Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].Cl.[CH3:19][O:20][C@@H:21]([CH3:24])[CH2:22][NH2:23].C(N(C(C)C)CC)(C)C>C(O)C>[Br:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]2[NH:23][CH2:22][C@@H:21]([O:20][CH3:19])[CH3:24]
Reactant: CO[C@@H](C)CN
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1NC[C@H](C)OC
Reaction time: 16 h

Procedure:
Suspend ethyl-6-bromo-4-chloro-quinoline-3-carboxylate (389 g, 1.24 mol) and (2S)-2-methoxypropan-1-amine, hydrochloride (171 g, 1.36 mol, 1.1 eq.) in ethanol (5.84 L). Add diisopropylethylamine (474 mL) and heat the mixture at 50° C. overnight. After 16 hours, cool the reaction to room temperature and concentrate in vacuo. Add methyl tert-butyl ether (2 L) to the residue and stir for 20 min. Filter the precipitate and wash it with methyl tert-butyl ether (2×250 mL). Concentrate the filtrate in vacuo to afford the titled compound in almost quantitative yield. The compound will be used in the next step without further purification. MS (ESI) m/z (M+H)+367.0, 369.0.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:13])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5].[I-:14].[Na+]>CC(C)=O>[I:14]/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:13])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5]
Reactant: [I-]
Reactant: CC1(C(=O)/C=C/Cl)CC2(CCC2)C1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C(=O)/C=C/I)CC2(CCC2)C1
Yield: 87 %

Procedure:
In a procedure as described in Example 9H, 1-chloro-3-(2-methylspiro[3.3]hept-2-yl)-1E-propen-3-one was reacted with sodium iodide in acetone to yield 1-iodo-3-(2-methyspiro[3.3]hept-2-yl)-1E-propen-3-one (87%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N:34]([CH:37]([CH3:39])[CH3:38])=[C:35]=[O:36]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:35]([NH:34][CH:37]([CH3:39])[CH3:38])=[O:36])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)N=C=O
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)nc(-c3cccc(Cl)c3)c2c1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1nc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 60 °C
Yield: 20.4 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.00021 mol) obtained in Example B19, and 2-isocyanato-propane (3 equiv, 0.00063 mol) in THF (1 ml) was heated at 60° C. for 5 hours. A few drops of water were added. The mixture was evaporated till dryness and purified by HPLC. The product fractions were collected and the solvent was evaporated, yielding 0.024 g (20.3%) of N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinazolinyl]-N′-(1-methylethyl)-urea, MS (ESI) m/z: 561 563 565.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.Cl.[NH2:40][C@@H:41]([CH3:46])[C:42]([NH:44][CH3:45])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][C@@H:41]([CH3:46])[C:42]([NH:44][CH3:45])=[O:43])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)[C@H](C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](C)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), (S)-2-amino-N-methylpropanamide-HCl (6.43 mg, 0.046 mmol), and HATU (31.7 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-methyl(S)propanamide (9.6 mg, 0.019 mmol, 40.2% yield): LCMS=516.1 [M+H]+; 1H NMR (Mixture of Diastereomers, 400 MHz, methanol-d4) δ ppm 8.11-8.25 (4 H, m), 7.50-7.78 (14 H, m), 5.16 (2 H, d, J=3.08 Hz), 4.37 (2 H, qd, J=7.08, 1.43 Hz), 2.75 (3 H, s), 2.72 (3 H, s), 1.39 (3 H, d, J=7.26 Hz), 1.35 (3 H, d, J=7.04 Hz); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.3 min+2.4 min (mixture of diastereomers).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]C1(C(OC(C)(C)C)=O)CC1.[CH:16]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.BrCCCCBr.[Li+].CC([N-]C(C)C)C>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:16]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCCCOC(=O)C1CCCC1
Reactant: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: BrCCCCBr
Product: CCCCOC(=O)C1(CCCCBr)CCCC1

