Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[C:27]([O-:30])(O)=O.[Na+].C(Cl)(Cl)=O.[CH2:36]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21])[CH2:16][N:15]2[C:27](=[O:30])[N:43]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CCCCCCNCc1ccc(OC)cc1
Reactant: C=CC1CC1(NC(=O)C1CC(O[Si](C)(C)C(C)(C)C)CN1)C(=O)OCC
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reaction time: 1 h
Yield: 50 %

Procedure:
Compound 124 (5.88 g, 15.4 mmol) was dissolved in THF (200 ml), NaHCO3 (s) (appr. 10 ml) was added followed by phosgene-solution (20% in toluene, 15.9 ml, 30.7 mmol). The reaction mixture was stirred vigorously for 1 h and then filtrated, evaporated and redissolved in DCM (200 ml). NaHCO3 (s) (appr. 10 ml) was added followed by hept-6-enyl-(4-methoxy-benzyl)-amine (5.58 g, 23.9 mmol). The reaction mixture was stirred at room temperature overnight, filtrated and evaporated on silica. The crude product was purified by column chromatography on silica (EtOAc/n-Heptane 25/75-50/50) to give the title compound (4.9 g, 50%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9]1(=[O:14])O[CH2:12][CH2:11][CH2:10]1>>[N:1]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:14]
Reactant: O=C1CCCO1
Reactant: NCCCCCCN
Product: O=C1CCCN1CCCCCCN1CCCC1=O

Procedure:
11.62 g (0.1M) of 1,6-diaminohexane and 21.66 g (0.25M) of γ-butyrolactone were mixed and heated to 150°-165° for 22 hours. Excess γ-butyrolactone was then distilled off at reduced pressure (80°/2 mm). The light brown residue was poured into a crystallization dish where it immediately solidified. The solid was taken in chloroform, powdered, filtered and the tan powder was washed with chloroform. Yield 22.0 g (87%); melting point 101°-103°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[CH:31]=1)=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:26][O:27][C:28](=[O:29])[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:36][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:14])([F:15])[F:16])=[C:2]([Cl:1])[CH:3]=2)[CH:31]=1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccnc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1ccnc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3) was reacted with methyl-2-aminopyridin-4-carboxylate and HBTU at 80° C. for 5 h to give the title compound as white solid. MS (m/e)=528.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([O:14]C)=[O:13])[CH2:4]1.COC1C(O[N+]([O-])=O)CC(C(OC)=O)C1>>[CH3:1][O:2][CH:3]1[CH:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][CH:5]([C:12]([OH:14])=[O:13])[CH2:4]1
Reactant: COC(=O)[C@@H]1C[C@H](OC)[C@@H](O[N+](=O)[O-])C1
Agent: COC(=O)C1CC(OC)C(O[N+](=O)[O-])C1
Product: COC1CC(C(=O)O)CC1O[N+](=O)[O-]

Procedure:
The title compound was prepared by following step D for example 1, except that the reagent (+)-methyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate was replaced by methyl (1RS,3RS,4SR)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate. 1H NMR (500 MHz, CDCl3) δ 2.15-2.27 (m, 3H), 2.34-2.41 (m, 1H), 3.15-3.20 (m, 1H), 3.40 (s, 3H), 4.03 (m, 1H), 5.42 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cn1nccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 75.3 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-1H-pyrazole-5-carboxylic acid (114 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (71.0 mg, 75%) was obtained as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.FC(F)(F)S(O[CH2:18][CH:19]([F:21])[F:20])(=O)=O.O>CN(C=O)C>[F:20][CH:19]([F:21])[CH2:18][N:11]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[S:2][CH3:1]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CSc1nc2cccnc2[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2cccnc2n1CC(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine (600 mg) and 2,2-difluoroethyl trifluoromethanesulfonate (816 mg) in DMF (7 mL) was stirred at 80° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compound (400 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:25]=[C:24]4[C:29](=[CH:28][CH:27]=2)[NH:21][CH:22]=[CH:23]4)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]ccc4c3)ccn2c1=O
Yield: 47.4 %

