Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:15](=[O:25])[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:15](=[O:25])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2cc(Cl)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Yield: 73.9 %

Procedure:
A solution of 2.1 g of 2-chloro-5-(4-nitrobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 400 ml of ethyl acetate-ethanol (1:1) and 0.25 g of palladium-on-carbon is hydrogenated in a Parr hydrogenator under 38 pounds per square inch of hydrogen. The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness. The solid (1.94 g) is dissolved in dichloromethane and the solution filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with dichloromethane and the filtrate concentrated. The residue is crystallized from dichloromethane-hexane to give 1.43 g of crystals, m.p. 211°-214° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH:18]=[CH:19][C:20]3[C:25]([C:16]=2[S:15][C:14]=1SC)=[CH:24][CH:23]=[CH:22][CH:21]=3.[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[CH2:41][S:40][C:39]1=[S:44].C(#N)C>C(N(CC)CC)C>[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41](=[C:14]2[N:13]([CH3:12])[C:17]3[CH:18]=[CH:19][C:20]4[C:25]([C:16]=3[S:15]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:40][C:39]1=[S:44]
Reactant: CSc1sc2c3ccccc3ccc2[n+]1C
Reactant: COCCOCCOCCN1C(=O)CSC1=S
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCOCCOCCN1C(=O)C(=C2Sc3c(ccc4ccccc34)N2C)SC1=S
Temperature: 5 °C
Reaction time: 4 h

Procedure:
2.5 g of 3-methyl-2-methylthionaphtho[2,1-d]thiazolium p-toluenesulfonate (synthesized from 2-methylthionaphtho[2,1-d]thiazole and methyl p-toluenesulfonate), 1.7 g of 3-methoxyethoxyethoxyethylthiazolidine-4-on-2-thion and 30 ml of acetonitrile were fed into a 100 ml three-necked flask, and cooled to 5° C. 1.2 g of triethylamine was added to the resultant mixture. After stirring at 10° C. for 4 hours, yellow precipitates thus formed were suction-filtered, washed with 10 ml of acetonitrile twice and dried to obtain the intended compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:35])([CH3:34])[CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH:56]1[O:61][CH2:62][CH2:63]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O>[C:30]([Si:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:16][CH2:15][C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:63][CH2:62][O:61][CH:56]3[CH2:57][CH2:58][CH2:59][CH2:60][O:55]3)[CH:8]=2)[N:5]=1)([CH3:35])[CH3:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(O)c2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
A mixture of Intermediate 153d (0.53 g, 1.09 mmol) in dry TI-IF (8 mL) was treated with triphenylphosphine (0.57 g, 2.18 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.22 mL, 1.64 mmol). The mixture was cooled to 0° C. then diisopropylazodicarboxylate (0.43 mL, 2.18 mmol) was added dropwise. After stirring at ambient temperature for 20 h the mixture was treated with water (0.1 mL) and concentrated in vacuo to a yellow oil. The oil was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title compound as an orange oil (0.41 g, 61%). LCMS (Method 3): Rt 5.25 min, m/z 614.6 [MH+].
Reaction SMILES: C([NH+](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([O-])=[O:23])=[N:16]2)=[C:11]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:10]=1.O1CCCC1.C(Cl)(=O)OCC.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:23])=[N:16]2)=[C:11]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:10]=1
Reactant: C1COCCN1
Reactant: COc1ccc(C(=O)c2cc(Cl)ccc2-n2nc(C(=O)[O-])nc2CCl)cc1
Agent: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cc(Cl)ccc2-n2nc(C(=O)N3CCOCC3)nc2CCl)cc1
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 5.07 parts of 1-[4-chloro-2-(4-methoxybenzoyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid triethylammonium salt in 60 volume parts of dry tetrahydrofuran, 1.0 volume part of ethyl chlorocarbonate is added under cooling with ice-salt. After 5 minutes a solution of 2.6 volume parts of morpholine in 3 volume parts of dry tetrahydrofuran is added to the mixture. After stirring for an additional 5 minutes the reaction mixture is diluted with water and concentrated under reduced pressure. The concentrate is extracted with ethyl acetate and the ethyl acetate layer is washed with water. After evaporation of the solvent the residue is treated with ethanol-ether to yield 1-[4-chloro-2-(4-methoxybenzoyl)phenyl]-5-chloromethyl-3-morpholinocarbonyl-1H-1,2,4-triazole as crystals. Recrystallization from aqueous ethanol gives colorless prisms melting at 180°-181°C. The crystals are hemihydrate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>C(#N)C>[CH:10]1([NH:13][C:2]2[N:3]=[C:4]([NH:13][CH:10]3[CH2:12][CH2:11]3)[CH:5]=[C:6]([Cl:8])[N:7]=2)[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CC#N
Product: Clc1cc(NC2CC2)nc(NC2CC2)n1
Reaction time: 0.5 h

