Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:31])[CH2:8][NH:9][C:10](=[O:30])[CH:11]([N:19]([O:22]CC1C=CC=CC=1)[CH:20]=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].C(O)CCC.CC(O)=O.O>CO.CC(O)=O.O.[Pd]>[CH2:1]([NH:6][C:7](=[O:31])[CH2:8][NH:9][C:10](=[O:30])[CH:11]([N:19]([OH:22])[CH:20]=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCNC(=O)CNC(=O)C(Cc1ccccc1)N(C=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CCNC(=O)CNC(=O)C(Cc1ccccc1)N(O)C=O
Reaction time: 1 h

Procedure:
127 mg of the compound of Example 31 are dissolved in 3 ml of the mixture CH3OH/AcOH/H2O, 4/5/1 and hydrogenated at ordinary pressure in the presence of 30 mg of 10% Pd/C. After 1 hour, the theoretical volume is absorbed or filtered, and concentrated to dryness giving a white solid. W 88 mg. Rdt 88%; Rf 0.85; BuOH/AcOH/H2O, 4/1/1/.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[C:10]([NH:17][CH3:18])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC([O:29][C:30](Cl)(Cl)Cl)=O>O1CCOCC1>[C:1]1([N:7]2[CH2:8][C:9]3[C:10](=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=3)[N:17]([CH3:18])[C:30]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1ccccc1)C2
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A mixture of 200 mg (0.77 mmol) of 5-phenylaminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine in 15 ml of dioxan was added dropwise to a solution, cooled in ice, of 150 mg (0.79 mmol) of trichloromethyl chloroformate in 10 ml of dioxan. The mixture was then left to warm to room temperature. After a further 10 minutes the mixture was evaporated. 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate solution were added to the residue. The phases were separated and the dichloromethane phase was dried over magnesium sulfate, filtered and evaporated to give 162 mg (74%) of 3-phenyl-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4](=O)[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8]2.C1([NH3+])CCCCC1>>[CH3:14][C:9]1([CH3:15])[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([CH2:4][C:3]([OH:17])=[O:2])[CH:6]=2)[CH2:10]1
Reactant: COC(=O)C(=O)c1ccc2c(c1)CC(C)(C)C2
Agent: [NH3+]C1CCCCC1
Product: CC1(C)Cc2ccc(CC(=O)O)cc2C1

Procedure:
2,2-dimethyl-α-oxo-5-indanacetic acid methyl ester is reduced in a manner analogous to that described in Example 4. The cyclohexyl-ammonium salt of the title compound has an M.P. of 155°-156°.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](I)[CH:8]=2)[N:3]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:34][OH:35])=[C:29](B(O)O)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]3[CH:26]=[C:25]([F:24])[CH:30]=[CH:29][C:28]=3[CH2:34][OH:35])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Reactant: OCc1ccc(F)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CO)ccc2n1
Temperature: 100 °C

Procedure:
10.405 g of (2-amino-6-iodoquinazolin-4-yl)-(1,3-dihydroisoindol-2-yl)methanone are dissolved in 450 ml of ethanol. 5 g of 5-fluoro-2-hydroxymethylphenylboronic acid, 10.4 g of potassium carbonate, 1 g of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and 450 μl of water are added to this solution, and the mixture is heated at 100° C. under argon for 1 h. The hot mixture is filtered off through Celite, and the filter cake is rinsed with 500 ml of hot ethanol. The filtrate is evaporated to dryness in vacuo, and the reddish residue obtained is triturated with 50 ml of acetonitrile, during which a beige solid precipitates out. This is filtered, washed with 20 ml of acetonitrile and dried at 40° C. in a drying cabinet for 16 h
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C@H:35]2[CH2:39][O:38][C:37](=[O:40])[NH:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:36]4[C@@H:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:39][O:38][C:37]4=[O:40])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4C(=O)OC[C@@H]4c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (S)-4-phenyl-oxazolidin-2-one.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27](O)(=[O:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:27]([NH:2][NH:1][C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=1)(=[O:29])[CH3:28]
