Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.C([O-])(=[O:15])C.[Na+].C(OCC)(=O)C.O>CN(C)C=O>[F:8][C:5]1[N:4]=[C:3]([C:9]([O:11][CH3:12])=[O:10])[C:2](=[O:15])[NH:7][CH:6]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1nc(F)cnc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(F)c[nH]c1=O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 10.1 %

Procedure:
In 3.0 mL of N,N-dimethylformamide was dissolved 0.3 g of methyl 3,6-difluoro-2-pyrazinecarboxylate. After adding 0.16 g of sodium acetate at an ice-cooled temperature, the mixture thus obtained was stirred at 50° C. for 2.5 hours. The reaction mixture was poured into a mixture of 50 mL of ethyl acetate and 30 mL of water, and the organic layer was separated. The remaining aqueous phase was extracted with three 25 mL portions of ethyl acetate. The organic layers were united, washed successively with 15 mL of water and 15 ml of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate=1:2] to obtain 0.03 g of methyl 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a colorless solid product.
Reaction SMILES: N(C1N=[C:12]([C:14]2[N:18]([CH:19]([CH3:21])[CH3:20])[C:17](C=NOC)=[N:16][CH:15]=2)C=CN=1)C1C=CC=CC=1.[CH3:26][C:27]([N:29]([CH3:31])[CH3:30])=O.CN(C=[O:36])C>>[CH3:30][N:29]([CH3:31])[CH:27]=[CH:26][C:12]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[CH:17]=[N:16][CH:15]=1)=[O:36]
Reactant: CN(C)C=O
Reactant: CON=Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C(C)C
Reactant: CC(=O)N(C)C
Product: CC(C)n1cncc1C(=O)C=CN(C)C
Temperature: 25 °C
Yield: 53 %

Procedure:
5-Acetyl-1-isopropylimidazole (Method 3; 15.3 g, 100 mmol) was dissolved in a mixture of DMF (90 ml) and DMF.DMA (150 ml) and the mixture was heated under reflux, under an atmosphere of nitrogen, for 18 hours. The reaction mixture was allowed to cool to ambient temperature and the product crystallised. The solid product was collected by filtration, washed with DMF.DMA and then ether and dried under vacuum at 40° C. to give the title compound (11 g, 53%) as a pale solid. NMR: 1.43 (d, 6H), 2.95 (m, 6H), 5.32 (m, 1H), 5.58 (d, 1H), 7.60 (m, 2H), 7.90 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37]([NH:39][C@@H:40]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:44])=[O:43])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:69][CH2:70][CH2:71][C:72]([OH:74])=[O:73].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:72]([CH2:71][CH2:70][CH2:69][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37]([NH:39][C@@H:40]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:44])=[O:43])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:74])=[O:73]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
19.3 mg (20 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylsulphonyl)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate were dissolved in 1.2 ml of dioxane/water and, analogously to the preparation of Intermediate 61, reacted with 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride. After lyophilization from dioxane, 8.6 mg (45% of theory) of the title compound were obtained in the form of a solid.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:43]=[CH:42][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:44][CH3:45].O.[C:47]1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:47])[C:5]3[C:11]2=[N:12][C:2]([NH:21][C:22]2[CH:43]=[CH:42][C:25]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[CH:24][C:23]=2[O:44][CH3:45])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Solvent: O
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 127; 50 mg, 0.16 mmol) and tert-butyl 4-[(4-amino-3-methoxy-benzoyl)amino]piperidine-1-carboxylate (Intermediate 234; 85 mg, 0.24 mmol) were dissolved in 4-methyl-2-pentanol (1 mL) and p-toluenesulphonic acid monohydrate (44 mg, 0.32 mmol) added. The reaction mixture was heated at 90° C. by microwave irradiation for 20 minutes and then at 150° C. for a further 45 minutes.