Procedure:
A solution of 151.5 g (1 mol) of 2,4,6-trichloropyrimidine in 300 ml of acetonitrile is taken and 285 g (5 mols) of cyclopropylamine are added dropwise at 20°-30°, whilst cooling. The solution is warmed to 40° for 5 hours and to 70° for about 12 hours. The suspension is concentrated to dryness on a rotary evaporator and the residue is thoroughly stirred with 1,500 ml of methylene chloride and 1,000 ml of water for 30 minutes. The undissolved constituent is filtered off on a cloth filter. It consists of practically pure 4,6-di-cyclopropylamino-2-chloropyrimidine. The phases of the filtrate are separated and the organic phase is again extracted with water, dried and concentrated to give an oil. This is distilled under a high vacuum (boiling point 149°-51°/0.1 mm) and is then recrystallised from methanol, with addition of water. The colourless product has a melting point of 58°-60°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])[N:13]=1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Reactant: C[C@@H](N)CO
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(N[C@H](C)CO)nc21

Procedure:
The product of Example 44, and (R)-2-aminopropan-1-ol were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.81 (m, 6H), 1.30 (m, 2H), 1.96 (m, 2H), 2.36 (m, 2H), 3.71 (m, 2H), 4.25(m, 1H), 5.31 (m, 0.5H), 5.56 (m, 0.5H), 5.71 (br s, 1H), 6.26 (br d, 1H, J=9.6), 7.12 (d, 1H, J=9.6 Hz), 7.30-7.54 (m, 4H). LC MS (m/e)=401 (MH+). Rt=2.07 min
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)Oc1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol (0.46 g, 1.5 mmol) and 4-fluoronaphthalene-1-carboxylic acid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and the mixture was stirred at room temperature for 5 hrs. To the reaction solution was added water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:ethyl acetate=10:1) to give the objective substance (0.65 g, 91%) as crystals.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.O>ClCCl>[F:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(F)cnc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: COc1ncc(F)nc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
After dissolving 447 mg of methyl 6-fluoro-3-methoxypyrazine-2-carboxylate in 8 ml of dichloromethane, the solution was cooled to −78° C. Next, 1.76 ml of diisobutylaluminium hydride (1.5 M, toluene solution) was added dropwise and the mixture was stirred for 30 minutes. After adding 10 ml of 1N hydrochloric acid dropwise to the reaction solution, water was added and extraction was performed with dichloromethane. After then drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (245 mg, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH:37]1([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:8][CH2:9][C:10]([N:45]2[CH2:46][CH2:47][N:42]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:43][CH2:44]2)=[O:12])=[CH:13][CH:14]=1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCC(=O)N1CCN(C2CCCC2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
To a mixture of 3-(4-chlorobenzoyl)propionic acid (31.9 g, 150 mmol), DMF (200 ml), and N-hydroxybenzotriazole (40.6 g, 301 mmol) was added a solution of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.8 g, 150 mmol) in DMF (100 ml). The mixture was stirred at room temperature for 1.5 hour, and a solution of 1-cyclopentylpiperazine (23.2 g, 150 mmol) in DCM (100 ml) was added. The mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the residue was distributed between ethyl acetate (1.0 I) and a saturated, aqueous NaHCO3 solution (1.0 I). Phases were separated, the organic layer was dried (MgSO4), and concentrated, and the residue was redissolved in 1 molar aqueous hydrochloric acid (150 ml). The solution was concentrated, and the residue was dried by coevaporation with ethanol. Recrystallization of the residue from ethanol yielded 31.1 g (54%) of the title compound. Concentration of the mother liquor gave additional 19.4 g (34%) of product.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16]([NH:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 83 %

Procedure:
(3S)-3-Amino-1-chloro-4-phenyl-2-butanone hydrochloride (100 mg) was dissolved in water (4.3 ml). A solution (5.3 ml) of benzyl chloroformate (0.794 ml) in toluene was added to the obtained solution. Further, an aqueous solution (1.0 ml) of sodium hydrogencarbonate (71.9 mg) was added dropwise to the obtained mixture. They were stirred at room temperature for 50 minutes to conduct the reaction and then the aqueous layer was separated. The obtained toluene layer was analyzed by HPLC to find that (3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone (118 mg) was obtained in a yield of 83%.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[H-].[Na+].S([O-])(=O)(=O)C>CN(C=O)C>[N:19]1([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: c1nc[nH]n1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cncn2)CC1
Temperature: 60 °C
Reaction time: 120 h

