Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])[CH2:6][CH2:7]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CN(C)CCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a solution of N,N-dimethyl-N-(2-piperazin-1-ylethyl)amine (0.80 g, 5.0 mmol) and triethylamine (1.0 g, 10 mmol) in dichloromethane (7 mL) was added 6-chloropyridine-3-sulfonyl chloride (1.0 g, 5.0 mmol; described in: Naegeli et al. Helv. Chim. Acta, 1938, 21, 1746, 1750) in dichloromethane (3 mL) at room temperature. After stirring over night at room temperature the solvent was removed in vacuo, the residue was partitioned between aqueous sodium hydroxide (2 M), diethyl ether (3×15 mL), and dichloromethane (3×15 mL). The combined extracts were dried (MgSO4), and the solvents were removed in vacuo to afford 1.3 g of the crude product. The residue was purified on a silica gel column using acetonitrile/triethylamine, (90:10), as the eluent to afford 1.0 g (60% yield) of title compound: 1H NMR (CDCl3, 400 MHz) δ 8.73 (d, J=2 Hz, 1H), 7.95 (dd, J=8, 2 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 3.08 (t, J=5 Hz, 4H), 2.56 (t, J=5 Hz, 4H), 2.47 (t, J=7 Hz, 2H), 2.35 (t, J=7 Hz, 2H), 2.19 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 155.8, 148.8, 137.8, 131.3, 124.6, 56.7, 56.0, 52.4, 45.8, 45.8.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])[CH:6](O)[CH:7]=[CH:8][CH3:9])[CH3:2].S(Br)(Br)=O.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[CH:7]/[CH:8]([P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[CH3:9])[CH3:2]
Reactant: CC=CC(O)C(NC=O)C(=O)OCC
Reactant: CCOP(OCC)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C/C(C)P(=O)(OCC)OCC)NC=O

Procedure:
The starting material is manufactured as follows: Reaction of crotonaldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to Example 1, 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 (12 hours) yields E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][Br:31])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
4-Methoxyphenethyl alcohol (50 g) and triphenylphosphine (103 g) were dissolved in methylene chloride (600 ml), followed by the addition of N-bromosuccinimide (70 g) in small portions under ice-cooling, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated, and to the resulting residue was added hexane. The insoluble matters were filtered off, while the resulting filtrate was evaporated, to give the title compound as a colorless oil (50.32 g, yield; 71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6](N)[CH:5]=1.C(I)[I:20].[N+]([O-])([O-])=O>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([I:20])[CH:5]=1
Reactant: ICI
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Agent: O=[N+]([O-])[O-]
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1

Procedure:
3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester was treated with methylene iodide and isoamy nitrate using the procedure of step 3 of preparation 4, to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=353.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1.O1CCOCC1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.Cl[C:53]1[N:58]=[C:57]([NH2:59])[C:56]([N+:60]([O-:62])=[O:61])=[C:55]([NH2:63])[N:54]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:53]3[N:54]=[C:55]([NH2:63])[C:56]([N+:60]([O-:62])=[O:61])=[C:57]([NH2:59])[N:58]=3)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under argon, 860 mg (2.32 mmol) of the compound from Example 6A were introduced into 1,4-dioxane (86 ml), and the reaction mixture was flushed with argon for 10 min. Then 3.51 ml (6.95 mmol) of hexabutylditin and 483 mg (2.55 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine (prepared by the method of Helvetica Chimica Acta (1951), 34, 835-40) were added. Subsequently 860 mg (0.744 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the reaction mixture was heated at reflux overnight. The mixture was then cooled to RT, water was added and the mixture was extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulphate, filtered and concentrated. The residue was subjected to extractive stirring in ethyl acetate, and the solid was isolated by filtration and dried under high vacuum. This gave 355 mg (62% purity, 24% of theory) of the desired compound. The crude product was reacted without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=3)=[CH:5][C:4]=2[N:3]=1.C(O)C>[Pt].CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3cc(OCc4cccc([N+](=O)[O-])c4)ccc3c2n1CC(C)(C)O
Agent: [Pt]
Solvent: CO
Solvent: CCO
Product: COCCc1nc2c(N)nc3cc(OCc4cccc(N)c4)ccc3c2n1CC(C)(C)O
Reaction time: 5 h
Yield: 53.4 %