Procedure:
Methyl 1-cyclopropyl-8-(1H-indol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 1H-indol-5-yl-boronic acid (83 mg, 0.51 mmol) to afford the title compound as a yellow solid (60 mg, 47%). ESI-MS m/z: 373 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]([C:7]([C:9]2[NH:13][N:12]=[N:11][C:10]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])=[C:5]([N+:23]([O-:25])=[O:24])[CH:4]=1.O.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30](S(O)(=O)=O)=[CH:29][CH:28]=1.C(OCC)(OCC)[O:39][CH2:40][CH3:41]>C(Cl)Cl>[CH2:40]([O:39][C:31]([N:12]1[N:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:7](=[O:8])[C:6]2[CH:19]=[C:20]([O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:23]([O-:25])=[O:24])=[N:13]1)([CH2:30][CH2:29][CH3:28])[CH2:32][CH2:27][CH3:37])[CH3:41]
Reactant: CCOC(=O)c1nn[nH]c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(OCC)OCC
Solvent: O
Solvent: ClCCl
Product: CCCC(CCC)(OCC)n1nc(C(=O)OCC)c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (Synthesis Example 2) (140 mg) and p-toluenesulfonic acid monohydrate (2 mg) were suspended in methylene chloride (2 ml) under an argon atmosphere. 4-Heptane (0.14 ml) and triethyl orthoformate (0.17 ml) were added to the suspension. The mixture was stirred at room temperature for 2 hr. Further, p-toluenesulfonic acid monohydrate (4.5 mg) was added thereto. The mixture was stirred at room temperature for 2 hr. The mixture was post-treated by a conventional method and subjected to separation and purification to give ethyl 2-(4-ethoxyheptan-4-yl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (160 mg, 82%) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH:55]([C:58]1[O:62][N:61]=[C:60]([C:63](O)=[O:64])[CH:59]=1)([CH3:57])[CH3:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([C:60]2[CH:59]=[C:58]([CH:55]([CH3:57])[CH3:56])[O:62][N:61]=2)=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)c1cc(C(=O)O)no1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 18 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-isopropylisoxazole-3-carboxylic acid as starting materials in 18% yield. LCMS for C31H34ClN8O3 (M+H)+: m/z=601.2.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].[CH2:11]([N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24](Cl)[C:18]=2[S:17]1(=[O:27])=[O:26])[CH2:12][CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH2:11]([N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([S:10][CH2:7][CH2:8][CH3:9])[C:18]=2[S:17]1(=[O:27])=[O:26])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCS
Reactant: CCCCCN1Cc2cccc(Cl)c2S1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN1Cc2cccc(SCCC)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.0 g of potassium-t-butoxide in 40 ml of dry dimethylformamide was added 4.0 ml of propyl mercaptan at -5° to 0° C. under an inert atmosphere followed by 11.0 g of 2-pentyl-7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide. The mixture was stirred at room temperature for 16 hours, poured into water and extracted with n-butyl chloride. The extract was washed with water and brine, dried over MgSO4 and concentrated to give 10.3 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:27][CH:28]=2)[N:3]=1.C(O[CH2:44][CH3:45])(OCC)OCC.C([O-])(=O)C.[NH4+:50]>>[NH2:9][C:8]1[C:7]2[C:6]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=3)=[C:5]([C:20]#[N:21])[C:4]([S:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[O:27][CH:28]=3)=[N:3][C:2]=2[N:1]=[C:44]([CH3:45])[N:50]=1
Reactant: [NH4+]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CC(=O)[O-]
Product: Cc1nc(N)c2c(-c3ccc(OCCO)cc3)c(C#N)c(SCc3coc(-c4ccc(Cl)cc4)n3)nc2n1
Temperature: 25 °C

