:8]([O:10][C:12](=[O:13])[NH:11][C:6]=12)=[O:9]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: C1COCCO1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Reaction time: 8 h

Procedure:
To a mixture of 10.0 g (66.0 mmol) of 6-methylanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.579 (98.7%) of the 3-methoxyisatoic anhydride as a light brown solid. MS (Cl mode) m/z 160 (M-18,100%),178 (M+H, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:12][CH2:13][Cl:14])[CH2:9][CH2:10][Cl:11])[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O>CO.O1CCCC1.[Pd]>[ClH:11].[CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:9][CH2:10][Cl:11])[CH2:12][CH2:13][Cl:14])[CH:5]=[CH:4][C:3]=1[NH2:15]
Reactant: Cc1cc(N(CCCl)CCCl)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N(CCCl)CCCl)ccc1N
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a reactor, 300 mg (1.1 mmol) of 2-methyl-4-[N,N-bis(2-chloroethyl)amino]nitrobenzene were dissolved in a mixed solvent of 5 ml of methanol and 2 ml of tetrahydrofuran, followed by the addition of 200 mg of 10% Pd/C under a nitrogen gas atmosphere. The reactor was purged with hydrogen gas, followed by stirring at room temperature for one hour. After completion of the reaction, the reactor was purged with nitrogen gas, followed by stirring for 30 minutes. The 10% Pd/C was then filtered off. To the thus-obtained methanol solution, 400 μl of a solution of 4N hydrochloric acid/dioxane were added, whereby 2-methyl-4-[N,N-bis(2-chloroethyl)amino]aniline hydrochloride was obtained. In 10 ml of DMF, 309 mg (1.1 mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid and the 2-methyl-4-[N,N-bis(2-chloroethyl)amino]aniline hydrochloride obtained above were dissolved, followed by cooling to 0° C. Under a nitrogen gas atmosphere, 330 μl (2.4 mmol) of triethylamine and then 197 μl (1.3 mmol) of DECP were added to the resultant solution, followed by stirring for 20 minutes as was. Stirring was conducted for further 15 minutes at room temperature. The reaction mixture was then allowed to stand overnight. The solvent was distilled out under reduced pressure. The residue so obtained was purified by chromatography on a silica gel column (ethyl acetate/n-hexane=1/1), whereby 329 mg of yellow powder were obtained (yield: 59%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>>[OH:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:8])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Product: Cc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part A: 4,6-Dihydroxy-2-methylpyrimidine (60 g) was added in portions to fuming nitric acid (120 mL) at 0° C. while cooling the reaction flask. After completion of addition, the reaction was stirred an additional 1 h at 0° C. followed by another 1 h at room temperature. The reaction mixture was then poured over ice (200 g) and the ice was allowed to melt. A light pink solid was isolated by filtration and washed with cold water (100 mL). The solid was dried in a vacuum oven overnight to yield 4,6-dihydroxy-2-methyl-5-nitropyrimidine (72.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:28])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][CH:29]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(OCC(=O)OCCOC(=O)COc2ccc(N)cc2)cc1
Reaction time: 6 h
Yield: 75.8 %

Procedure:
(4-nitro-phenoxy)-acetic acid-2-[2-(4-nitrophenoxy) acetoxy]ethyl ester 42 (100 g, 238 mmol) was dissolved in dry dimethylformamide (500 ml) in a pressure vessel, palladium on carbon (5%, 22 g) added, and the mixture stirred under an atmosphere of hydrogen (4 Kg) for 6 hours. The catalyst was removed by filtration and ice water (2.5 L) was added to the filtrate. Crude 43 was filtered off, dried and recrystallised in a mixture of methanol:chloroform (1:1) to give pure 43 (65 g, 78%) as a light brown shining powder. M.p: 124-125.8° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2].CI.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:13]1[C:7]2[CH:6]=[C:5]([O:22][CH2:23][CH3:24])[C:4]([O:3][CH2:1][CH3:2])=[CH:21][C:8]=2[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][CH2:11][C:12]1=[O:14])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NCC(=O)N2
Reactant: BrCc1ccccc1
Solvent: CI
Product: CCOc1cc2c(cc1OCC)N(Cc1ccccc1)C(=O)CN=C2c1ccccc1
Yield: 32 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIag), and MeI by benzyl bromide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 32%. M: 158–160° C. 1H-NMR (CDCl3, 300 MHz): d 1.33 (t, 3H, CH3), 1.40 (t, 3H, CH3), 3.84–3.95 (m, 3H, OCH2+1H CH2) 4.04 (q, 2H OCH2), 4.87 (m, 1H CH2), 5.15 (AB system, ? d=0.74, JAB=15.4, 2H, —NCH2), 6.58 (s, 1H Ar), 6.81 (s, 1H Ar), 7.07–7.46 (m, 10H Ar).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29]([C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)=[O:30])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccco3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-furoyl chloride (8.5 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH2:1]([NH:17][C:18]([C:20]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-])=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[OH:40])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>C(O)(C)C.[Fe]>[OH-:19].[NH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:40])=[C:20]([C:18](=[O:19])[NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:29]=1
Reactant: CCCCCCCCCCCCCCCCNC(=O)c1cc(Oc2ccccc2[N+](=O)[O-])c2ccccc2c1O
Agent: [Fe]
Agent: Cl
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCNC(=O)c1cc(Oc2ccccc2N)c2ccccc2c1O
Product: [OH-]
Yield: 118.8 %

Procedure:
The thus obtained 2-hexadecylcarbamoyl-4-(2-nitrophenoxy)-1-naphthol (10 g) was reduced with iron in isopropanol. The reaction mixture was filtered, condensed under reduced pressure and added with concentrated hydrochloric acid, and precipitated crystals were collected by a filtration to give 5.8 g of 4-(2-aminophenoxy)-2-hexadecylcarbamoyl-1-naphthol hydroxide. Yield: 57%.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11](O)=[N:12][CH:13]=1.IC>CN(C)C=O>[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:1](=[O:4])[N:12]([CH3:11])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Reaction time: 18 h

Procedure:
Cesium carbonate (44.6 g, 137 mmol) was added to a solution of 5-bromo-2-hydroxy-3-nitropyridine (20.0 g, 91.3 mmol) and iodomethane (19.4 g, 137 mmol) in N,N-dimethylformamide (500 mL). After 18 h, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 233.1 (MI).