Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(Cl)(=[O:11])C>[OH-].[Na+].O.O1CCCC1>[C:5]([OH:11])(=[O:6])[CH3:7].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Hydroquinone (440 g) was dissolved in a solution of sodium hydroxide (160 g) in water (1600 ml) and to the resulting solution was added dropwise a solution of acetyl chloride (346 g) in tetrahydrofuran (346 g), while maintaining the temperature at 0° C. with ice-cooling. After addition, the mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with a small amount of water. Ethyl acetate was removed and the residue was distilled under a reduced pressure to give hydroquinone monoacetate (188 g). b.p. 144°-147° C./4 mmHg.
Reaction SMILES: [CH2:1]([C:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:13]1CC1>>[CH3:3][C:2]([CH3:5])([CH2:1][C:6](=[CH2:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:4]
Reactant: CC(C)(C)CC(=O)CC(C)(C)C
Reactant: C1CC1
Product: C=C(CC(C)(C)C)CC(C)(C)C

Procedure:
The ratio between dineopentyl ketone and the cyclopropane derivative in this case was 2.26 g/g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O.[NH2:10][NH2:11]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:10][NH2:11])[N:3]=1
Reactant: Clc1cccc(Cl)n1
Reactant: NN
Solvent: O
Product: NNc1cccc(Cl)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
The title compound was prepared according to the method described in U.S. Pat. No. 4,260,767 (1981). A mixture of 2,6-dichloropyridine (25.0 g, 169 mmol) and hydrazine monohydrate (60 mL, 1.24 mol) was heated and stirred at 100° C. for 4 hours. The solution was ice cooled, and the resulting crude crystals were collected by filtration. The crystals were washed with cold water and air dried. The crystals thus obtained were recrystallized from chloroform/hexane to give the title compound (15.8 g, 65% yield).
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.N1C=CN=C1>>[CH:26]1([N:32]2[C:21](=[O:22])[C:5]3[C:4]4[C:19]5[C:8](=[CH:7][CH:6]=3)[C:9]3[C:20]6[C:13]([CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=6[C:18]=5[CH:1]=[CH:2][C:3]=4[C:24]2=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Reactant: NC1CCCCC1
Agent: c1c[nH]cn1
Product: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1C1CCCCC1)c54
Temperature: 140 °C

Procedure:
0.30 g (0.93 mmol) of perylene-3,4-dicarboxylic anhydride is mixed with 0.28 g (2.8 mmol) of cyclohexylamine and 3 g of imidazole, and the mixture is heated under nitrogen at 140° C. for 3 h. The reaction product is removed from the flask by washing with ethanol, treated with 200 ml of 10% hydrochloric acid and boiled until no more ethanol is present. The residue is filtered off with suction, boiled in potassium carbonate solution and again filtered off with suction. The residue is washed with hot water until the filtrate is hardly coloured any more and then dried in a drying cabinet at 120° C. The orange shiny powder thus obtained is recrystallized twice by extraction with methanol. Yield 0.30 g (80%) of orange small crystals, strong red solid fluorescence, m.p. 370°-372° C. Rf (CHCl3 /silica gel)=0.41. UV (CHCl3): λmax (ε)=505 (29970), 483 (30309), 354 (3160), 336 (3160), 294 (3300), 264 (29090). Fluorescence (CHCl3): λmax (Irel)=539 (1), 567 (0.51).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][N:12]=[C:13]3[C:17]=2[NH:16][CH:15]=[C:14]3[C:18](=[O:22])[C:19]([O-])=[O:20])=[CH:5][CH:4]=1.[K+].[C:24]([N:32]1[CH2:37][CH2:36][NH:35][CH:34]([CH3:38])[CH2:33]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([N:32]1[CH2:37][CH2:36][N:35]([C:19](=[O:20])[C:18]([C:14]2[C:13]3[C:17](=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH:10]=[CH:11][N:12]=3)[NH:16][CH:15]=2)=[O:22])[C@H:34]([CH3:38])[CH2:33]1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1CN(C(=O)c2ccccc2)CCN1
Reactant: COc1ccc(-c2ccnc3c(C(=O)C(=O)[O-])c[nH]c23)cc1
Agent: [K+]
Product: COc1ccc(-c2ccnc3c(C(=O)C(=O)N4CCN(C(=O)c5ccccc5)C[C@H]4C)c[nH]c23)cc1