Procedure:
To a stirred solution of: tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (5.9 g, 21.1 mmol) and 1,2,4-triazole (1.75 g, 1.2 equiv.) in DMF at ambient temperature was added sodium hydride (60% in mineral oil, 1.0 g, 1.2 equiv.). The mixture was stirred at 60° C. for 5 days, and the TLC showed no starting mesylate left. The mixture was poured into ice water and extracted with ethyl acetate (3×). The organic layer was dried, evaporated and purified by silica flash column eluting with 0-10% methanol in ethyl acetate to give tert-butyl 4-(1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate as a white solid. The solid was then treated with hydrogen chloride in dioxane (4 N, 10 mL) for 2 hours. The mixture was then evaporated to remove most of the dioxane to give a white solid, which was washed with ethyl acetate to give the desired 4-(1H-1,2,4-triazol-1-yl)piperidine hydrochloride salt (5.55 g). 1H NMR (300 Mz, CD3OD): 10.00 (s, 1H), 8.97 (s, 1H), 5.10-5.00 (m, 1H), 3.63-3.58 (br. d, 2H), 3.33-3.26 (br. d, 2H), 2.50-2.30 (m, 4H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2)(=[O:3])[CH3:2].C1(C)C=CC=CC=1.CCCCCC.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C)C1C=CN=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH:19][C:33](=[O:35])[CH3:34])=[N:11][C:10]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(=O)Nc1nc2c(ncn2COCCOC(C)=O)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
9-(2-Acetoxyethoxy)methylguanine (2 gms, 7.5 mmol) was dissolved in 15 ml of acetic anhydride. The mixture was heated to 120° C. and 0.1 gms (0.8 mmol) of 4-dimethylaminopyridine (DMAP) added. The reaction mixture was kept at 120° C. for 3 hours, then the mixture was cooled to 40° C. and 10 ml of toluene added. Hexane (20 ml) was added slowly to effect crystallization of the product. The solid was collected by filtration and washed with hexane, yielding 1.82 gms of 9-(2-acetoxyethoxy)methyl-N2 -acetylguanine (79%) with a N-9/N-7 isomer ratio of >200:1. Characteristic analytical data are as follows: 1H NMR (DMSO-d6) δ1.85 (3H, singlet, --NHCOCH3), 2.08 (3H, singlet, --O2CCH3) , 3.6 (2H, multiplet, --OCH2 --) , 3.95 (2H, multiplet, --CH2O--), 5.4 (2H, singlet, --NCH2O--) , 8.06 (1H, singlet, --N=CH--N--).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[S:11][C:12]([C:15]([NH:17][C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:16])=[CH:13][N:14]=1>CN(C=O)C.CCOC(C)=O>[CH2:1]([NH:8][C:10]1[S:11][C:12]([C:15]([NH:17][C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:16])=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cnc(Br)s3)s2)cc1
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnc(NC(=O)c3cnc(NCc4ccccc4)s3)s2)cc1
Yield: 70.8 %

Procedure:
Benzylamine (0.143 mL, 1.32 mmol) was added to a solution of 2-bromo-N-(5-p-tolylthiazol-2-yl)thiazole-5-carboxamide (250 mg, 0.66 mmol) in DMF (4 mL). The reaction mixture was stirred at reflux for 2 hrs. Then it was diluted with AcOEt and washed with water, dried with Na2SO4 and concentrated. The crude product was purified by precipitation (AcOEt/PE), yielding 2-(benzylamino)-N-(5-p-tolylthiazol-2-yl)thiazole-5-carboxamide (190 mg, 71%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH2:48])=[CH:42][CH:41]=1>C(#N)C.C(N(CC)C(C)C)(C)C>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH:48][C:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])=[CH:13][CH:12]=2)=[O:11])=[CH:42][CH:41]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)Cc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methoxy-2-oxoethyl)benzoic acid (1.00 g) in acetonitrile (50 ml), N,N-diisopropyl ethyl amine (2.63 ml), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.94 g) and 2-(4-chlorophenyl)ethylamine (790 ml) were added, and the mixed solution was stirred at room temperature for 16 hours. The solvent was removed by evaporation under reduced pressure, and the resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate/n-hexane=30 to 50%) to give methyl (4-{[2-(4-chlorophenyl)ethyl]carbamoyl}phenyl)acetate (2.02 g).
Reaction SMILES: [Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=1NCC(O)COC1C=CC(C)=CC=1C)[NH:6]2.[CH3:44][CH:45]([NH2:52])[CH2:46][C:47]1[S:48][CH:49]=[CH:50][CH:51]=1.CCN(CC)CC>CCO>[Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=1[NH:52][CH:45]([CH3:44])[CH2:46][C:47]1[S:48][CH:49]=[CH:50][CH:51]=1)[NH:6]2
Reactant: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3c(Cl)c4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1
Reactant: CC(N)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2c(Cl)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O