Procedure:
50 mg (0.10 mmol) of the compound from Example 15A, 113 mg (0.69 mmol) of triethyl orthoformate and 38 mg (0.50 mmol) of ammonium acetate were combined and reacted in a microwave at 160° C. for 10 min. After cooling to RT, the reaction was purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([C:14]([O:16]CC)=[CH2:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.Cl.[O:23]1C=CN=C1.CO>O1CCCC1>[C:14]([C:11]1[C:12]([F:13])=[C:6]([OH:5])[C:7]([NH:8][C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:23])=[C:9]([C:20]#[N:21])[C:10]=1[CH3:19])(=[O:16])[CH3:15]
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Reactant: c1cocn1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1c(C)c(C#N)c(NC(=O)C2CC2)c(O)c1F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-78) (1.0 g, 3.49 mmol) was dissolved in tetrahydrofuran (10 ml), aqueous 1 N hydrochloric acid solution (2.0 ml) was added, followed by stirring at room temperature for 19 hours. At this point in time, it was known that a mixture with an oxazole-opened compound is given, and for complete ring opening, methanol (5 ml) was added followed by stirring overnight at room temperature. The solvent was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, followed by fractionation with water.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[C:8]3[N:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](SC)[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1.C(Cl)Cl.[O-:26][S:27]([O-:30])(=S)=O.[Na+].[Na+].[C:33]([O-])([O-])=O.[Na+].[Na+]>>[NH2:1][C:2]1[N:7]2[C:8]3[N:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:27]([CH3:33])(=[O:30])=[O:26])[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: CSc1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To solution of 21 (200 mg, 0.65 mmol) in CH2Cl2 (50 ml) mCPBA (320 mg, 1.30 mmol) was added. The mixture was stirred for 2 hours at room temperature. A saturated aq. Na2S2O3 solution was added (5 ml) and was basified with saturated aq. Na2CO3. The organic layer was separated and the aqueous layer extracted with CH2Cl2. The organic solutions were dried and evaporated together to give 9-Amino-5-(2-methanesulfonylpyrimidin-4-yl)pyrido[3′,2′:4,5]-pyrrolo[1,2-c]pyrimidine(201 mg, 91%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:36]([O:38][CH3:39])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[ClH:50]>CO.[H][H]>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:36]([O:38][CH3:39])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[ClH:50]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@@H](CCCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@H](N)CCCC(=O)OC(C)(C)C)C(C)C

