Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[CH2:14][C@@H:11]([CH2:12][CH2:13]1)[C:10]1[CH:9]=[C:8]3[N:3]([CH2:4][CH2:5][NH:6][C:7]3=[O:15])[C:2]2=1.Br[C:17]1[N:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[O:20].C([O-])(=O)C.[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Cl:25][C:21]1[CH:22]=[CH:23][N:24]=[C:17]([N:6]2[C:7](=[O:15])[C:8]3[N:3]([C:2]4[C@H:1]5[CH2:14][C@@H:11]([C:10]=4[CH:9]=3)[CH2:12][CH2:13]5)[CH2:4][CH2:5]2)[C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1c(Cl)ccnc1Br
Reactant: O=C1NCCn2c1cc1c2[C@H]2CC[C@@H]1C2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2[C@@H]2CC[C@H]3C2)C1=O
Temperature: 80 °C
Yield: 59.2 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (30 mL), (1S,11R)-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-7-one 170a (400 mg, 2.0 mmol), 2-bromo-4-chloronicotinaldehyde 103a (1.30 g, 6.0 mmol), and potassium acetate (390 mg, 4.0 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, Xantphos (110 mg, 0.20 mmol) and tris(dibenzylideneacetone)dipalladium(0) (180 mg, 0.20 mmol) were added, and the reaction mixture was heated at 80° C. for 10 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (50 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (20 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to afford 170b (405 mg, 59%) as a yellow solid. MS-ESI: [M+H]+ 342.2
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH:11]([CH3:25])[CH2:12][CH2:13][NH:14][C:15]([C:17]3[C:18]([CH3:24])=[N:19][CH:20]=[N:21][C:22]=3[CH3:23])=[O:16])[CH2:7][CH2:6]2)[O:4]CC1>CC(C)=O.Cl>[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH3:25])[CH2:12][CH2:13][NH:14][C:15]([C:17]2[C:22]([CH3:23])=[N:21][CH:20]=[N:19][C:18]=2[CH3:24])=[O:16])[CH2:7][CH2:6]1
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(=O)CC1
Yield: 21.6 %

Procedure:
A solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid [3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-amide (3.11 g, 8.95 mmol) in acetone (10 ml) and HCl 6N (aq, 8 ml) was refluxed for 18 h. The reaction mixture was quenched with NaOH (aq, 15%) to pH 7-8. The organic material was extracted with CH2Cl2 and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% MeOH in CH2Cl2; 2.5% NH4OH) to afford 4,6-dimethyl-pyrimidine-5-carboxylic acid [3-(4-oxo-piperidin-1-yl)-butyl]-amide (589 mg, 23%). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.6 Hz), 1.64-1.72 (m, 1H), 1.81-1.91 (m, 1H), 2.15-2.30 (m, 4H), 2.52 (s, 6H), 2.62-2.72 (m, 2H), 2.84-2.98 (m, 3H), 3.47-3.62 (m, 1H), 3.69-3.77 (m, 1H), 6.94 (br s, 1H), 8.93 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=1>>[Cl:37][C:35]1[CH:36]=[C:31]([CH2:30][CH2:29][NH:28][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:32]=[C:33]([Cl:39])[C:34]=1[OH:38]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: NCCc1cc(Cl)c(O)c(Cl)c1
Product: Oc1c(Cl)cc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)cc1Cl

Procedure:
Intermediate 7 was coupled with 4-(2-Amino-ethyl)-2,6-dichloro-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 458. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 7.05-7.6 (m, 6H) 7.0 (m, 1H) 4.95 (m, 1H) 3.6-4.0 (m, 3H) 3.4 (m, 2H) 3.1-3.2 (m, 2H) 2.8-2.95 (m, 2H) 2.25 (m, 3H) 1.7 (m, 2H).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:21])=[N:16][S:17]([Cl:20])(=[O:19])=[O:18]>CCOCC>[C:2]1([CH:1]([NH:14][C:15]([NH:16][S:17]([Cl:20])(=[O:19])=[O:18])=[O:21])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: O=C(NC(c1ccccc1)c1ccccc1)NS(=O)(=O)Cl
Yield: 93.8 %

