Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[C:24]([NH:28][C:29]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=3)=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[C:24]([NH:28][C:29]([C:31]4[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:30])[CH:25]=[CH:26][CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2CC(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of N-(3-{[1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl]oxy}phenyl)-3-methylpyridine-2-carboxamide (9.68 g, 18.2 mmol), trifluoroacetic anhydride (30 mL) and tetrahydrofuran (250 mL) was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, ethanol (200 mL) and 4M aqueous sodium hydroxide solution (60 mL) were added to the residue, and the mixture was stirred at room temperature for 19 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane) to give the title compound (4.52 g, 69%) as a pale-yellow oil.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)=[CH:18][CH:17]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOCC.O.CN(C=O)C>[C:1]1([N:7]2[N:11]=[C:10]([C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]4[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]4)=[CH:18][CH:17]=3)=[O:14])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cnn(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cnn(-c4ccccc4)n3)cc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
In a 25 mL round-bottomed flask, 2-phenyl-2H-1,2,3-triazole-4-carboxylic acid (CAS 13306-99-5) (59.8 mg, 316 μmol, Eq: 1.1), (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (80 mg, 287 μmol, Eq: 1.00), N-methylmorpholine (87.2 mg, 94.8 μl, 862 μmol, Eq: 3) and HBTU (164 mg, 431 μmol, Eq: 1.5) were combined with DMF (2 ml) to give a yellow solution. The reaction mixture was stirred overnight at 60° C. The mixture was poured into water (10 ml) and extracted twice with EtOAc. The organic layers were washed with NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to give a brown crude mixture. This mixture was diluted with ether, stirred for 15 minutes and the suspension was filtered. The resulting solid was washed several times with ether to afford the desired compound as a light-yellow solid (35 mg, 27.1%).
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH:24]1([C:27]2[O:31][N:30]=[C:29]([CH2:32][N+:33]#[C-:34])[N:28]=2)[CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([C:27]2[O:31][N:30]=[C:29]([C:32]3[N:33]=[CH:34][N:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:16]=[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)[C:8]=34)[N:28]=2)[CH2:26][CH2:25]1
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Reactant: Clc1nc2ccccc2nc1N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)nc(N1CCOCC1)c1c(-c3noc(C4CC4)n3)ncn12
Temperature: 20 °C

Procedure:
A solution of potassium t-butoxide (3.7 g, 32 mmol) in dry DMF (25 ml) was added to a stirred solution of 2-chloro-3-morpholino-quinoxaline (4 g, 16 mmol) and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole in dry DMF (50 ml), the temperature being kept at 0°-5° C. Then the temperature was raised to 20° C. and the solvent was evaporated in vacuo. The residue was partitioned between water (50 ml) and dichloromethane (50 ml). The organic phase was dried and evaporated and the residue was triturated with a small amount of ethyl acetate. The resulting crystalline product was collected by filtration and dried to give 3.2 g of the title compound, m.p. 169°-173° C. (Compound 9).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.C(O)(C(F)(F)F)=O.N.CO>C(Cl)Cl>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:16]=[C:15]([NH:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: CN(C)CCCNc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCNc1nc(NC2CCNCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(2-(3-(dimethylamino)propylamino)quinazolin-4-ylamino)piperidine-1-carboxylate (3.3 g, 7.71 mmol) in CH2Cl2 (20 ml) at 0° C. was added CF3COOH (4 ml, 53.9 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was then neutralized with 7 N NH3-MeOH. The resulting white solid was filtered away. The filtrate was concentrated and purified by silica gel column chromatography using 10% NH3 ca. 7 N MeOH in CH2Cl2 and 90% CH2Cl2 solution as eluent to obtain the title compound as a pure white solid.