Reaction SMILES: C(NC(C)C)(C)C.C[Li].[C:10]([O:14][C:15](=[O:24])[CH2:16][C@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:13])([CH3:12])[CH3:11].I[CH2:26][CH2:27][CH2:28][CH3:29].[Cl-].[NH4+]>CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C>[C:10]([O:14][C:15](=[O:24])[C@H:16]([CH2:26][CH2:27][CH2:28][CH3:29])[C@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:11])([CH3:13])[CH3:12]
Reactant: CCCCI
Reactant: CCCCC[C@@H](O)CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CCCCC[C@@H](O)[C@@H](CCCC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
A dried two-necked flask was cooled to −78° C., after which diisopropylamine (5.41 g, 53.5 mmol) was introduced thereto. Then, methyllithium (a 0.98M diethyl ether solution, 45 ml, 44.1 mmol) was added dropwise thereto, and stirred for 10 minutes. The resulting mixture was heated to 0° C., and stirred for another 30 minutes. The reaction solution was cooled to −48° C., the (R)-3-hydroxyoctanoic acid t-butyl ester (3.50 g, 16.2 mmol) obtained in Production Example B-1 was added dropwise thereto, and then the mixture was stirred for 30 minutes. To the obtained mixture was added hexamethylphosphoric triamide (HMPA) (7 ml), the mixture was stirred for one minute, then 1-iodobutane (3.87 g, 21.0 mmol) was added dropwise thereto. After the reaction solution was stirred at −48° C. for one hour, a saturated ammonium chloride solution was added thereto, and extracted 3 times with diethyl ether. The resulting organic layer was dried with anhydrous magnesium sulfate, filtered, and condensed. The obtained residue was purified by column chromatography (silica gel: 150 g, n-hexane/ethyl acetate=15/1) to produce the target compound (1.98 g, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([S:29](Cl)(=[O:31])=[O:30])=[CH:24]2.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([S:29]([N:11]1[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]1)(=[O:30])=[O:31])=[CH:24]2
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2c(Cl)cccc2c1)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 69 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (193 mg, 3.888 mmol) with 5-chloronaphthalene-2-sulfonyl chloride (202.1 mg, 0.777 mmol) was carried out according to the representative sulfonation procedure described in Example 1 using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (0.7 mL, 3.887 mmol) as base. 1-[(5-chloro-2-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine was obtained in 69% yield (256 mg) as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15]([OH:17])=O)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62])[CH2:57][CH2:58][CH3:59]>CN(C=O)C>[CH2:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][N:66]([C:15](=[O:17])[C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:11]2[N:10]=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:12]=2)[CH2:65][CH2:64]1)=[O:62])[CH2:57][CH2:58][CH3:59]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2cn(Cc3ccccc3)nn2)NC(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a solution of 836 mg (S)-3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-2-tert-butoxycarbonylamino-propionic acid in 20 ml DMF were added 0.61 ml N-ethylmorpholine, 0.79 g TOTU and 449 mg Piperazine-1-carboxylic acid butyl ester. After stirring for 2 h the reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 1.14 g.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[BrH:12].C(O[CH2:16][CH3:17])C.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>CO>[BrH:12].[BrH:12].[Br:12][C:17]1[CH:16]=[CH:22][C:18]([CH2:5][N:1]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[S:11])[C:2]2[CH:20]=[CH:19][CH:18]=[CH:22][N:3]=2)=[CH:19][CH:20]=1
Reactant: S=C=NCCCn1ccnc1
Reactant: C1CCOC1
Reactant: CCOCC
Agent: Br
Solvent: CO
Product: S=C(NCCCN(Cc1ccc(Br)cc1)c1ccccn1)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of N-1-(4-bromobenzyl)-1-(pyrid-2-yl)propane-1,3-diamine (616 mg, 1.92 mmol) in THF (15 mL) was treated dropwise with 3-(imidazol-1-yl)propyl isothiocyanate (323 mg, 1.92 mmol) in THF (10 mL) under a nitrogen atmosphere. After stirring overnight at room temperature, the solid was filtered. Evaporation of the filtrate under reduced pressure gave a yellow oil which was dissolved in methanol and acidified with methanolic hydrogen bromide. Addition of diethyl ether afforded a cloudy solution which produced a light tan solid upon standing in the refrigerator. The solid was filtered and dried to yield 0.94 g (75%) of the title compound. Recrystallization from absolute ethanol-diethyl ether afforded an analytical sample.