Procedure:
A solution of benzhydrylamine (4.0 g, 21.8 mmoles) in 50 mL Et2O was added dropwise to a solution of N-chlorosulfonyl isocyanate (1.90 mL, 21.8 mmoles) in 100 mL Et2O at 15° C. under an atmosphere of N2. Upon addition, the mixture turned cloudy but cleared up after one-half hour of stirring. The reaction mixture was concentrated in vacuo to give a pale yellow solid. Trituration with hexanes gave 6.64 g (94%) of the title compound, mp 80°-88° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH:25][C:43]([C:40]5[C:41](=[O:42])[N:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)[N:37]=[CH:38][CH:39]=5)=[O:44])=[CH:23][C:22]=4[F:28])[CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (100.0 mg, 0.256 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 70.53 mg, 0.301 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (144.3 mg, 0.753 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (101.7 mg, 0.753 mmol), N-ethyl-N-isopropylpropan-2-amine (162.2 mg, 1.255 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (103 mg, 66.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 615 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.41 (m, 2H), 8.23 (d, 1H), 7.98 (d, 1H), 7.60 (m, 2H), 7.39 (m, 2H), 7.24 (m, 3H), 6.46 (d, 1H), 6.28 (m, 1H), 4.04 (s, 4H), 2.78 (m, 2H), 2.52 (m, 2H), 1.98 (m, 2H).
Reaction SMILES: [NH2-].[Na+].[C:3]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(OCC)C>[CH2:10]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCCCC1
Reactant: ClCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C1CCCCC1Cc1ccccc1
Yield: 40.2 %

Procedure:
Sodium amide (15.6 g, 0.4 mol) was added portionwise to a solution of cyclohexanone (39.26 g, 1.46 mL, 0.4 mol) in 350 mL of anhydrous diethyl ether. The resulting suspension was heated under reflux for 3 h after which time benzyl chloride (46.8 g, 42.6 mL, 0.37 mol) was rapidly added. The mixture was heated under reflux for a further 5 h, then cooled and poured into cold water. The organics were washed once with a dilute HCI solution, a dilute sodium bicarbonate solution and finally with water. The organic layer was dried, filtered and the ether was removed to give 2-benzylcyclohexanone as an oil (28 g, 40%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(COC)OC>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:12]2[CH:11]=[CH:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=3)[CH:13]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc2cc(-c3ccccc3)ccc2c1
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: Brc1ccc(-c2ccc3cc(-c4ccccc4)ccc3c2)cc1
Reaction time: 15 h
Yield: 48 %

Procedure:
Under an argon gas atmosphere, 21.9 g (88.3 mmol) of 6-phenylnaphthalene-2-boronic acid, 25.0 g (88.3 mmol) of 4-bromoiodobenzene, 2.00 g (1.77 mmol) of tetrakis(triphenylphosphine) palladium(0), 400 mL of toluene, 100 mL of dimethoxyethane and 132 mL of 2M sodium carbonate solution were mixed, and stirred for 15 hours while being refluxed. After the reaction in the mixture was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 15.3 g of 2-(4-bromophenyl)-6-phenylnaphthalene was obtained with an yield of 48%.
Reaction SMILES: I[C:2]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([I:19])=[CH:13][C:3]=1[O:4][C:5]1[C:6]([NH2:12])=[N:7][C:8]([NH2:11])=[N:9][CH:10]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[I:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[C:3]([CH:13]=1)[O:4][C:5]1[C:6]([NH2:12])=[N:7][C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(I)c(Oc2cnc(N)nc2N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C#C[Si](C)(C)C)c(Oc2cnc(N)nc2N)cc1I
Temperature: 50 °C

Procedure:
5-(2,5-Diiodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.2 g, 2.5 mmol), bis(triphenylphosphine)palladium dichloride (175 mg, 2.5 mmol), and CuI (25 mg, 0.125 mmol) were added to 7 mL dry THF. Trimethylsilylacetylene ((0.48 mL, 3.3 mmol), and diisopropylethylamine (3.5 mL) were added, and the reaction mixture was heated to 50° C. under nitrogen for 27 hours. The reaction mixture was cooled, poured into 15% aqueous NH4Cl and extracted into EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-(4-Methoxy-2,5-bis-trimethylsilanylethynyl-phenoxy)-pyrimidine -2,4-diamine together with monoacetylenes 5-(2-iodo-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine and 5-(5-iodo-4-methoxy-2-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine. This residue was chromatographed on 125 g of flash silica (6:1:1 CH2Cl2:MeOH:NH4OH) to give 450 mg of 5-(4-Methoxy-2,5-bis-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=425.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1(C)[CH:12]=[CH:11][O:10][NH:9]1)([OH:3])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:20]C1ON=C(CCCO)C=1>>[OH:3][CH2:1][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:12]=[C:11]([CH3:20])[O:10][N:9]=1
Reactant: Cc1cc(CCCO)no1
Reactant: CC1(CCCCC(=O)O)C=CON1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(CCCCCO)no1
Yield: 84 %