Reaction SMILES: [S:1](=[O:30])(=[O:29])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[NH:23][CH2:24]CCC)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].[Si](I)(C)(C)[CH3:32]>>[S:1](=[O:29])(=[O:30])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[N:23]([CH3:32])[CH3:24])=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Reactant: C[Si](C)(C)I
Product: CN(C)C(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C

Procedure:
Compound 11p was synthesized in a similar manner as 11a except that TMS-I was used in place of BBr3. Compound 11p was prepared from compound 12. EI-MS m/z 404 M+; 1H NMR (300 MHz, DMSO-d6) δ 0.98 (s, 3H, CH3), 2.93 (brs, 6H, N(CH3)2), 5.86 (s, 1H, 16-CH), 6.97 (s, 1H, ArH), 7.02 (d, 1H, J=9 Hz, ArH), 7.31 (d, 1H, J=9 Hz, ArH), 7.89 (s, 2H, SO2NH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:30]=1.CO.[CH3:33][NH2:34].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([NH:34][CH3:33])[C:6]=2[CH:30]=1
Reactant: CN
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)s2)c2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
To a suspension of 7-chloro-5-oxo-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1 g) in methanol (40 ml) are added molecular sieve 4A (2 g) and 40% methylamine methanol solution (10 ml), and the mixture is refluxed for 6 hours, and cooled. To the mixture is added with stirring sodium borohydride (0.13 g) at room temperature, and the mixture is stirred at the same temperature overnight. The reaction solution is filtered on Celite, and to the filtrate is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-methylamino-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.93 g) as white powder.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[Se:8][C:7]=1[C:15]([O-:17])=[O:16])[CH3:3].[OH-].[Na+]>CO.O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[Se:8][C:7]=1[C:15]([OH:17])=[O:16])[CH3:1]
Reactant: CN(C)N=Nc1c(C(=O)[O-])[se]c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)N=Nc1c(C(=O)O)[se]c2c1CCCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
To a solution of ethyl and methyl esters of 3-[(dimethylamino)diazenyl]-4,5,6,7-tetrahydrobenzo[2,1-d]selenophene-2-carboxylate (1.0 g, 3.1 mmol) prepared as described in Example 5 step c) in methanol (10 mL) was added a solution of sodium hydroxide (500 mg, 12.6 mmol) in water (2 mL) and stirred at rt for 5 h. The mixture was diluted with ice cold water and extracted with chloroform (2×50 mL) to remove impurities. The aqueous layer was acidified with dil. HCl and stirred for 30 min. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent (550 mg, 57%). The crude product was recrystallized from chloroform-diethyl ether to give the product as a dark brown color solid (330 mg), mp 100-102° C. IR (Neat) νmax 3429, 2927, 2855, 1701, 1350, 1110, 1050, 1023, 880 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.71 (1H, br s, —COOH), 3.59 (3H, s, —NCH3), 3.20 (3H, s, —NCH3), 2.83 (2H, t, J=5.4 Hz, H-4), 2.73 (2H, t, J=5.6 Hz, H-7), 1.75-1.81 (4H, m, H-5,6); 13C NMR (100 MHz, CDCl3): δ 164.5, 151.3, 148.9, 131.5, 124.0, 44.1, 36.5, 28.8 (2C), 22.8, 22.4; LC-MS (positive ion mode): m/z 300, 302 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C1COCC1.C[C@H]1O[C@H]2[C@H](O)[C@@H](O)[C@H](OC3C4C(=CC5OCOC=5C=4)[C@@H](C4C=C(OC)C(O)=C(OC)C=4)[C@@H]4[C@@H]3COC4=O)O[C@@H]2CO1.C1COP(NCCCl)(=O)N(CCCl)C1.[NH2-].[NH2-].Cl[Pt+2]Cl>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1
Agent: Cl[Pt+2]Cl
Agent: COc1cc([C@@H]2c3cc4c(cc3C(O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a stirred solution of ethyl 4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.93 g, 5.27 mmol) in THF (10 ml) was added 1 N NaOH (10 ml) and the reaction mixture was heated under reflux for 5 hr. After cooled to room temperature, the mixture was poured into ice-1 N HCl. The resulting precipitate was collected under a reduced pressure and the crude solid was recrystallized from MeOH—CHCl3—IPE to give 4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetic acid (910 mg, 51%) as a white crystalline powder. mp 224-225° C.; 1H-NMR (DMSO-d6) δ3.50 (s, 2 H), 7.18 (d, J=8.3 Hz, 2 H), 7.25-7.29 (m, 1 H), 7.40 (d, J=8.3 Hz, 2H), 7.62-7.69 (m, 2 H), 7.95-7.97 (m, 1 H), 8.06 (s, 1 H), 9.37 (s, 1 H), 12.27 (br s, 1H); Anal. Calcd. for C16H13F3N2O3: C, 56.81; H, 3.87; N, 8.28; F, 16.85. Found: C, 56.68; H, 3.87; N, 8.16; F, 16.89.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13](OCC)=O)=[O:9])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:4][NH:3]1.O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.ON1C2C=CC=CC=2N=N1.[Cl:50][C:51]1[CH:52]=C(C=[CH:57][C:58]=1[Cl:59])CN.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:50][C:51]1[CH:52]=[C:12]([CH:13]=[CH:57][C:58]=1[Cl:59])[CH2:11][NH:10][C:8]([C:7]1[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH:6]=1)=[O:9]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 13 for the preparation of ethyl 3-[(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carbonyl)amino]propionate, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 30 cm3 of N,N-dimethylformamide, 0.233 g of 1-hydroxybenzotriazole, 0.19 cm3 of 3,4-dichlorobenzylamine, 0.31 cm3 of N,N-diisopropylethylamine and 0.65 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 0.28 g of N-(3,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at 265° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[C:5]#[N:6].N>CO.[Ni]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6]