Procedure:
4-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (18 mg, 0.04 mmol), 1-methyl-2-thiophen-2-yl-ethylamine (8.5 mg, 0.06 mmol) and Et3N (0.2 mL, 1.43 mmol) in EtOH (1.0 mL) was heated at 80° C. for 17 h and then concentrated to result a residue which was subjected to HPLC purification to furnish the title compound in TFA salt form (6.73 mg, 25%). 1H NMR (DMSO-d6) δ 1.36 (d, J=6 Hz, 3H, CH3), 1.95 (m, 2H), 2.52 (m, 2H), 2.74 (s, 3H, CH3), 3.02-3.22 (4H), 3.45 (m, 2H), 4.08 (m, 1H), 4.28 (m, 1H), 6.19 (d, J=8 Hz, 1H), 6.89 (m, 1H), 7.00 (m, 1H), 7.29 (m, 1H), 7.39 (m, 1H), 8.09 (s, 1H), 11.01 (d, J=8 Hz, 1H), 11.35 (d, J=6 Hz, 1H); ESI-MS m/z 551.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)=[C:5]([C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[C:6]#[N:7])[CH3:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([Cl:34])[C:25]=1[NH:35][NH2:36].Cl>C(O)C>[NH2:7][C:6]1[N:35]([C:25]2[C:24]([Cl:23])=[CH:29][C:28]([C:30]([F:31])([F:33])[F:32])=[CH:27][C:26]=2[Cl:34])[N:36]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=1[C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(OCC)=C(C#N)C(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: CCOc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
An aliquot of the above solution of step A containing approximately two millimoles of 3,3-bis-ethoxy-2-(3-trifluoromethylbenzoyl)acrylonitrile was reacted with 0.49 g (2.0 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 10 mL of ethanol under reflux overnight. The cooled mixture was poured into dilute hydrogen chloride (HCl) and the product was extracted into ethyl acetate (EtOAc), washed with water and brine, and dried over magnesium sulfate (MgSO4). Chromatography on silica gel with 4:1 hexane/EtOAc gave the title product, 320 mg (31%), m.p. 77°-78° C. from pentane.
Reaction SMILES: [CH:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:5](=[O:10])/[CH:6]=[C:7](\[NH2:9])/[CH3:8])([CH3:3])[CH3:2].N.[H][H]>[Ni].CO>[NH2:9][CH:7]([CH3:8])[CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: C/C(N)=C/C(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(N)CC(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 79.4 %

Procedure:
(Z)-3-Aminobut-2-enoic acid N-isopropyl-N-[4-(phenylamino)phenyl]amide (13.9 g, 0.0449 mol) and Raney nickel (K0840 Ni B113W) (2.0 g) in methanol (140 g) were introduced into an autoclave. Ammonia (5.5 g, 0.3230 mol) was introduced in the course of 5 minutes. The temperature of the reaction mixture was 25° C. The pressure rose to 5 bar. After the introduction of ammonia, the reaction mixture was warmed to 80° C. (no further pressure rise). Hydrogen was injected at 80° C. until the pressure was 100 bar. The reaction mixture was heated to 110° C. and stirred at this temperature for 4.5 h. In the course of this, a pressure of 100 bar was maintained by continuous injection of hydrogen. The reaction mixture was cooled to 25° C. and the pressure was carefully let down. The reaction mixture was filtered off and the filtrate was concentrated to one half. The concentrate was treated with 1 g of active carbon, stirred for 1 h, filtered and concentrated to dryness. 12.8 g of crude product were obtained, which was melted at 175° C. The melt could be crystallized on an aluminium foil. 11.1 g of 3-amino-N-isopropyl-N-[4-(phenylamino)phenyl]butyramide (79.3%) were obtained.