Procedure:
Example 67, 1-benzoyl-3-(R)-methyl-4-[(7-(4-methoxyphenyl)-4-azaindol-3-yl)oxoacetyl]piperazine was prepared from potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate and the corresponding 1-benzoyl-3-methylpiperazine according to the above general procedure. MS m/z: (M+H)+ Calc'd for C28H27N4O4: 483.20; found 483.16. HPLC retention time: 1.28 minutes (column A).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[O:14])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Product: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)NCCN(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) N1,N1-dimethyl-ethane-1,2-diamine gave the title compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O)(=O)[C:10](O)=[O:11].C=O>O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:10]=[O:11])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)C(=O)O
Agent: C=O
Solvent: O
Product: O=Cc1c(O)cccc1O
Reaction time: 1 h

Procedure:
In terms of weight, 110 parts of resorcinol, 0.62 part of oxalic acid, and 248 parts of water were charged into a flask, to which 50 parts of 37% formalin was dropwise added at 60° C. in one hour under stirring. Then, the stirring was further continued for 1 hour to obtain a resorcinol-formaldehyde condensate (B) containing excess resorcinol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][NH:8][CH2:9][CH2:10][C:11]#[N:12])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)CC>[O:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH2:5][CH2:6]1
Reactant: N#CCCNN=C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: Nc1ccnn1C1CCOCC1
Yield: 31.9 %

Procedure:
To a solution of 3-[2-(tetrahydro-4H-pyran-4-ylidene)hydrazinyl]propanenitrile (5 g, 30 mmol) in 1-propanol (50 mL) is added NaOH (29 mg, 0.74 mmol) and reaction mixture is heated at reflux for 16 h. The solvent is evaporated under reduced pressure and the residue is filtered through neutral alumina eluting with ethyl acetate to afford the title compound as a yellow solid (1.6 g, 32%) which is used in the next step without purification.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[C:3]1=[O:9].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH:10](=[N:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[C:3]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: NN1CCNC(=O)C1=O
Solvent: CC(=O)O
Product: O=C1NCCN(N=Cc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
1.3 pts. by wt. of 1-amino-2,3-dioxo-piperazine, 1.3 pts. by wt. of benzaldehyde and 7 pts. by vol. of glacial acetic acid are warmed to 90° for 90 minutes and then left at 5° for 30 minutes. The precipitate is filtered off, washed first with 3 pts. by vol. of glacial acetic acid and then with three times 10 pts. by vol. of ethyl acetate and dried over P2O5. 1.75 pts. by wt. (81.8% ) of 1-benzylideneamino-2,3-dioxo-piperazine of melting point 236°-240° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH2:23])[CH:17]=1.C(N(CC)CC)C>C1COCC1>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=1[NH:23][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: Nc1cc(Br)ccc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cc(Br)ccc2O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A solution of 4-methoxy-3-nitro-benzoyl chloride (7.12 g, 33.0 mmol) in THF (50 ml) was added dropwise with stirring to a solution of 4-bromo-2-aminophenol (6.20 g, 33.0 mmol) in THF (50 ml) containing triethylamine (6.82 ml, 66.0 mmol). After addition was complete the reaction was stirred at room temperature overnight. The reaction mixture was concentrated to approximately half the original volume and the precipitate collected by filtration. The solid was washed with methanol and ether and dried under vacuum to give the subtitle compound as a brown solid (5.24 g, 42%). 1H NMR (DMSO) δ 8.58(d, 1H), 8.36(dd, 1H), 7.55(d, 1H), 6.96(m, 2H), 6.68(dd, 1H), 4.05(s, 3H).
Reaction SMILES: [K+].[NH:2]1[CH2:6][C@H:5]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[CH2:4][C:3]1=[S:23].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:40][CH2:41]I)(=[O:39])[CH:36]([CH3:38])[CH3:37]>C(OCC)(=O)C>[C:35]([O:40][CH2:41][O:14][C:13]([C:12]1[N:11]2[C:16](=[O:21])[C@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:10]2[C@@H:9]([CH3:22])[C:8]=1[S:7][C@H:5]1[CH2:6][NH:2][C:3](=[S:23])[CH2:4]1)=[O:15])(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CNC(=S)C3)[C@H](C)[C@H]12
Reactant: CC(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)OCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a mixture of (1R, 5S, 6S)-2-[(4R)-pyrrolidine-2- thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2- em-3-carboxylic acid potassium salt (0.34 g), N,N-dimethylformamide (3 ml) and potassium carbonate (0.12 g) is added dropwise isobutyryloxymethyl iodide (0.27 g) under ice cooling. After stirring the mixture at the same temperature for 30 minutes, ethyl acetate (10 ml) is added to the reaction mixture, and the mixture is washed with water, and the organic layer is dried and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel flash column chromatography (eluent, chloroform: ethanol=20:1), followed by crystallization from isopropyl ether and ethyl acetate to give (1R, 5S, 6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester (0.12 g) as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:21]#[N:22])[N:12]3[C:17]([S:18][CH3:19])=[CH:16][C:15]([CH3:20])=[N:14][C:13]=23)=[C:4]([CH3:23])[CH:3]=1.[OH-:24].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:21]([NH2:22])=[O:24])[N:12]3[C:17]([S:18][CH3:19])=[CH:16][C:15]([CH3:20])=[N:14][C:13]=23)=[C:4]([CH3:23])[CH:3]=1
Reactant: CSc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C#N)n12
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CSc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C(N)=O)n12
Temperature: 60 °C