Reactant: N#Cc1ccc(Cl)c(N)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-Amino-4-chloro-benzonitrile (1.32 g, 8.33 mmol), Ra-Nickel (0.25 g) and 80 ml NH3 in MeOH was stirred for 4 h at rt under H2-atmosphere (3 bar). The mixture was filtered and concentrated and the sub-title compound was used without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:5][CH:6]=1.[N:21]1([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)[CH:25]=[N:24][CH:23]=[N:22]1>>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([O:7][C:4]2[S:5][CH:6]=[C:2]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([N:21]5[CH:25]=[N:24][CH:23]=[N:22]5)=[CH:34][CH:33]=4)[CH:29]=[CH:30]3)[N:3]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: c1ncn(-c2ccc3[nH]ccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(-n5cncn5)ccc43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-Butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate 46) and 5-(1H-1,2,4-triazol-1-yl)-1H-indole (intermediate 58).
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=2[S:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.O.[NH2:18][NH2:19]>C(O)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH2:4][CH:3]3[C:2](=[N:18][NH:19][C:14](=[O:16])[CH2:13]3)[C:7]=2[CH:8]=1
Reactant: Cc1ccc2c(c1)C(=O)C(CC(=O)O)CS2
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C1=NNC(=O)CC1CS2
Yield: 50.9 %

Procedure:
A mixture of 2 g of α-(2,3-dihydro-4-oxo-6-methyl-4H-1-benzothiopyran-3-yl)acetic acid and 0.8 g of 100% hydrazine hydrate in 50 ml of ethanol is refluxed under heating for 8 hours. After about half the volume of ethanol is distilled off under reduced pressure and the residue is allowed to cool, the precipitated crystals are collected by filtration and recrystallized from acetic acid to give 1 g of 9-methyl- 2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin 3-one, melting at 217°-219° C., as colorless prisms.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl-].Cl[CH2:23][CH2:24][NH+:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:31]=[S:28]1(=[O:32])[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=4)[CH:8]=3)[CH2:2][CH2:3]2)[CH2:26][CH2:27]1
Reactant: O=S1(=O)CC[NH+](CCCl)CC1
Reactant: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc(N3CCN(CCN4CCS(=O)(=O)CC4)CC3)ncn2)s1
Temperature: 200 °C

Procedure:
12-3 (0.20 g, 0.39 mmol), 41-2 (0.11 g, 0.47 mmol) and DIEA (0.30 g, 2.33 mmol) were suspended in DMF (1 mL) in a sealed tube and heated at 200° C. for 15 minutes in the Smith personal chemistry microwave reactor. The crude material was purified on a C18 preparative hplc column to afford 41-3. Hi-Res MS: calc: 449.1576 found: 449.1532. 1H-NMR(CD3OD): 8.49(s, 1H); 8.02(s, 1H); 6.28(s, 1H); 4.02(m, 4H); 3.48(br s, 4H); 3.39(t, 2H); 3.16(m, 4H); 3.12(m, 4H); 2.97(m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:20]=[C:18]1[NH:17][C:16](=[O:21])[C:15](=[CH:14][C:11]2[CH:10]=[CH:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)=[CH:13][CH:12]=2)[S:19]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Product: O=C(Cc1ccccc1)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 96.5 %

Procedure:
In a manner similar to that of Example 1(d), by reacting 1.2 g (2.3 mmol) of 5-(3′-aminobiphenyl-4-ylmethylene)thiazolidine-2,4-dione with 430 μl (3 mmol) of phenylacetyl chloride, 920 mg (97%) of the expected product are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CN1CCCC1=O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:22][CH:23]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(CNc2ncnc3ccccc23)cc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a solution of 4-chloro-quinazoline described in Preparation Example X-1 (8 mg, 0.049 mmol) in 1-methyl-2-pyrrolidone (0.5 mL) were added 4-tert-butyl-benzylamine (10 μl, 0.059 mmol) and N,N-diisopropylethylamine (17 μl, 0.098 mmol), and the solution was stirred for 5 hours at 160° C. The reaction mixture was directly purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (16.5 mg, 0.041 mmol, 72%) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].Cl[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]>>[CH2:1]([O:3][CH:4]=[CH:5][C:7](=[O:8])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: C=COCC
Product: CCOC=CC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
145 g of ethyl vinyl ether were added dropwise to 137 g of ethyl chloroformylformate with cooling using ice/common salt; after warming to room temperature, the mixture was stirred for a further 20 hours. The volatile components were removed by distillation, and the residue was fractionated in a water-pump vacuum. Ethyl 4-ethoxy-2-oxobut-3-enoate of boiling point 140°-143° C./13 torr were obtained. 17.5 g of product were dissolved in 200 ml of toluene. 17.5 g of 2,6-dichlorophenylhydrazine were added at 0° C. were stirring. The mixture was slowly heated to boiling, and ethanol and water were removed in a water separator until the boiling point remained constant at 111° C. The residue was diluted with toluene, washed twice with 2 N hydrochloric acid, saturated hydrogen carbonate solution and water, dried, evaporated to dryness and recrystallized from ethanol. Yield: 18.3 g. Melting point: 51°-53° C.
