Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:10]([C:23]([O:25]CC)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4.50 g (11.9 mmol) of the compound of Example 37A are provided in 107 ml of 1,4-dioxane, 107 ml (214 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 2 h. The mixture is concentrated, a 2N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 4.11 g (99% of theory) of the title compound are obtained.
Reaction SMILES: C1N(CCS(O)(=O)=O)CCN(CCS(O)(=O)=O)C1.ClCC([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C(O)(=O)C>O>[NH2:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CCl)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)CCN1CCN(CCS(=O)(=O)O)CC1
Solvent: O
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.25 h

Procedure:
Ten microliters of 0.2 M piperazine-N,N'-bis(2-ethanesulfonic acid) [=PIPES] buffer, pH 7.3, and 10 μl of 100 mM N-chloroacetyl-L-phenylalanine (adjusted to pH 6-7 with NaOH) are dissolved in 20 μl of water. After 10 μl of an enzyme solution (30-50 μg/ml) is added, the mixture is incubated at 37° C. for 15 minutes. Then, 50 μl of 50% acetic acid is added to stop the enzymatic reaction. The amount of L-phenylalanine produced from the substrate in the reaction solution is determined by the Yemm-Cocking ninhydrin colorimetric method (E. W. Yemm & E. C. Cocking: Analyst, Vol. 80, page 209, 1955) or with an amino acid automatic analyzer (Model 835-50, Hitachi Limited).
Reaction SMILES: [C:1]([N:10]([CH3:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(=O)(=O)(O)O.[CH:22](O)([CH3:24])[CH3:23]>>[CH:22]([O:14][C:13](=[O:15])[CH2:12][CH2:11][N:10]([C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:16])([CH3:24])[CH3:23]
Reactant: CCCCCCCC(=O)N(C)CCC(=O)O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CCCCCCCC(=O)N(C)CCC(=O)OC(C)C

Procedure:
Fifty-seven(57) grams of N-octanoyl-N-methyl-β-alanine and 500 ml of isopropanol were charged into a 1,000-milliliter flask, and 1 ml of conc. sulfuric acid was further added thereto as the catalyst. The mixture was heated under reflux reaction for 8 hours.
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])NC4C=CC=C(C(F)(F)F)C=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.[CH3:39][C:40]1[N:41]=[CH:42][N:43]([C:45]2[CH:46]=[C:47]([CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=2)[NH2:48])[CH:44]=1.NC1C=CC=CC=1>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:48][C:47]4[CH:49]=[C:50]([C:52]([F:55])([F:53])[F:54])[CH:51]=[C:45]([N:43]5[CH:44]=[C:40]([CH3:39])[N:41]=[CH:42]5)[CH:46]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Solvent: Nc1ccccc1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(NC(=O)c4cccc5c(N)nccc45)c3)cc(C(F)(F)F)c2)cn1
Yield: 7.5 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 and Step (4) of Example 1 were repeated step by step, except for using 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline obtained in Step (1) above instead of aniline in Step (1) of Example 2 to obtain the title compound (3.0 mg, 7.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:77])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1.C1(C)C=CC=CC=1>[F:8][C:6]1[CH:7]=[C:2]([NH2:77])[CH:3]=[C:4]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:5]=1
Reactant: CN1CCC(N(C)c2cc(F)cc(Br)c2)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCC(N(C)c2cc(N)cc(F)c2)CC1
Reaction time: 2 h

Procedure:
The (3-bromo-5-fluorophenyl)-methyl-(1-methylpiperidin-4-yl)-amine intermediate is then aminated at the benzo 3-position, as for example, by reacting the intermediate with BINAP, Pd2dba3, benzhydrylideneamine, and sodium t-butoxide, in a suitable solvent, such as toluene or the like, under an inert atmosphere for about 1-3 hr., say about 2 hr., at about 50° C. to 100° C., say about 80° C. The resulting intermediate is treated with 1M HCl or the like in a suitable solvent, such as THF at 0° C. to ambient temperature, preferably ambient temperature for 1-2 hours, say about 1 hr. The resulting intermediate, 5-fluoro-N-methyl-N-(1-methylpiperidin-4-yl)benzene-1,3-diamine may then be isolated and purified by common procedures such as, but not limited to, solvent removal, extraction and/or chromatography, etc.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH:15]([CH2:18][CH3:19])[CH2:16]O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH:15]([CH2:18][CH3:19])[CH2:16][N:26]4[C:25](=[O:27])[C:24]5=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]5[C:22]4=[O:32])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.6 %