Procedure:
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (5.70 g) was added into conc. H2SO4 (100 mL) and heated for 60° C. for 5 hours. The reaction mixture was cooled to room temperature, poured into ice-water and then 10% aqueous NaOH solution was added to make the aqueous mixture alkaline (pH=8) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: ethyl acetate) to give 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (3.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[C:6]([CH3:24])=[N:7][CH:8]([NH:13]C(=O)OCC3C=CC=CC=3)[C:9](=[O:12])[N:10]([CH3:11])[C:4]=2[CH:3]=1.CS(O)(=O)=O.[OH-].[NH4+]>C1(OC)C=CC=CC=1>[NH2:13][CH:8]1[N:7]=[C:6]([CH3:24])[C:5]2[CH:25]=[CH:26][C:2]([Br:1])=[CH:3][C:4]=2[N:10]([CH3:11])[C:9]1=[O:12]
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)N(C)c2cc(Br)ccc21
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: COc1ccccc1
Product: CC1=NC(N)C(=O)N(C)c2cc(Br)ccc21
Temperature: 40 °C
Yield: 82.1 %

Procedure:
162c (0.831 g, 2.00 mmol) was dissolved in anhydrous anisole (16 ml) and then methane sulfonic acid (3.84 g, 40 mmol) was added in one portion, and then the reaction was heated to 40° C. for 30 minutes with stirring. The reaction was cooled to 0° C. in an ice bath then basified to pH=10 with concentrated ammonium hydroxide. The aqueous solution was then extracted with chloroform (3×50 ml) and the organic layers combined, dried over magnesium sulfate, filtered and the filtrate concentrated to give a residue. The residue was purified to silica gel column chromatography eluting with 10% methyl alcohol in chloroform to give the title compound 162d (0.463 g, 82%).
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][C:14]=1[CH3:15]
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(C)c(Br)c23)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(C)c(Br)c12
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
A solution of 5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (1.60 g, 4.21 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (2.10 g, 9.26 mmol) in THF (45 mL) was heated at 60° C. for 60 min. The cooled mixture was diluted with EtOAc (about 70 mL), stirred for 15 min, and the precipitate was collected by filtration, washed with EtOAc and dried. The filtrate was concentrated, and the residue was triturated with MeOH, filtered, and the collected precipitate was washed with MeOH. The two solids were combined to give 4-bromo-7-(ethoxycarbonyl)-3-methyl-9H-carbazole-1-carboxylic acid as a pale yellow solid (1.40 g, 88% yield). Mass spectrum m/z 376, 378 (M+H)+.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].C(O)(=O)C.[CH3:10][C:11]1[O:15][C:14]([CH:16]=[CH:17][CH2:18][CH2:19]O)=[CH:13][CH:12]=1.[Cl-].[Na+]>O>[CH2:17]([C:16]1[C:14](=[O:15])[CH2:13][CH:12]([OH:3])[C:11]=1[CH3:10])[CH:18]=[CH2:19]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(C=CCCO)o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCC1=C(C)C(O)CC1=O
Reaction time: 0.58 h
Yield: 219.8 %

Procedure:
A buffer solution was prepared by dissolving sodium acetate (1.03 g) and Paion D-408 (polyoxyethylene alkyl phenyl ether; manufactured by Takemoto Yushi Inc.) (0.44 g) in water (200 ml) and adjusting the pH value to 6.0 with acetic acid. In a reaction vessel, 5-methyl-2-furylallylcarbinol (5 g) and the entire amount of the buffer solution as prepared above were charged, and the temperature was elevated up to 150° C. in 35 minutes while stirring. The mixture was stirred at the same temperature for 3.5 hours. After ice-cooling, sodium chloride (50 g) was added, and the mixture was extracted with methyl isobutyl ketone (100 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove methyl isobutyl ketone, whereby an oily substance (4.6 g) was obtained. The crude product was purified by column chromatography with silica gel (60 g) (developing solvent, ethyl acetate-n-hexane (1:2 by volume)) to obtain 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone (4.2 g). Yield, 84%.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.CO[C:11](=N)[C:12]([Cl:15])([Cl:14])[Cl:13].C1(C)C=CC=CC=1>C(O)(=O)C>[Cl:13][C:12]([Cl:15])([Cl:14])[C:11]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1ccccc1N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1

Procedure:
To a solution of 10 g Benzene-1,2-diamine in 250 mL acetic acid, 22.8 g 2,2,2-Trichloro-acetimidic acid methyl ester were added drop wise at RT. After 2 h 500 mL toluene were added and the solvents were removed under reduced pressure. The residue was codestilled additional two times with toluene. After drying under reduced pressure the product was pure enough for the next reaction step.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1(=[O:20])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=CC=CC=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:13]2=[O:20])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCCCN1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C1NCCCCC1C(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A mixture of 4-nitrobenzoyl chloride (50.16 g, 0.27 mol), freshly distilled ε-caprolactam (30.59 g, 0.27 mol), and 500 ml of benzene are added to a 1L three-necked round-bottom flask equipped with an overhead stirrer, condenser and a nitrogen inlet tube. The solution is heated to 90°-100° C. and after all the solids are dissolved, 160 ml of pyridine is added. White pyridine salts form immediately, the reaction solution being kept at 90°-100° C. for 1 hour. The pyridine salts are removed by filtration, and the solvent is separated from the filtrate under reduced pressure. The residue is washed with a 5 percent NaHCO3 aqueous solution and with distilled water several times before being dried. The product is then recrystallized from a mixture of ethyl acetate and hexane to obtain 67 g (95 percent) of white crystals: mp 105°-106° C.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].[Si]([O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][C:7]1[C:6](=[O:9])[N:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[O:1][CH2:32][C:31]1[CH:30]=[CH:29][C:28]([C:26](=[O:27])[C:25]2[CH:36]=[CH:37][C:22]([OH:21])=[CH:23][CH:24]=2)=[CH:35][CH:34]=1
Reactant: Cc1c(O)nc2ccccn2c1=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccccn2c1=O
Yield: 4.7 %