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(NN)c3)c2cc1OC
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(NNC(C)=O)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-(2-hydrazino-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (2.0 g) and acetic acid (20 ml) is stirred at room temperature for 96 hours. After the reaction is complete, to the mixture are added methylene chloride and an aqueous potassium carbonate solution. The methylene chloride layer is separated, concentrated under reduced pressure, and the residue is crystallized from chloroform to give 1-[2-(2-acetylhydrazino)-pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.84 g), which is listed in Table 10.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.O1CCOCC1.[S-:21][C:22]#[N:23]>C1COCC1.O>[NH2:23][C:22]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[S:21]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
1,1-Dimethylethyl 1-piperazinecarboxylate (24 g, 129 mmol) in THF (1 L) was treated with 4 N HCl in dioxane (32.2 mL, 129 mmol)), and thiocyanate (12.52 g, 129 mmol) dissolved in minimal amount of water was added. After stirring at rt overnight, the volatiles were removed under reduced pressure. The residue was taken up in MeOH and filtered to remove inorganic salts and the solvent removed in vacuo and the cycle was repeated 3 more times. Then twice taken up in DCM and filtered and concentrated to give the title compound of Step A (29 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (br. s., 2H), 3.50 (br. s., 4H), 3.07 (t, J=5.0 Hz, 4H), 1.40 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.N>[O:13]=[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]1[C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: N
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1ccc(-n2ccccc2=O)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
A mixture of 4-bromobenzoic acid ethyl ester (4.58 g, 20.00 mmol), 2-hydroxypyridine (0.95 g, 10.00 mmol), potassium carbonate (1.39 g, 10.00 mmol), and CuI (0.095 g, 0.50 mmol) was stirred at 120° C. for 6 h under a nitrogen atmosphere. The diluted aqueous ammonia (50 mL) was added, and the solution was extracted with ethyl acetate (3×50 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered. The solvent was removed in vacuo to afford ethyl 4-(2-oxopyridin-1(2H)-yl)benzoate in 86% yield (2.10 g); NMR (CDCl3, 300 MHz) δ 8.15 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.39 (ddd, J=2.0, 6.6, 9.0 Hz, 1H), 7.31 (dd, J=2.0, 6.6 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H), 6.26 (dt, J=1.1, 6.6 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH3:24])[N:26]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1ccc(N)n1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2ccn(C)n2)cn1
Yield: 87 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 1-methyl-1H-pyrazol-3-ylamine instead of 2-aminoethyl isopropylether, to the title compound (110 mg, 87%) which was obtained as a colourless oil. MS: m/e=390.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH:14]([CH3:18])[CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[O:28])[CH:14]([CH3:18])[CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC1CN(c2ccnc3cc(Cl)ccc23)CCN1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1CN(c2ccnc3cc(Cl)ccc23)CCN1C(=O)Nc1ccc(F)cc1

Procedure:
7-Chloro-4-(3-methylpiperazin-1-yl)quinoline (0.13 g, 0.5 mmol) and 4-fluorophenyl isocyanate (57 μL, 0.5 mmol) in CH2Cl2 (10 mL) are reacted according to method C yielding the title product after column chromatography with hexane-EtOAc.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2.[CH2:26]([NH:29][C:30]1[C:31]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:27]C>C1COCC1.ClCCl>[CH3:27][CH2:26][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([C:23]([C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][C:16]=3[CH:17]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: CCCNc1cccnc1N1CCNCC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1cccnc1N1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