Procedure:
Pd-on-charcoal catalyst is added to a solution of 2.3 g of Z-D-Aad(OBut)-Val-Tyr(But)-OMe in 100 ml of methanol and hydrogen is passed through the solution at pH 4.5 (autotitrator), while stirring and while adding approx. 2 N methanolic hydrochloric acid, until no further methanolic hydrochloric acid is taken up. The catalyst is then filtered off and the filtrate is concentrated. Yield 1.98 g, melting point 85°-87°, [α]D22 =-14.9° (c=1, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:21]([NH:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(OC([N:40]1[CH2:43][CH:42]([C:44](O)=[O:45])[CH2:41]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.O1CCOCC1>CC(N(C)C)=O>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:12]([NH:11][S:8]([C:4]3[CH:3]=[C:2]([NH:1][C:44]([CH:42]4[CH2:43][NH:40][CH2:41]4)=[O:45])[CH:7]=[CH:6][CH:5]=3)(=[O:9])=[O:10])=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:24]=[C:25]([O:31][CH3:32])[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(N)c2)cc(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)C3CNC3)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial was added 3-amino-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide (0.24 mmol, 1 equiv), prepared using procedures similar to those described in Example 15, DMA (5 mL) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.336 mmol, 1.4 equiv). Hunig's Base (0.792 mmol, 3.3 equiv) and HATU (0.288 mmol, 1.2 equiv) were added to the vial and the reaction mixture was then stirred at room temperature, overnight. Completion of the reaction was indicated by LCMS. The solvent was removed by rotary evaporation. The crude mixture was carried forward without further purification. The residue was suspended in 5 mL ethyl acetate and chilled in an ice bath. A solution of 4 N HCl in dioxane (3 mL, 5 equiv) was added with stirring. The reaction mixture was then stirred at room temperature overnight. The solid materials were collected by filtration, washed with ethylacetate then purified further by preparative reverse-phase HPLC (ammonium acetate/ACN). A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C18, OCD 5 μM, 30×70 mm column and running a 5-100% gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification. N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide was obtained (26 mg, 20%). 1H-NMR (400 MHz, d6-DMSO): 10.26 (s, 1H), 8.81 (s, 1H), 8.25 (t, 1H), 8.14 (s, 1H), 7.74 (d, 1H), 7.69 (d, 1H), 7.41-7.39 (m, 1H), 7.36 (d, 1H), 7.32 (d, 2H), 7.30-7.28 (dd, 1H), 7.14-7.11 (m, 2H), 6.14 (t, 1H), 4.09 (d, 4H), 3.78 (s, 6H); MS (EI) m/z C26H26N6O5S: 535.6 (MH+).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[NH4+:39]>>[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]2[NH:39][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [NH4+]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Agent: CC(=O)[O-]
Product: CCOC(=O)c1nc(-c2ccc(OCc3ccccc3)cc2)[nH]c1-c1ccc(OC)cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate, 4-benzyloxybenzaldehyde and ammonium acetate are reacted and treated in the same manner as in Example 22 to give ethyl 2-(4-benzyloxyphenyl)-5-(4-methoxyphenyl)imidazole-4-carboxylate. Ethyl 2-(4-benzyloxyphenyl)-5-(4-methoxyphenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-benzyloxyphenyl)-5-(4-methoxyphenyl)imidazole-4-carboxylic acid. 2-(4-Benzyloxyphenyl)-5-(4-methoxyphenyl)imidazole-4-carboxylic acid is reacted and treated in the same manner as in Example 1 to give 2-(4-benzyloxyphenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]([F:15])([F:14])[C:11]([OH:13])=[O:12].O>C(Cl)Cl>[N:7]([C:1]1([O:13][C:11](=[O:12])[C:10]([F:15])([F:14])[F:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: ON=C1CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=NC1(OC(=O)C(F)(F)F)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of cyclohexanone oxime (4.88 g, 43.16 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (19.14 g, 43.16 mmol) and trifluoroacetic acid (49.22 g, 431.6 mmol) in methylene chloride (200 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was purified by column chromatography to give 1-Nitroso-1-trifluoroacetoxycyclohexane as a bright blue liquid (30% yield): Rf 0.57 (pentane); 1H NMR (300 MHz, Benzene-d6) δ 1.1-1.9 (m, 10H); 13C NMR (300 MHz, Benzene-d6) δ 19.9 (2CH2), 22.9 (CH2), 27.4 (2CH2), 113.8 (q, J=286.2 Hz), 127.2 (O—C—N), 153.7 (q, J=42.5 Hz); 19F NMR (300 MHz, Benzene-d6) δ −75.7 (CF3).
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=3[C:5]=2[N:4]=1)[NH2:2].[C:17](/[N:19]=[C:20](\OC1C=CC=CC=1)/[NH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1)#[N:18]>C(O)(C)C>[N:4]1[C:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=[N:12][C:3]=1[N:1]1[C:17]([NH2:18])=[N:19][C:20]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)=[CH:26][CH:27]=2)=[N:2]1
Reactant: CN1CCN(c2ccc(N/C(=N/C#N)Oc3ccccc3)cc2)CC1
Reactant: NNc1ncc2c(n1)-c1ccccc1CC2
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3nc(N)n(-c4ncc5c(n4)-c4ccccc4CC5)n3)cc2)CC1
Temperature: -20 °C

Procedure:
2-Hydrazinyl-5,6-dihydrobenzo[h]quinazoline (40 mg, 0.19 mmol) and (Z)-phenyl N′-cyano-N-(4-(4-methylpiperazin-1-yl)phenyl)carbamimidate (67 mg, 0.20 mMol) were suspended in isopropanol and subjected to microwave irradiation (150° C., 20 min). A precipitate formed in the microwave vial. After further cooling at −20° C., the solid was filtered off, washed with cold isopropanol and dried under vacuum to give 1-(5,6-dihydrobenzo[h]quinazolin-2-yl)-N3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #92, 32 mg; 1H NMR (DMSO-d6, 300 MHz) 8.76 (s, 1H), 8.65 (s, 1H), 8.16 (d, 1H), 7.65 (s, 2H), 7.46-7.53 (m, 4H), 7.37 (m, 1H), 6.84 (d, 2H), 2.90-3.05 (m, 8H), 2.48 (m, 4H), 2.22 (s, 3H) ppm; MS (ES) 454.17 (M+H).