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C(OCC)C.C1COCC1>[N:9]1[CH:10]=[CH:11][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccncc1
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccncc1
Yield: 45 %

Procedure:
A solution of methyllithium (1.4 M; 30 ml, 42 mmol) in diethyl ether was added dropwise to a stirred solution of 4-acetylpyridine (4.65 ml, 42 mmol) in dry THF (100 ml) at -76° C., and the deep blue solution allowed to reach ambient temperature. After 24 hours the mixture was partitioned between ether and saturated aqueous sodium bicarbonate, and the ether phase was concentrated. Chromatography, on elution with ethyl acetate-dichloromethane-triethylamine 60:40:1, gave the title compound (2.59 g, 45%) as an oil. 1H-NMR (CDCl3) δ1.58 (6H, s, CMe2), 7.40 (2H, d, J 6.2 Hz, Py 3 and 5-H), 8.55 (2H, d, J 6.2 Hz, Py 2 and 6-H); MS m/z 137 (M+).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=4)/[CH:21]=[CH:22]/[C:23](O)=[O:24])[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CN(C)C=O.ClCCl>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:28]=[CH:27][CH:26]=[C:20](/[CH:21]=[CH:22]/[C:23]([N:12]5[CH:11]=[CH:15][N:14]=[CH:13]5)=[O:24])[CH:19]=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[C:9]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1)n1ccnc1
Reaction time: 18 h
Yield: 146.3 %

Procedure:
A slurry of (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid (from step (a), 0.50 g) in anhydrous N,N-dimethylformamide (10 mL) was heated briefly to near reflux under nitrogen. N,N′-carbonyldiimidazole (Aldrich, 0.202 g, 1.22 mmol) was then added to the pale yellow slurry, which thinned and turned orange as a gas evolved. Within minutes the slurry turned a bright yellow and thickened as a yellow solid formed. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The bright yellow solid was washed with dichloromethane (30 mL), and dried at 40° C. to provide (E)-1,3-bis(cyclohexylmethyl)-8-(3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl)-9H-purin-2,6(1H,3H)-dione as a yellow powder (0.403 g). To a mixture of this compound (0.40 g, 0.74 mmol) and nonaethylene glycol monomethyl ether, (part (a) of example 10, 0.350 g) in N,N-dimethyl fornamide (10 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (Aldrich, 0.112 g). The resulting solution was stirred at 55° C. for 20 h. The solution was cooled to room temperature and adjusted to pH 7 by addition of 1N HCl. Chloroform (50 mL) was added and the solution was washed with water (2×20 mL). The combined organic layers were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual waxy solid was chromatrographed on silica gel eluted with 10% methanol/chloroform to give (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid nonaethylene glycol methyl ether ester as a white waxy solid (0.421 g, 63%); 1H-NMR (DMSO-d6) δ: 8.53 (s, 1, aryl CH), 8.13 (d, J=7.7, 1, aryl CH), and 7.80 (d, J=8.5, 1, aryl CH), 7.71 (d, J=16, 1, CH═) 7.58, (m, 1, aryl CH), 6.78, (d, J=15.9, 1, CH═) 4.28 (m,2, CH2O), 3.91, (d, J=7.2, 2, CH2N), 3.77 (d, J=7.2, CH2N), 3.68 (m, 2, CH2O), 3.70-3.40 (m, 32, 16 CH2), 3.21 (s, 3, CH3), 2.1-1.6 and 1.4-1.0 (m, 22, cyclohexyl CH2 and CH).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:11].[Na+].[OH2:16]>CO>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)(=[O:11])=[O:16]
Reactant: CSc1ccc(O)cc1