Procedure:
3-(5-Hydroxypentyl)-5-methylisoxazole was prepared by reduction of 3-(4-carboxybutyl)-3-methylisoxazole with lithium aluminum hydride according to the procedure of part (e) above, and was obtained in 84% yield as an oil, b.p. 115°-125° C. (0.1 mm).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:31])=[C:11]([CH:17](C2N(C)N=C(C3C=CC=CC=3)N=2)[OH:18])[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.CS(OS(C)(=O)=O)(=O)=O.C(OC(N(C(OC(C)(C)C)=O)C1C2C(=CC(N)=CC=2)C=CN=1)=O)(C)(C)C>C(#N)C>[Si:1]([O:8][C:9]1[C:10]([F:31])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:17]=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3)nn2C)c1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 139.5 %

Procedure:
To a solution of Intermediate 368.3 (440 mg, 1 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.35 mL, 2 mmol) in ACN (30 mL) at −15° C. was added methanesulfonic anhydride (279 mg, 1.6 mmol). The mixture was stirred for 1 h as the temperature was raised to 23° C. 1-(di-(tert-butyloxycarbonyl)amino)-6-aminoisoquinoline (359 mg, 1 mmol) was added as a solid and the mixture stirred 18 h at 50° C. The mixture was concentrated and purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 394 mg of Intermediate 368.2. 1H NMR (400 MHz, CDCl3) δ ppm 0.04-0.20 (s, 6H) 0.77-1.02 (m, 12H) 1.08-1.37 (s, 18H) 1.09-1.32 (s, 9H) 2.35 (q, J=7.47 Hz, 2H) 3.82 (s, 3H) 5.96-8.33 (m, 13H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:17])[C:6](=[O:16])[NH:7]2.CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1>>[N:1]1([C:2]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]3[C:3]=2[NH:4][C:5](=[O:17])[C:6](=[O:16])[NH:7]3)[CH:20]=[CH:24][CH:23]=[CH:22]1
Reactant: Nc1cc(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c12
Reactant: COC1CCC(OC)O1
Product: O=c1[nH]c2cc(C(F)(F)F)cc(-n3cccc3)c2[nH]c1=O

Procedure:
12.2 mmol of 5-amino-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione were reacted with 12.2 mmol of 2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:14](N)[CH2:15][NH2:16].Cl.C>C(=S)=S>[CH2:1]([C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC#N
Reactant: NCCN
Agent: Cl
Solvent: S=C=S
Product: CCCCCCCCCCCC1=NCCN1
Temperature: 125 °C

Procedure:
18.32g (100 mmoles) of undecyl cyanide, 8.5ml (127 mmole) of ethylenediamine and 0.5ml of carbon disulfide were mixed and heated in an oil bath at 125° C. for 24 hours. The reaction mixture was cooled, treated with dilute hydrochloric acid and treated with charcoal. The light yellow filtrate was extracted with ethyl acetate, the organic extracts dried over magnesium sulfate and concentrated. The residue was Kugelrohr distilled and then recrystallized from toluene. Yield 13.7 g (61.1), m.p. 82° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.ClC1C=C(Cl)C=CC=1C1[C:28]([C:29]2[NH:30][CH:31]=[CH:32][N:33]=2)=[CH:27][N:26]=[C:25]([NH:34][CH2:35][CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][N:39]=2)[N:24]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]1[C:28]([C:29]2[NH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][N:26]=[C:25]([NH:34][CH2:35][CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][N:39]=2)[N:24]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(C(F)(F)F)cc3F)n2)nc1