Procedure:
A solution of diethyl azodicarhoxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (6.9 g, 23.6 mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped to dryness. The residue was stirred in ether (200 ml) and the insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g, eluted with dichloromethane, DCM, and 1-2% CH3OH in DCM) and (100 g of SiO2, eluted with DCM, 11, and 1% CH3OH in DCM, 1.2 l). Two close compounds were separated and the top compound on TLC (1.6 g) was recrystallized from isopropyl ether to yield 0.76 g of white crystals, m.p. 86-88° C.
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[NH2:17]>O1CCOCC1>[Br:13][C:14]1[CH:15]=[C:16]([NH:17][C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=2)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(Br)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2nccc(C)n2)c1
Temperature: 120 °C
Yield: 100 %

Procedure:
Acetic acid (0.234 mL, 4.08 mmol) was added to 2-chloro-4-methylpyrimidine (0.5 g, 3.89 mmol) and 3-bromo-5-methylaniline (1.096 g, 3.89 mmol) suspended in dioxane (7.78 mL). The reaction was heated to 120° C. overnight. Then, the reaction was cooled to room temperature and was directly purified by column chromatography on silica gel eluting with ethyl acetate/hexanes to give N-(3-bromo-5-methylphenyl)-4-methylpyrimidin-2-amine (1.08 g, 3.89 mmol, quant.) as a white solid. MS ESI: [M+H]+ m/z 278.0 and 280.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]([C:21]1[C:22](=[O:34])[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]([CH3:27])[C:25]=1[CH3:26])=[O:20])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(N)=O)[CH:7]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CC#[N:52]>CCOC(C)=O.O>[NH2:52][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([NH:18][C:19]([C:21]3[C:22](=[O:34])[N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]([CH3:27])[C:25]=3[CH3:26])=[O:20])=[C:2]([Cl:1])[CH:3]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Solvent: CC(=O)O
Solvent: O
Solvent: Ic1ccccc1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a mixture of 4-(3-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)picolinamide (160 mg, 0.33 mmol) in EtOAc (3 mL), CH3CN (2.5 mL) and H2O (1.3 mL) was added iodobenzene diacetate (130 mg, 0.40 mmol) at 0° C. The reaction was stirred at 0° C. for 30 minutes, then warmed up to rt and continued to stir for 3 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=25/1) to give the title compound as a beige solid (100 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[I-:11].[Na+].I.C(=O)([O-])[O-].[Na+].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([I:11])=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: [I-]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Agent: I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Product: Cc1c(Cl)nnc(I)c1C
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
A mixture of D9 (0.2 g, 1.13 mmol), sodium iodide (0.420 g, 2.8 mmol) and hydroiodic acid (57 wt. % in water, 2 ml) was stirred at 120° C. for 10 min., under microwave irradiation. The mixture was then poured into an aqueous saturated solution of sodium carbonate, Na2S2O3, water and dichloromethane. The organic phase was separated, filtered over cotton, and the solvent evaporated in vacuo. The residue was purified by column chromatography (dichloromethane/heptane 1:1 to 8:2) to yield D10 (0.235 g, 77%) as a solid. C6H6ClIN2 requires 268. Found 269 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2/[CH:21]=[CH:22]/[CH:23]=[O:24])=[CH:4][C:3]=1[CH3:25].[Li+].CC([N-]C(C)C)C.[C:34]([O:40][CH3:41])(=[O:39])[CH2:35][C:36]([CH3:38])=[O:37].C(B(CC)CC)C.[BH4-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2/[CH:21]=[CH:22]/[CH:23]([OH:24])[CH2:38][CH:36]([OH:37])[CH2:35][C:34]([O:40][CH3:41])=[O:39])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C2=C(/C=C/C=O)C(C)(C)CC(N3CCCC3)C2)ccc1F
Reactant: COC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: CCB(CC)CC
Agent: [BH4-]
Product: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)c(C)c2)CC(N2CCCC2)CC1(C)C