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(O)cc1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 4-(methylthio)phenol (7.0 g. 0.05 mol) in 30% aqueous methanol (100 ml) at 0° C. is added a solution of sodium periodate (10.7 g, 0.05 mmol) and the resulting suspension is stirred for 30 min. Water (500 ml) is then added and the precipitate removed by filtration. The filtrate is cooled to 4° C. and a further portion of sodium periodate (10.7 g, 0.05 mmol) added and the resulting suspension stirred for 48 h when a further portion of sodium periodate (5.35 g, 0.025 mmol) is added. After stirring for a further 18 h, the precipitate is removed by filtration, the filtrate extracted with ether which is evaporated to dryness and the residue is purified on a silica column using chloroform methanol, 9:1, as eluent to give the title compound (2.75 g, 32% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH2:21][C:22](OCC)=O)=O)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19]2[CH2:21][CH2:22][C:3]3[C:2](=[CH:7][CH:6]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=3)[NH:1]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: COC(=O)Cc1ccc(N)cc1
Product: COC(=O)Cc1ccc2c(c1)CCC(c1ccc(OC)cc1)N2

Procedure:
Using methyl p-aminophenylacetate and ethyl p-methoxybenzoylacetate as starting raw materials, treatment was made similarly to Example 1 to obtain aimed product.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5](=[NH:8])[O:6][CH3:7])#[N:3].[N+:9]([C:12]1[CH:17]=C[C:15](O)=[C:14](N)[CH:13]=1)([O-:11])=[O:10]>CO>[N+:9]([C:12]1[C:17]2[N:8]=[C:5]([CH2:4][C:2]#[N:3])[O:6][C:7]=2[CH:15]=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: COC(=N)CC#N
Agent: Cl
Solvent: CO
Product: N#CCc1nc2c([N+](=O)[O-])cccc2o1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
The mixture of methyl cyanoacetimidate hydrochloride (43.47 g, 0.32 mole) and 4-nitro-2-aminophenol (24.9 g, 0.16 mole) in methanol (260 ml) was heated at reflux for 3 h. The mixture was placed in an ice bath for 30 minutes and was filtered. The solid material was suspended in water (300 ml), stirred for a few minutes and filtered. It was washed with water (200 ml) and air dried to give 4-nitro-2-benzoxazoleacetonitrile (27.38 g, 83%).
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[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:36]([Sn](CCCC)(CCCC)CCCC)=[N+:37]=[N-:38]>C1C(Cl)=CC=C(Cl)C=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][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[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[N:36]=[N:37][NH:38][N:35]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C#N)n4)cc3)cc2)CC1
Solvent: Clc1ccc(Cl)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5nn[nH]n5)n4)cc3)cc2)CC1
Temperature: 110 °C

Procedure:
1-{4′-[4-(6-Cyano-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.046 g, 0.1 mmol) and azidotributyltin(IV) (0.0996 g, 0.3 mmol) were dissolved in dichlorobenzene (1 mL) and heated to 110° C. for 14 hours. After cooling the reaction mixture was directly purified by silica gel chromatography to afford the title compound.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[C:5]1([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:5]1([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:1][CH2:2][CH3:3])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(NCCCNCCc1ccc(Cl)cc1)Nc1ccccc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CCCNC(=O)Nc1ccccc1)CCc1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 72.2 %

Procedure:
Propyl iodide (51 mg, 0.30 mmol) was added to a mixture of N-phenylcarbamoyl-N′-[2-(4-chlorophenyl)ethyl]-1,3-diaminopropane (33 mg, 0.10 mmol) and potassium carbonate (28 mg, 0.20 mmol) in CH3CN (2 ml). The mixture was stirred at 75° C. for 5 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was purified by preparative normal phase HPLC using linear gradients of (A) chloroform and (B) methanol (0-5% B, in 0-10 min; 5-10% B, in 10-30 min; 10-15% B, in 30-40 min) at a flow rate of 10 ml/min. Fractions containing the major peak were pooled and concentrated to afford N-phenylcarbamoyl-N′-[2-(4-chlorophenyl)ethyl]-N′-propyl-1,3 diaminopropane (27 mg, 59%): MS(ES+) m/e 374 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=8.3 Hz, 2H), 7.25 (m, 4H), 7.07 (m, 3H), 5.98 (br, 1H), 5.00 (br, 1H), 3.31 (m, 2H), 2.78 (m, 6H), 2.59 (m, 2H), 1.76 (m, 2H), 1.52 (m, 2H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]#N)[C:10]1=[O:18].[OH2:19].[OH-:20].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]([OH:20])=[O:19])[C:10]1=[O:18]
Reactant: O
Reactant: [OH-]
Reactant: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1F
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 1-(2,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (600 mg, 2.44 mmol) in conc. sulfuric acid (3 mL)/water (3 mL) was stirred at 120° C. for 17 hr. The reaction solution was allowed to cool to room temperature, and alkalified with 8N aqueous sodium hydroxide solution. The aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with 2N hydrochloric acid and the precipitate was collected by filtration and washed with water to give the title compound (600 mg, 93%) as a white solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[NH:3])[CH3:2].Br[CH2:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:23])[C:21]=1[Br:22])=O.C(N(CC)C(C)C)(C)C>CC1CCCO1.COCCOC>[C:9]([O:8][C:6](=[O:7])[NH:5][N:4]1[CH:14]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[Br:22])[N:3]=[C:1]1[CH3:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(=N)NNC(=O)OC(C)(C)C
Reactant: Cn1ncc(C(=O)CBr)c1Br
Solvent: CC1CCCO1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cnn(C)c2Br)cn1NC(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
tert-Butyl 2-ethanimidoylhydrazinecarboxylate (5.9 g, 34 mmol), 2-bromo-1-(5-bromo-1-methyl-1H-pyrazol-4-yl)ethanone (from the previous step, 8.00 g, approximately 24 mmol) and N,N-diisopropylethylamine (10.9 mL, 62.6 mmol) were heated to reflux in a mixture of 2-methyltetrahydrofuran (200 mL) and 1,2-dimethoxyethane (50 mL). After 2.5 hours, the reaction was cooled and washed with 50% saturated aqueous sodium chloride solution (75 mL). The aqueous layer was extracted with 2-methyltetrahydrofuran (50 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (Gradient: 0% to 8% methanol in dichloromethane), and the purified material (7.5 g) was dissolved in diethyl ether (25 mL), treated with hexane (4 drops), and allowed to crystallize. The resulting solid was collected and washed with a small amount of cold diethyl ether to provide the product as a very pale pink solid. Yield: 6.49 g, 18.2 mmol, 59% over 2 steps. LCMS m/z 358.4 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.49 (br s, 9H), 2.16 (br s, 3H), 3.85 (s, 3H), 7.17 (s, 1H), 7.89 (s, 1H), 8.8-9.3 (v br s, 1H).
Reaction SMILES: [Cl-].[Zr+4:2].[Cl-].[Cl-].[Cl-].[B:6](O)(O)O.[Mg]>>[B:6].[B:6].[B:6].[B:6].[B:6].[B:6].[B:6].[B:6].[B:6].[B:6].[B:6].[B:6].[Zr:2]
Reactant: OB(O)O
Reactant: [Zr+4]
Agent: [Cl-]
Agent: [Mg]
Product: [B]
Product: [Zr]

Procedure:
Accordingly, the present invention provides an improved process for the production of zirconium boride, which comprises mixing powders of zirconium chloride in the range of 20-25% wt, Boric acid (H3BO3) in the range of 35-44 wt % and small cut turnings Magnesium (Mg) in the range of 33-40 wt % and pelletising the mixture so prepared, igniting the prepared pellets under inert atmosphere and leaching the resultant product (ZrB2 and MgO) with leachant to obtain zirconium boride.