Procedure:
A solution of 2-hydroxy-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.158 g), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (12.24 g) and potassium carbonate (5.07 g) in DMF (50 ml) was stirred at room temperature for 24 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate =1:2) and recrystallized from chloroform-methanol-ethyl acetate to provide the title compound as colorless solid (325 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)c1nc(C)ccc1Br
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cccnc1

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 3-Amino-pyridine was performed in accordance with the general method of Example 78, step 3 to yield the title compound as a light yellow crystalline solid, MS (ISP): m/e=258.1 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH:23]([CH3:26])[CH2:24][NH2:25])[N:19]2[CH:27]=[CH:28][N:29]=[C:18]2[CH:17]=1.[NH2:30][C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33](Cl)[N:32]=1.C(N(CC)C(C)C)(C)C>>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH:23]([CH3:26])[CH2:24][NH:25][C:33]2[N:32]=[C:31]([NH2:30])[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=2)[N:19]2[CH:27]=[CH:28][N:29]=[C:18]2[CH:17]=1
Reactant: CC(CN)Nc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(CNc1ccc([N+](=O)[O-])c(N)n1)Nc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12

Procedure:
N6-(2-{[7-(2,4-Dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]amino}propyl)-3-nitropyridine-2,6-diamine (Example 83) is prepared in analogy to Example 82 from Example 37A (300 mg, 0.47 mmol), 2-amino-6-chloro-3-nitropyridine (161 mg, 0.93 mmol) and N,N-diisopropylethylamine (600 mg, 4.6 mmol). The crude product is reprecipitated from N,N-dimethylformamide and acetonitrile. The product is filtered off and washed with acetonitrile and dried. 99 mg (45% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C(C)(C)C)(C)C)[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]>>[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: c1ccc(NC2CC2)cc1
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(c3ccccc3)C3CC3)c2)C[C@H]1C

Procedure:
N-Cyclopropylaniline was then be coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)-benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-cyclopropyl-N-phenylbenzamide as a yellow powder. NMR (200 MHz, DMSO-d6): δ0.44 (m, 2H); 0.70 (m, 2H); 0.93 (d, J=6.1 Hz, 3H); 1.01 (d, J=5.7 Hz, 3H); 1.74 (dd, J1 =7.7 Hz, J2 =11.8 Hz, 1H); 2.05 (dd, J1 =6.8 Hz, J2 =11.1 Hz, 1H); 2.39 (br d, J=10.5 Hz, 1H); 2.41-2.54 (m, 2H); 2.69 (br d, J=11.8 Hz, 1H); 2.83 (dd, J1 =6.6 Hz, J2 =13.6 Hz, 1H); 3.05-3.36 (m, 2H); 4.83 (s, 1H); 5.10 (d, J=9.8 Hz, 1H); 5.17 (d, J=17.4 Hz, 1H); 5.70-5.86 (m, 1H); 6.57 (d, J=7.1 Hz, 1H); 6.63 (s, 1H); 6.65 (d, J=8.2 Hz, 1H); 7.03-7.38 (m, 10H); 9.34 (s, 1H). Mass spectrum (CI--CH4) m/e: 496 (M+1, 100%), 342 (45%), 153 (90%). [α]D20 =+7.1° (abs. ethanol, c=1.1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.95 followed by precipitation with diethyl ether from dichloromethane to give the monohydrochloride salt as a hygroscopic orange powder. Calc. for C32H37N3O2HCl 1.50H2O: C, 68.74; H, 7.39; N, 7.51; Cl, 6.34. Found: C, 68.56; H, 7.49; N, 7.26; Cl, 6.37.