Procedure:
{4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-imidazol-2-ylpyrimidin-2-yl}{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 2-fluoro-4-(trifluoromethyl)benzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][C:4](O)=[O:5].[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:4](=[O:5])[CH2:3][CH2:2][NH2:1])=[CH:23][CH:22]=1)[CH3:18]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)CCN)cc1

Procedure:
Z-beta-Ala-OH and ethyl-4-aminobenzoate according to 1.2., followed by deprotection according to 6.1. to give 4-(3-Amino-propionylamino)-benzoic acid ethyl ester, MS: 236 (M).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1.CO.C1COCC1.[OH-].[Na+]>O>[O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCC(CC)n1cc(-c2csc(C(=O)OC)c2)c2c(=O)[nH]ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)n1cc(-c2csc(C(=O)O)c2)c2c(=O)[nH]ccc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a solution of methyl 4-(4-oxo-1-(pentan-3-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxylate (23.5 mg) obtained in Example 7 in a mixed solvent of methanol (1 mL)/THF (1 mL)/water (1 mL) was added 8N aqueous sodium hydroxide solution (0.021 mL) at 0° C. The reaction mixture was stirred at 90° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (23.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:26]1([N:32]=[C:33]=[S:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[S:34])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Solvent: C1COCCO1
Product: O=c1c(Cc2ccccc2)nc2cccnc2n1-c1cccc(NC(=S)Nc2ccccc2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
A mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (150 mg), phenylisothiocyanate (79 mg) in 1,4-dioxane (2 ml) was stirred at 80° C. for 4 hours. The precipitates were collected and washed with isopropyl ether to give 2-benzyl-3-oxo-4-[3-(3-(phenyl)thioureido)phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (113 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])=[S:11].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:16])[CH2:14][CH3:15])[S:11][CH3:17]
Reactant: CCC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC(=O)N=C(Nc1c(Cl)cccc1Cl)SC

Procedure:
33.2 g (0.12 M) of N-(2,6-dichlorophenyl)-N'-propionyl-thiourea, 10.5 g (0.08 M) of ground potassium carbonate, 9.6 ml (0.15 M) of methyliodide and 300 ml of acetone are boiled in a reflux for 4 hours under energetic shaking. The acetone is distilled off, 300 ml of water are added to the residue. The sediment is filtered and dried. 34.4 g (98.5% of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-propionyl-S-methyl-isothiourea with a melting point of 165°-170° are obtained. After recrystallization from ethyl alcohol 23.5 g of the product (68.2 % from the raw one) are obtained with a melting range of 173°-176°.
Reaction SMILES: C[N:2]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:3]([C:16]([OH:18])=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1.[OH-].[Na+]>C(O)C>[C:22]([O:21][C:19]([NH:2][C@H:3]([C:16]([OH:18])=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a ethanol solution of methyl N-(t-butoxycarbonyl)-O-methyl-3-nitro-L-tyrosine(6.74 g) was added 1N sodiumhydroxide solution (25 ml) and was stirred for 2 hours at roomtemperature. The solvent was evaporated and water (70 ml) and 1Nhydrochloric acid solution (27.5 ml) was added, extracted with ethylacetate (50 ml×3). After ethyl acetate layer was washed withsaturated brine, the residue was dried over anhydrous sodiumsulfate. The solvent was evaporated in vacuo. To the residue wasadded hexane and ether and it was crystallized to give N-(t-butoxycarbonyl)-O-methyl-3-nitro-L-tyrosine (6.61 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S,4S)-4-Aminopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (7.3 g, 30 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. DIPEA (3 equiv) was added, followed by benzyl chloroformate (1 equiv). The mixture was stirred at room temperature for 3 hours and then diluted with DCM (200 mL). The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (10.4 g, 28 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C12H21NO7S, 323.4. found 324.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(#N)C.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>C(N(CC)CC)C>[C:13]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)Oc1ccc(C=O)cc1
Reaction time: 2 h

Procedure:
To 61 g of 4-hydroxybenzaldehyde, 400 ml of acetonitrile and 84 ml of triethylamine were added to effect the dissolution. The resulting solution was cooled to 0° C. by ice-methanol and thereto 48.4 ml of methacrylic acid chloride was gradually added dropwise. After 2 hours, the reaction solution was extracted by liquid separation with water and ethyl acetate and then subjected to silica gel column chromatography to produce the objective compound. The objective compound obtained was immediately used in the following reaction.