Procedure:
1-[4-Amino-2-(2-methoxyethyl)-7-(3-nitrobenzyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (3.1 g, 6.66 mmol) was mixed with 100 mL of warm ethanol and 1 g of 5% platinum on carbon. The mixture was shaken under hydrogen pressure (50 psi, 3.4×105 pa) for 5 hours. The material had come out of solution so an additional 100 mL of methanol and 0.5 g platinum catalyst were added. After shaking under hydrogen pressure overnight, the mixture was filtered through CELITE filter agent. The filter cake was washed with 3×75 mL portions of hot methanol and the filtrates were combined and concentrated under reduced pressure. An orange foam resulted which was purified by column chromatography using silica gel. The polar component of the eluent was chloroform:methanol:2% aqueous ammonium hydroxide 80:18:2 (CMA), and elution was carried out with CMA:chloroform in a gradient from 0:100 to 40:60. Fractions containing product were combined and concentrated to yield 1.55 g of 1-[4-amino-7-(3-aminobenzyloxy)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid. A small portion was recrystallized from acetonitrile to provide an analytical sample, mp 203.0-206.0° C.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:16][CH2:17][C:18](=O)[C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[S:25][C:21]=4[CH:20]=3)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:41]2)=CC=1>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[S:41][C:18]([C:19]4[CH:28]=[CH:27][C:22]5[NH:23][C:24](=[O:26])[S:25][C:21]=5[CH:20]=4)=[CH:17][N:16]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)NCC(=O)c1ccc2[nH]c(=O)sc2c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccc(-c3cnc(CN4CCC(Cc5ccc(F)cc5)CC4)s3)cc2s1
Yield: 18 %

Procedure:
To a stirred solution of 2-[4-(4-fluorobenzyl)piperidin-1-yl]-N-[2-oxo-2-(2-oxo-2,3-dihydrobenzothiazol-6-yl)ethyl]acetamide (0.50 g, 1.13 mmol) in 1,4-dioxan (30 mL) was added [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's reagent) (0.69 g, 1.70 mmol). The resulting suspension was heated at reflux for 24 hours. The reaction mixture was condensed to dryness in vacuo, redissolved in EtOAc, and washed with saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic phase was dried (MgSO4) and condensed to dryness in vacuo. The material was then subject to column chromatography [silica gel, EtOAc/Heptanes (0-50% EtOAc over 60 min)] gave 6-{2-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]thiazol-5-yl}-3H-benzothiazol-2-one (0.087 g, 18%) as an off-white solid:
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH2:23][CH2:24][CH3:25])[N:10]=1)C1C=CC=CC=1.C1COCC1.[H][H]>[C].[Pd].C(O)C>[OH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH2:23][CH2:24][CH3:25])[N:10]=1
Reactant: [H][H]
Reactant: CCCc1nc(OCc2ccccc2)c(C(=O)OC)cc1C(=O)OC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1nc(O)c(C(=O)OC)cc1C(=O)OC
Yield: 89.2 %

Procedure:
A mixture of dimethyl 2-(benzyloxy)-6-propylpyridine-3,5-dicarboxylate (53.8 g), 10% palladium carbon (containing 55% water, 20 g), THF (50 mL), and ethanol (50 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered off, and then, the obtained filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether to obtain the title compound (35.4 g).
Reaction SMILES: C(O)=O.C(N(CC)CC)C.CC1(C)[O:19][C:17](=[O:18])[CH2:16][C:14](=O)O1.C(=O)[C:22]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=1>CN(C)C=O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH2:14][CH2:16][C:17]([OH:19])=[O:18])[CH:31]=[CH:30][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CN(C)C=O
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 110 °C

Procedure:
After adding 6.25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1 to 15 ml of dimethylformamide, 3.60 g (0.025 mol) of Meldrum's acid and 4.15 g (0.025 mol) of veratraldehyde were added to the above mixture, which was then heated to 110° C. during 1 hour and reacted at the same temperature for 3 hours. The product was separated from the reaction mixture by the method as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([O-])=[O:5].[C:24]1(C)[C:25](C)=[CH:26]C=[CH:28][CH:29]=1.Cl>[Cl-].[Zn+2].[Cl-].CCC(=O)CC>[CH2:25]([C:24]1[NH:1][C:2]2[C:3]([C:4](=[O:5])[C:29]=1[CH3:28])=[CH:7][C:8]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=1)=[C:9]([CH3:11])[CH:10]=2)[CH3:26]
Reactant: Cc1ccccc1C
Reactant: Cc1cc(N)c(C(=O)[O-])cc1Oc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(=O)CC
Product: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Temperature: 70 °C
Reaction time: 50 h
Yield: 87.3 %