Procedure:
In a manner similar to Scheme I, 33 (2.27 g, 6.65 mmol) was treated with the LDA derived anion of methyl acetoacetate (7.98 mmol) followed by triethylborane, methynol, and NaBH4. Workup and purification by HPLC using 1% Et3N in EtOAc as eluent provided the oily product.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[OH:19][C:20]([CH3:25])([CH3:24])[C:21](=[O:23])[CH3:22].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl>O1CCCC1>[CH3:24][C:20]([O:19][Si:27]([CH3:30])([CH3:29])[CH3:26])([CH3:25])[C:21]([O:23][Si:27]([CH3:30])([CH3:29])[CH3:26])=[CH2:22]
Reactant: CC(=O)C(C)(C)O
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C)C(C)(C)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
A solution of 1.6M n-butyllithium/n-hexane solution (100 ml) was dropwise added to a solution of diisopropylamine (22.4 ml) in dry tetrahydrofuran (50 ml) at -10° C., and the mixture was stirred for 1 hour. A solution of 3-hydroxy-3-methyl-2-butanone (8 ml) in dry tetrahydrofuran (50 ml) was dropwise added at -10° C. and the mixture was stirred for 1 hour. Then, trimethylchlorosilane (20.4 ml) was dropwise added at -10° C. After stirring at 4° C overnight, the reaction mixture was filtered with celite and the solid was washed with diethyl ether (500 ml). The combined filtrate was washed with 1N hydrochloric acid (150 ml×2) and a saturated aqueous solution of NaHCO3 (150 ml×2), and dried over MgSO4. The solvent was distilled away under reduced pressure. The residue was distilled under reduced pressure to give 16 g of the title compound (bp=85°-90° C./20 mmHg) as colorless liquid (see Table 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH2:22]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH3:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CC(C)(C)CN
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCC(C)(C)C

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 2,2-dimethyl-propylamine following general procedure B to afford 4-(2,2-dimethyl-propylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (220 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (160 mg) following general procedure E. The above ethylamide (0.50 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-(2,2-dimethyl-propyl)-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (5 mg). LCMS: m/z 342 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[C:3]([O:5]C)=[O:4].[I-].[Li+].Cl>N1C(C)=CC(C)=CC=1C>[CH3:1][C:2]([CH3:31])([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)CCCCOc1cc(-c2ccc([N+](=O)[O-])cc2)c2ccccc2n1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(CCCCOc1cc(-c2ccc([N+](=O)[O-])cc2)c2ccccc2n1)C(=O)O

Procedure:
The mixture comprising methyl 2,2-dimethyl-6-{[4-(4-nitrophenyl)-2-quinolyl]oxy}hexanoate (2.95 g) and dry lithium iodide (6.1 g) in 2,4,6-collidine (115 cc) is refluxed, under inert atmosphere, for 1 hour and 30 minutes and then poured in a 2N solution of hydrochloric acid (150 cc) at 0° C. The aqueous phase is extracted with ethyl ether (3×50 cc). The combined organic phases are washed with distilled water until neutrality, dried over sodium sulphate and then concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on silica gel (30-60 mm; n-hexane-ethyl acetate 1--1, white solid; m.p.=85°-92° C.)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:10]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][CH:15]=1)(=[O:12])[CH3:11].[OH-].[Na+].ClCCl>O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][S:18]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.9 %

Procedure:
A mixture of 1.25 g of 1H-imidazol-1-propanamine in 25 ml of water was stirred at room temperature then 2.34 g of N-acetylsulfanilyl chloride was added and stirring was continued for 20 hours resulting in a clear solution. With the addition of 4 ml of 5N sodium hydroxide the solution turned milky and resulted in the separation of an oil. The addition of dichloromethane resulted in the formation of a suspended precipitate which was collected by filtration and gave 2.67 g of the desired compound as tan crystals, mp 178°-180° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>CCOCC>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml of triethylamine and 0.14 ml of 4-fluorobenzoyl chloride are mixed together then the reaction medium is agitated at ambient temperature for 2 hours. Then ether is added, followed by separating, drying, taking up in water, extracting with methylene chloride, drying and evaporating the solvents. In this way 283 mg of expected product is obtained.
Reaction SMILES: [C:1]1(=O)O[CH2:4][CH2:3][CH2:2]1.[C:7]1(OC)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:4]1[CH:8]2[CH:7]3[CH:3]4[CH2:4][CH:3]1[CH2:2][CH:1]1[CH:2]4[CH2:1][CH:11]([CH2:10][CH:9]12)[CH2:12]3
Reactant: O=C1CCCO1
Reactant: COc1ccccc1
Product: C1C2CC3C4CC5CC(C14)C(C2)C3C5