1,1'-carbonyldiimidazole (0.42 g) is added to a 20°-25° solution of 5-chloroindole-2-carboxylic acid (I, 0.5 g) in THF (5 ml). After 1 hour of stirring at 20°-25°, the above reaction is added dropwise over 10 minutes via cannula to a -10° (ice/acetone bath) solution of [3-(ethylamino)-2-pyridinyl]piperazine (II, 0.58 g) in THF (5 ml). After 30 minutes of stirring at -10°, the reaction is warmed to 20°-25° and stirring is continued for 5 hours. The reaction is diluted with dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (40 ml), water (40 ml) and saline (40 ml). The organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography (50 g silica gel), eluting with ethyl acetate/hexane (1/1). The appropriate fractions are pooled and concentrated to give the title compound, mp 208°-209°; IR (mineral oil) 3200, 2920-3000, 1632, and 1425 cm-1 ; NMR (300 MHz, CDCl3) 9.77, 7.72, 7.60, 7.36, 7.22, 6.97, 6.86, 6.75, 4.23, 4.09, 3.23-3.15, and 1.33 δ; MS (m/e) 383, 178, 176, 162, 150, 148, 137, 134, and 120.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:3]=1[C:4]#[N:5].Cl.Cl[C:19]([NH2:21])=[NH:20].Cl>>[NH2:21][C:19]1[N:20]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:6]=2)[N:1]=1
Reactant: N=C(N)Cl
Reactant: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: Cl
Product: Nc1nc(N)c2cc(Cc3ccccc3)ccc2n1
Temperature: 120 °C

Procedure:
A finely ground mixture of amino nitrile 10a (60 mg, 0.29 mmol) and chloroformamidine hydrochloride (132 mg, 1.16 mmol) was placed in a 10 mL pear-shaped flack, which was immersed in an oil bath and triturated continuously with a glass rod while being heated to 120° C. (internal temperature) under a gentle stream of N2 as described (Rosowsky, A. et al.; J. Med Chem. 1993; 36, 3103-3112). After 20 min the reaction mixture was cooled to room temperature, the resulting glassy solid was dissolved in MeOH (0.75 mL), and the solution was diluted with CHCl3 (12 mL) and chilled at 0° C. for 1 h. The solid precipitate was collected, washed with CHCl3, and discarded. This solid consists mainly of by-products arising from the self-condensation of chloroformamidine, whereas the pooled filtrates contain the HCl salt of the desired product, along with a variable amount of the salt of what is presumed to an intermediate non-cyclized amidinonitrile of the type previously observed (Rosowsky, A. et al.; J. Med Chem. 1993; 36, 3103-3112). To ensure complete ring closure, excess i-Pr2NH (0.5 mL) was added to the filtrate to neutralize the acid, the mixture was concentrated dryness on a rotary evaporator, and the solid residue was heated for 1.5 h at 70° C. under high vacuum (0.1 Torr). The crude product was then dissolved in boiling MeOH, and the solution treated with a little decolorizing carbon (Darco) and hot-filtered through a bed of Celite. When the filtrate became cool it was basified to pH 10 with ammonia, and the precipitate was collected. Recrystallization from MeOH—H2O afforded 8a as a white crystalline solid (32 mg, 44%): mp 220-222° C.; MS: m/z 251.4, calcd 251.3 (M+1); IR (KBr) v 3340, 3170, 1620, 1570, 1510, 1450, 1400 cm−1; 1H NMR (DMSO-d6) δ 3.92 (s, 2H, CH2), 5.84 (br s, 2H, 2-NH2), 7.13 (d, J=8.6 Hz, 1H, H-8), 7.16-7.35 (m, ca. 6H, H-7 and other aromatic protons), 7.89 (s, 1H, H-5). In contrast to the majority of the other diaminoquinazolines described below, the hydrogens on the 4-NH2 group apparently gave a signal at around δ 7.2 which was too broad to be observed. Anal. Calcd. for C15H15N4-0.3H2O: C, 70.46, H, 5.75, N, 22.16. Found: C, 70.20; H, 5.42; N, 22.28.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][CH:3]=1.N#N>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:14][CH:15]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(Cl)cc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(c1ccc(Cl)cc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Yield: 69.8 %