Procedure:
2-amino-4-methyl-5-(4-(trifluoromethoxy)phenoxy)benzoate (3.69 g), 20 ml of xylene, 5.3 ml of 3-pentanone, and 0.256 g of zinc chloride were added into a 50-ml glass flask equipped with a stirring device, a thermometer, a reflux condenser, and a Dean-Stark device under a nitrogen atmosphere, and the temperature was raised to reflux with stirring. A reaction was allowed to proceed for 50 hr while adding 1.1 g of zinc chloride in four divided portions. After the completion of the reaction, the mixture was cooled to 70° C., and 10 ml of 0.1 N hydrochloric acid was added to the cooled solution, followed by cooling to room temperature. The precipitated solid was collected on a suction filter, was washed with an aqueous methanol solution and distilled water, and was dried to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one as a light brown solid (3.29 g, yield: 87.3%).
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[N:10][C:9]2[C:4]1=[N:5][C:6]([NH:12][CH3:13])=[N:7][CH:8]=2)[CH3:2].[F:14][C@@H:15]1[C@@H:19]([CH2:20][OH:21])[O:18][C@@H](N2C=CC(=O)NC2=O)C1.[N-]=[N+]=[N-].[K+].[C@@H:34]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)[CH2:35]1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[F:14][C@@H:15]1[C@@H:19]([CH2:20][OH:21])[O:18][C@@H:1]([N:3]2[CH:11]=[N:10][C:9]3[C:4]2=[N:5][C:6]([NH:12][CH3:13])=[N:7][C:8]=3[CH2:34][CH3:35])[CH2:2]1
Reactant: CCn1cnc2cnc(NC)nc21
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Solvent: CO
Product: CCc1nc(NC)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 144 h
Yield: 50 %

Procedure:
6 Ethylmethylamino-9H-purine (0.46 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 moles) were suspended in 50 ml, 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 6 days, 150 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (9:1). Solvent was removed and lyophilization yielded 0.323 g of 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-ethylmethylamino-9H-purine (50%): mp 99°-100° C.; TLC Rf 0.75 (silica gel, MeCN:15N NH4OH:H2O/85:5:10);
Reaction SMILES: [N+:1]([CH2:4][C:5](=O)[CH3:6])([O-:3])=[O:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])=[CH:11][N:10]=1.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:5]([CH3:6])=[CH:4][N+:1]([O-:3])=[O:2])=[CH:11][N:10]=1
Reactant: CN(CCN)Cc1ccc(Cl)nc1
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Yield: 70.1 %

Procedure:
Nitroacetone (1.1 g) and N-(2-chloro-5-pyridylmethyl)-N-methylethylenediamine (2.0 g) were dissolved in toluene (60 ml), and the solution was refluxed for 3 hours in a flask equipped with a water separating device while removing water formed by the reaction. Toluene was concentrated under reduced pressure, and the remaining solid was recrystallized from ethanol to give the desired N-(2-chloro-5-pyridylmethyl)-N-methyl-N'-(1-methyl-2-nitrovinyl)ethylenediamine (2.0 g) having a melting point of 78° to 80° C.
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][O:8]C)(=O)C.N1CCCN[CH2:11]1.[O:16]1[CH:20]=[CH:19][NH:18]C1=O>O>[NH:18]([CH2:6][CH2:7][OH:8])[CH2:19][CH2:20][OH:16].[CH:7](=[O:8])[CH:6]([CH3:11])[CH3:5]
Reactant: C1CNCNC1
Reactant: COCCCOC(C)=O
Reactant: O=c1[nH]cco1
Solvent: O
Product: CC(C)C=O
Product: OCCNCCO

Procedure:
216.7 g of Methoxypropyl acetate and 116.1 g of a polyisocyanate containing isocyanurate groups and based on hexamethylene diisocyanate, consisting mainly of N,N',N"-tris-(6-isocyanatohexyl)-isocyanurate, are introduced under a nitrogen atmosphere into a reaction vessel equipped with stirrer and cooling and heating means. A mixture of 29.9 g of hexahydropyrimidine B8 and 70.7 g of an oxazolone which has been obtained by the reaction of one equivalent of diethanolamine with one equivalent of isobutyraldehyde with elimination of water is then added dropwise at 50° C., the temperature rising to 70° C. Stirring is then continued for 10 hours. An approximately 50% solution of the cross-linking agent B13 containing the hexahydropyrimidine groups and oxazolane groups in a ratio of 1:2 is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:7])[CH3:6].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[OH2:16]>C1COCC1>[CH3:3][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:4]([CH3:3])[C:5](=[O:16])[CH3:6])[C:5](=[O:7])[CH3:6]
Reactant: CNC(C)=O
Reactant: BrCCCCCCBr
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)CCCCCCN(C)C(C)=O
Yield: 53 %