Procedure:
1.0 g of the polymer (A-12) produced in Production Example 1 was dissolved under heat in a mixed solvent of 5.0 ml of gamma-butyrolactone and 5.0 ml of anisole to prepare a coating solution. The ratio of all carbon atoms of the cage structure (diamantane) to all carbon atoms of the total solid content of the insulating film-forming coating solution was about 36%. The solution was filtered through a 0.1-micron tetrafluoroethylene filter, and then applied onto a silicon wafer in a mode of spin coating. The coating film was heated on a hot plate in a nitrogen stream atmosphere at 180° C. for 60 seconds, and then further on a hot plate at 300° C. for 10 minutes. The specific dielectric constant of the thus-formed insulating film having a thickness of 0.5 microns was 2.57. The Young's modulus of the film was 6.0 GPa. 3σ of the film thickness was calculated, and it was 2.8%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[C:12](O)=[N:13][C:14]([CH2:17][CH3:18])=[N:15][CH:16]=1)=[O:10])[CH3:7]>C(N(CC)CC)C>[CH2:6]([O:8][C:9]([C:11]1[C:12]([Cl:3])=[N:13][C:14]([CH2:17][CH3:18])=[N:15][CH:16]=1)=[O:10])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(CC)nc1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(CC)nc1Cl
Temperature: 0 °C

Procedure:
7.5 ml of triethylamine were slowly introduced into 300 ml of phosphorous oxychloride cooled to 0° C., then were added 30 g of 5-ethoxycarbonyl 4-hydroxy 2-ethyl pyrimidine (VII) prepared in the preceding stage and the suspension was brought up to 40° C. under nitrogen scavenging. After dissolution, the phosphorous oxychloride was evaporated and the residue diluted in a mixture of water and chloroform. This was decanted, the chloroform phase was twice washed with water, dried on sodium sulfate and the solvent evaporated. The raw product obtained, after checking the purity by thin layer chromatography, was reacted in the following stage 3.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5]1.[Cl-:20].[Mn+2:21].[Cl-:22]>CO>[Cl:20][C:4]1([CH2:3][CH:2]([CH3:19])[CH3:1])[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][N:5]1[Cl:22].[Mn+2:21]
Reactant: CC(C)CC1CNCCNCCNCCNCCN1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CO
Product: CC(C)CC1(Cl)CNCCNCCNCCNCCN1Cl
Yield: 48 %

Procedure:
A solution of 2-(2-methylpropyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 5D (0.66 g, 2.4 mmole) and anhydrous manganese(II) chloride (0.31 g, 2.4 mmole) in anhydrous methanol (40 ml) was refluxed under a dry nitrogen atmosphere overnight. The solution was filtered and the solvent removed in vacuo. The resulting yellow solid was recrystallized from THF-ethyl ether to give 0.46 g (48% yield) of the product as an off-white solid: FAB mass spectrum (NBA) m/z (relative intensity) 396 (M+, 1), 361/363 [(M-Cl)+ 84/26], 272 [(M-MnCl2 +H) + 100]. Anal. Calcd. for C14H33Cl2MnN5 : C, 42.33; H, 8.37; N, 17.63. Found: C, 41.90; H, 8.22; N, 17.30.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@@H:22]([NH2:31])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:31][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc([C@H](N)CN2CCC2)ccc1Cl
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: Cc1cc([C@@H](CN2CCC2)Nc2ncnc3c(C(N)=O)ccnc23)ccc1Cl

Procedure:
Compound 46 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-chloro-3-methyl-phenyl)-ethylamine dihydrochloride to give the title compound as an off-white solid. LC/MS [397 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.01 (s, 1H), 8.99 (d, J=4.5 Hz, 1H), 8.53 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.17 (s, 1H), 7.45 (s, 1H), 7.39-7.24 (m, 2H), 5.34-5.17 (m, 1H), 3.20-2.98 (m, 5H), 2.83-2.71 (m, 1H), 2.29 (s, 3H), 2.01-1.84 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])[S:5][C:6]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].S([CH2:42][N+:43]#[C-:44])(C1C=CC(C)=CC=1)(=O)=O>CO.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])[S:5][C:6]=1[C:7]1[O:8][CH:44]=[N:43][CH:42]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1-c1cnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carbaldehyde (0.32 g, 0.86 mmol) in methanol (20 mL) was added potassium carbonate (0.30 g, 2.17 mmol) and tosylmethyl isocyanide (0.23 g, 1.17 mmol). The reaction mixture was stirred at ambient temperature for 1 h, heated to reflux for 1 h, and then cooled to ambient temperature. The mixture was diluted with ethyl acetate, washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a colorless solid in 47% yield (0.32 g): mp 160-162° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.85 (s, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.07 (s, 1H), 4.53 (s, 2H), 4.12-4.06 (m, 2H), 3.49-3.44 (m, 2H), 2.43 (s, 3H); 1H NMR (75 MHz, CDCl3) δ 157.5, 155.6, 149.8, 145.4, 145.1, 139.8, 130.5, 128.5, 125.9, 122.4, 122.1, 111.7, 47.6, 42.1, 42.0, 16.7; MS (ES+) m/z 409.1 (M+1).