Procedure:
A flask-containing a solution of 2-{4-[1-(4-chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide (Example 41, 30 mg, 0.08 mmol) in 1:1 ethanol/ethyl acetate (6.0 mL) was charged with N2 and evacuated (3×). Palladium on carbon (10 wt %) was added to the solution, and the flask was charged with H2 and evacuated (3×), and then maintained at ˜1 atm H2 for 2.5 h. The flask was evacuated and then charged with N2. The reaction mixture was filtered through a pad of Celite®, which was washed with ethanol (50 mL), ethyl acetate (50 mL) and then methanol (2×50 mL). The filtrate was concentrated under reduced pressure. Purification of the residue by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded the title compound (21 mg, 68%). TLC (silica, 1% methanol saturated with ammonia/9/% methanol/CH2Cl2): Rf=0.35. MS (ESI+): mass calculated for C22H18ClN3O, 375.1, m/z found, 376.1. [M+H]+. 1H NMR (500 MHz, CD3OD): δ 8.16 (br s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.62 (br s, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.30-7.26 (m, 4H), 4.27-4.24 (m, 1H), 1.67 (d, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13].[C:14]1([CH3:23])[C:15]([N:20]=[C:21]=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=1>N1C=CC=CC=1>[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([NH:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13])=[O:22]
Reactant: Nn1c(=O)c(=O)[nH]c2ccccc21
Reactant: Cc1ccccc1N=C=O
Solvent: c1ccncc1
Product: Cc1ccccc1NC(=O)Nn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 70 °C
Yield: 90.5 %

Procedure:
The procedure of Leeson, P. D. et al., J. Med. Chem 35:1954-68 (1992) was adapted. A suspension of 1-amino-1,4-dihydro-2,3-quinoxalinedione (37 mg, 0.21 mMol) in pyridine (2.5 mL) was stirred at 70° C. until dissolving was completed. To the solution was then added o-tolyl isocyanate (27.8 mg, 0.21 mMol, Aldrich), which was stirred at 60° C. for 2 h, then overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was washed by ether (2×2 mL) to give 59 mg of crude 1-[[(o-tolylamino)carbonyl]amino]-1,4-dihydro-2,3-quinoxalinedione (66% product; 30% tolyl-byproduct; 4% 1-amino-1,4-dihydro-2,3-quinoxalinedione by 1H NMR). Separated by chromatograph with silica gel (2 g) column, eluted with 100% benzene (20 mL) and benzene:acetone=1:1 (20 mL) and 100% acetone (20 mL) to remove most of impurity. The residue (43 mg of 1-[[(o-tolylamino)carbonyl]amino]-1,4-dihydro-2,3-quinoxalinedione) was washed with ethanol (2×2 mL) and ether (2×1 mL) to give 38 mg of pure 1-[[(o-tolylamino)carbonyl]amino]-1,4-dihydro-2,3-quinoxalinedione as a white powder (60%). Mp:decomposed from 265° C. IR (KBr, cm-1): 3375; 3237; 1718; 1693; 1675. NMR (1H, DMSO-d6) δ2.161 (s, 3H); 6.996-7.380 (m, 8H); 8.530 (s, 1H), 9.343 (s, 1H); 12.155(s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:13][CH2:14][C:15]1[CH:47]=[CH:46][CH:45]=[CH:44][C:16]=1[CH2:17][N:18]1[C:22]([CH3:33])([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:21](=[O:34])[N:20]([CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[CH:39]2)[C:19]1=[O:43]>ClCCl>[N:38]1([CH2:37][CH2:36][CH2:35][N:20]2[C:21](=[O:34])[C:22]([CH3:33])([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[N:18]([CH2:17][C:16]3[CH:44]=[CH:45][CH:46]=[CH:47][C:15]=3[CH2:14][NH:13][S:2]([CH3:1])(=[O:4])=[O:3])[C:19]2=[O:43])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: CC1(c2cccc3ccccc23)C(=O)N(CCCn2ccnc2)C(=O)N1Cc1ccccc1CN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cccc3ccccc23)C(=O)N(CCCn2ccnc2)C(=O)N1Cc1ccccc1CNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