Procedure:
To a 50% oil suspension of sodium hydride (3.36 grams, 70 mmol) in dry THF (60 mL) under nitrogen was added N-methylacetamide (5.0 grams, 69 mmol) in 10 mL THF, and the mixture was refluxed for five hours. Then, 6.0 grams (24 mmol) of 1,6-dibromohexane was added, and the resulting mixture was refluxed for an additional two hours. Two hundred milliliters of cold water was added, and the aqueous phase was extracted with 100 mL of chloroform three times. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated in vacuo to yield an oil. Kugelrohr distillation of this material gave 2.5 grams of a pure oil (53%), boiling point 138° C. (0.1 torr).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:20][CH:15]([CH2:16][CH:17]([NH2:19])[CH2:18]2)[N:14]([CH3:21])[CH2:13][CH:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[C:23]1(=O)[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:20][CH:15]([CH2:16][CH:17]([N:19]4[C:26](=[O:27])[C:25]5[C:24](=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23]4=[O:28])[CH2:18]2)[N:14]([CH3:21])[CH2:13][CH:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C23CC(N)CC(C2)N(C)CC3C)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)N(C)CC3C)c1
Yield: 61.9 %

Procedure:
5-(3-Isopropoxy-phenyl)-2,4-dimethyl-2-aza-bicyclo[3.3.1 ]non-7-ylamine (2.4) (1.69 g, 5.6 mmol) was dissolved in toluene followed by the addition of phthalic anhydride (2.5 g, 16.8 mmol) and the reaction mixture was refluxed with a Dean-Stark trap overnight. The solution was then cooled, diluted with ethyl acetate, and filtered into a separatory funnel. The organic layer was washed with 1 N NaOH (3×30 ml) and water. The organic layer was collected, dried (Na2SO4) and the solvent removed under reduced pressure yielding crude product. The crude product was purified by filtering through a short column of neutral alumina (Brockman activity II-III) eluting with ethyl acetate to afford the title compound (1.50 g, 62%) as an off white solid. 1H NMR (CDCl3) δ: 7.76 (m, 2H), 7.65 (m, 2H), 7.23 (t, 1H, J=7.8), 7.00-6.72 (m, 3H), 5.08 (m, 1H), 4.52 (sept., 1H, J=6.1 Hz), 3.15 (m, 1H), 2.96 (m, 1H), 2.62 (m, 1H), 2.45-2.32 (m, 4H), 2.23 (s, 1H), 2.11 (m, 1H), 1.67 (m, 2H), 1.31 (d, 6H, J=6.0 Hz), 1.15 (m, 1H), 0.94 (m, 1H), 0.73 (d, 3H, J=6.9 Hz).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[C:4]([NH2:12])[CH:3]=1.Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Br.CCN(C(C)C)C(C)C>C(O)CO.O>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1nc2c(Br)cc(N)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: OCCO
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Temperature: 100 °C
Reaction time: 20 h
Yield: 57.8 %

Procedure:
A mixture of 7-bromo-2-methyl-3H-benzo[d]imidazol-5-amine (25 g, 111 mmol), 1-bromo-2-(2-bromoethoxy)ethane (38 g, 166 mmol) and DIPEA (21 g, 166 mmol) in ethylene glycol (600 mL) was stirred at 100° C. for 20 h. It was cooled to rt, and diluted with water (200 mL) and extracted with DCM (300 mL×4). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated. The residue was purified by column chromatography (eluted with petroleum ether/ethyl acetate=1/1) to give the product (19 g, 58%) as a yellow solid; LC/MS: MS (ES+) m/e 296 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.44 (s, 3H), 3.07 (t, J=4.8 Hz, 4H), 3.74 (t, J=4.8 Hz, 4H), 6.85 (d, J=2.1 Hz, 1H), 7.04 (d, J=2.1 Hz, 1H), 12.20 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)c2OC
Yield: 31.4 %

Procedure:
Following a procedure analogous to 101b, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (46 mg) and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine (60 mg) were reacted to give 7-{5-Chloro-4-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-2-ylamino}-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (29 mgs, 26%) as an off-white solid. 1H-NMR (CDCl3, 400 MHz): δ 8.27 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.06 (s, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 6.94 (d, J=8.9 Hz, 1H), 6.59-6.55 (m, 2H), 3.93 (s, 3H), 3.85-3.81 (broad m, 2H) 3.80 (s, 3H), 3.26-3.23 (m, 4H), 2.65-2.63 (M, 4H), 2.39 (s, 3H), 2.32 (broad s, 2H), 1.74 (broad s, 4H), 1.22 (t, J=6.1 Hz, 3H); LC/MS Found (M+H)+=565.98; MP: 186-187° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:19])[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.CN1CCCC1=O>[C:20]([N:19]=[C:6]1[CH2:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[C:7]1[C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: O=C(N=C1CC([N+](=O)[O-])=CC=C1c1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
In the first step, 4,4'-dinitro-2-biphenylamine is reacted with benzoyl chloride in the presence of 4-dimethylamine pyridine in N-methyl-2-pyrrolidinone (NMP) to give 2-(N-benzoylimino)-4,4'-dinitrobiphenyl. The hydrogenation of the latter in N,N-dimethylacetamide (DMAc) at room temperature with 10% Pd/C as a catalyst provides the desired 2-(N-benzoylimino)-4,4'-diaminobiphenyl.