Reaction SMILES: C([O:5][CH2:6][C:7]([CH2:20][O:21]C(=O)C=C)([CH2:14][O:15]C(=O)C=C)[CH2:8][O:9]C(=O)C=C)(=O)C=C>CO>[OH:5][CH2:6][C:7]([CH2:20][OH:21])([CH2:14][OH:15])[CH2:8][OH:9]
Reactant: C=CC(=O)OCC(COC(=O)C=C)(COC(=O)C=C)COC(=O)C=C
Solvent: CO
Product: OCC(CO)(CO)CO
Temperature: 10 °C

Procedure:
The alkylidenediamine (ADA for abbreviation) is added into a round-bottom flask equipped with a stirring, a reflux condenser and a thermometer, and cooled to 10° C. below under nitrogen. The methanol solution of pentaerythritol tetraacrylate (PETA for abbreviation) is then added to the flask, and the mixture is allowed to react at 25˜35° C. for 20˜48 hours, preferably, at 25˜30° C. for 24˜30 hours. The result solution is subjected to vacuum distillation to remove excess alkylidenediamine (ADA) and methanol at 60˜110° C. for 5˜10 hours, to obtain a light-amber viscous material, i.e., intermediate pentaerythritol core, amino terminated dendrimer (PETA-ADA-12NH for abbreviation), wherein a general reaction equation thereof is as follows:
Reaction SMILES: [C:1](Cl)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCCCCCCCC.[O:25]=[C:26]([CH2:28][N:29]([C:31](=[NH:33])[NH2:32])[CH3:30])[OH:27].N1C=CC=CC=1.C(=O)=O>ClCCl.CC(C)=O>[C:1]([NH:33][C:31](=[NH:32])[N:29]([CH2:28][C:26]([OH:27])=[O:25])[CH3:30])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(CC(=O)O)C(=N)N
Agent: O=C=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)NC(=N)N(C)CC(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the docosanoyl chloride solution, 12.59 g (96 mmol) of creatine is suspended, with stirring, in 100 ml of dry dichloromethane. To this suspension a catalytic amount (0.1 mmol) of pyridine is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of between about −15° C. and 0° C. When the target temperature is reached the drop wise addition of docosanoyl chloride is commenced. Addition of docosanoyl chloride continues, with cooling and stirring, until all of the docosanoyl chloride is added, after which the reaction is allowed to warm to room temperature with constant stirring. The solution is then filtered to remove any remaining creatine, and the volatile dichloromethane and pyridine are removed under reduced pressure yielding 2-(3-dodecanoyl-1-methylguanidino)acetic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:7](CC2C=CC=CC=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][O:5][CH2:4]1>CO.[Pd]>[NH2:1][CH2:2][C:3]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][O:5][CH2:4]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Agent: [Pd]
Solvent: CO
Product: NCC1(NCc2ccccc2)COC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3-Aminomethyl-oxetan-3-yl)-dibenzyl-amine in methanol (10 ml) was added a catalytic amount of 10% Pd/C and the reaction mixture was then stirred at RT under an atmosphere of H2 for 8 h. The catalyst was removed by filtration, the filtrate concentrated under reduced pressure to provide the title compound (90 mg) as colorless oil, MS (EI): 192 (M+).