0.02 ml (0.24 mmol) of methansulfonyl chloride was added to 10 ml dichloromethane solution of 0.06 ml (0.4 mmol) of triethylamine and 0.10 g (0.2 mmol) of 1-(2-aminomethyl-benzyl)-3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione prepared in Example 35-1) at 0° C. After stirring for 1 hour at room temperature, it was washed with saturated potassium carbonate solution and saturated sodium chloride solution sequentially. After removal of dichloromethane, chromatography using a solvent mixture of methanol-dichloromethane (7:93) as the eluent was carried out to obtain 0.1 g (0.18 mmol, Yield: 87%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.Cl.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[C:20](O)=[O:21].CCN(C(C)C)C(C)C.CS(C)=O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([CH:10]([CH3:12])[CH3:11])[C:20](=[O:21])[CH:15]3[CH2:16][O:17][CH2:18][CH2:19][N:14]3[C:6]=2[N:7]=1
Reactant: CC(C)Nc1cnc(Cl)nc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)N1C(=O)C2COCCN2c2nc(Cl)ncc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A round-bottom flask was charged with 2,4-dichloro-N-isopropylpyrimidin-5-amine (940 mg, 4.56 mmol), morpholine-3-carboxylic acid hydrochloride (994 mg, 5.93 mmol), DIPEA (3.19 mL, 18.25 mmol) and DMSO (8 mL). The flask was heated overnight at 100° C. The solution was diluted with water and refrigerated for 2 hours. The aqueous solution was extracted twice with EtOAc. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 2-chloro-5-isopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a brown solid (1.2 g). MS [M+H] Found 283.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[OH:22])[C:16]([OH:18])=[O:17].[OH-].[Na+].Cl>C(O)C.O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Yield: 30.6 %

Procedure:
In 100 ml of ethanol were dissolved 18 g of 1-bromo-n-decane and 9 g of 3-chloro-4-hydroxybenzoic acid, an aqueous solution of 40 g of sodium hydroxide in 100 ml of water was added to the above solution, and the mixture was heated and refluxed for 10 hours. Then the reacted solution was made weakly acidic by an addition of 1N hydrochloric acid and thrown in an enough quantity of water to precipitate the reaction product. The precipitate was recovered by filtration and recrystallized from ethanol to obtain 5 g of 3-chloro-4-decyloxybenzoic acid, then 15 g of thionyl chloride was added to 3 g of 3-chloro-4-decyloxybenzoic acid, and a reaction was carried out under reflux for 3 hours. The unreacted thionyl chloride was removed by distillation under a reduced pressure to obtain 3-chloro-4-decyloxybenzoic acid chloride quantitatively. Then the product was dissolved in a diethyl ether/THF (1/1) mixed solvent, 2.3 g of 4,4'-acetoxybiphenol and 2 g of triethylamine were added to the solution successively, and a reaction was carried out at room temperature with stirring overnight. The reacted solution was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water, in this order, and the organic phase was dried with anhydrous sodium sulfate. The solvent was evaporated, the reaction product was recovered by the silica gel chromatography, then the reaction product was dissolved in 100 ml of a THF/methanol (9/1) mixed solvent, a 1N aqueous solution of lithium hydroxide was added to the resulting solution which was cooled with ice-cold water, and a reaction was carried out with stirring for 30 minutes. Then the reacted solution was made weakly acidic by addition of 1N hydrochloric acid, extracted with a diethyl ether/benzene (1/1) mixed solvent, and the extract was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water in this order. The organic phase was recovered and dried with anhydrous magnesium sulfate, and the organic solvent was evaporated to obtain a product. The product was recrystallized from an n-hexane/ethanol mixed solvent. The compound in which Z is fluorine can be similarly obtained by using 3-fluoro-4-hydroxybenzoic acid instead of 3-chloro-4-hydroxybenzoic acid.