Procedure:
Compound 103c was prepared, likewise the procedure described for 103b, starting from butyl cyclopentanecarboxylate (Payne, G. B. et al. J. Org. Chem., 1957, 22, 1680-1682) (80.0 g, 0.42 mol), 1,4-dibromobutane (183.3 g, 0.84 mol) and LDA (2 M in THF/heptane/ethylbenzene, 250 mL, 0.50 mol) to give, after purification by fractional distillation under reduced pressure, 103c (62.8 g, 49%) as a light yellow liquid. bp: T=116-117° C. (p=0.040-0.051 Torr). 1H NMR: δ 4.07 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 2.16-2.10 (m, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 1.65-1.59 (m, 8H), 1.50-1.31 (m, 6H), 0.94 (t, J=7.2 Hz, 3H). 13C NMR: δ 177.6, 64.1, 53.9, 38.2, 36.0 (2×), 33.3, 33.0, 30.6, 24.8 (2×), 24.6, 19.1, 13.6. HRMS calcd for C14H25BrO2 (M+): 304.1038, found: 304.1042.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:3]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.O=C1C2C(C(OCC)=O)=CC=CC=2NC(C2C=NC=CC=2)C1C1C=NC=CC=1.O.[NH2:57][NH2:58]>CO>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:4]2[NH:5][C:6]3[C:11]4[C:2](=[N:57][NH:58][C:12](=[O:14])[C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH:3]2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccnc1)C(c1cccnc1)N2
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1cccnc1)C(c1cccnc1)N2
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1cccnc1)C2c1cccnc1
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of methyl 4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (480 mg, 1.34 mmol) in hydrazine monohydrate (20 mL) and methanol (5 mL) was heated to reflux for 2 hr. The mixture was then cooled to room temperature and filtered to give 8,9-di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (320 mg, yield 68%) as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 4.51-4.53 (d, J=8.4 Hz, 1H), 4.89-4.91 (d, J=8.4 Hz, 1H), 7.18-7.20 (m, 1H), 7.24-7.27 (m, 1H), 7.31-7.33 (m, 1H), 7.43-7.44 (m, 1H), 7.60 (s, 1H), 7.58-7.63 (m, 2H), 7.79-7.81 (m, 1H), 8.32-8.34 (m, 2H), 8.41-8.43 (m, 1H), 8.45-8.46 (d, J=1.6 Hz, 1H); LC-MS (ESI) m/z: 342(M+1)+.
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=C(F)C=C(N)C=4C)C=3C=2)CC1)=O.Cl[C:31]1[C:32]2[CH:39]=[C:38]([C:40]3[CH2:41][CH2:42][O:43][CH2:44][CH:45]=3)[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(N5CCC6C(=CC=C(C(O)(C)C)C=6)C5=O)C=4CO)C=3C=2)CC1)=O.[C:89]([C:93]1[CH:118]=[CH:117][C:96]([C:97]([NH:99][C:100]2[CH:105]=[C:104]([F:106])[CH:103]=[C:102](B3OC(C)(C)C(C)(C)O3)[C:101]=2[CH3:116])=[O:98])=[CH:95][CH:94]=1)([CH3:92])([CH3:91])[CH3:90]>>[C:89]([C:93]1[CH:118]=[CH:117][C:96]([C:97]([NH:99][C:100]2[CH:105]=[C:104]([F:106])[CH:103]=[C:102]([C:31]3[C:32]4[CH:39]=[C:38]([C:40]5[CH2:41][CH2:42][O:43][CH2:44][CH:45]=5)[NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[C:101]=2[CH3:116])=[O:98])=[CH:95][CH:94]=1)([CH3:92])([CH3:90])[CH3:91]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ncnc2[nH]c(C3=CCOCC3)cc12
Agent: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(N5CCc6cc(C(C)(C)O)ccc6C5=O)c4CO)ncnc3[nH]2)CC1
Agent: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCOCC3)cc12

Procedure:
Example 49 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with Intermediate 11 and Intermediate 5 with Intermediate 38.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C([O-])(=O)C.[NH4+]>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(CNc2ccccc2[N+](=O)[O-])cc1
Yield: 92.2 %

Procedure:
Reaction of 2-chloronitrobenzene (10 g, 63 mmole), 4-methoxybenzylamine (52.1 g, 380 mmole) and ammonium acetate (4.6 g) substantially as described in 1C above producted 15 g (100%) of title compound as orange crystals: mp 75°-78°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:12]3[C:13](=[O:16])[NH:14][CH2:15][C:11]=3[CH:10]=[C:9]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:8]=2)[CH:4]=[N:3]1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][C:10]1[C:11]2[CH2:15][NH:14][C:13](=[O:16])[C:12]=2[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:8][C:9]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Solvent: ClCCl
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Br)c3c2C(=O)NC3)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.4 %

Procedure:
To a round bottomed flask was added tert-butyl (1S,2R)-2-(4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (124 mg, 0.291 mmol) in DCM (30 mL). The resulting white suspension was heated with a heat gun while stirring until all the starting material was dissolved. The solution was cooled to 0° C., and while stirring, 1-bromopyrrolidine-2,5-dione (51.7 mg, 0.291 mmol) was added. The reaction mixture was allowed to warm to RT and was stirred for 30 min. The solution was diluted with DCM (20 mL) and was washed with saturated aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL). The organic layer was collected and concentrated to an orange solid, which was treated with Et2O (5 mL). Solids began to precipitate after the solution was allowed to sit undisturbed for 5 min. The mixture was allowed to sit for 1 h and was then filtered through paper. The solids were washed with Et2O (5 mL) and collected to give the title compound as a tan solid (137.3 mg, 93%). [M+H] calc'd for C22H29BrN6O3, 505. found, 505.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:3]=1[C:4]([NH:6][C:7](Cl)=[O:8])=[O:5].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1>>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:3]=1[C:4]([NH:6][C:7]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([Br:15])=[CH:21][N:20]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(Cl)NC(=O)c1c(F)cccc1Cl
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Br)cn1

Procedure:
To a portion of 2-chloro-6-fluorobenzamidocarboxylic acid chloride dissolved in an organic solvent, a hydrogen halide acceptor is added, and a portion of 5-bromo-2-aminopyridine is added. After a period of stirring, the reaction mixture is washed with water and neutralized, and the product named in the heading is isolated as described in Example 12. The product is identical to that of Example 2 above.
Reaction SMILES: [I:1]Cl.[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1>CO.C(O)(=O)C>[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[I:1]
Reactant: ClI
Reactant: NC(=O)c1ccc(O)cc1
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 30.2 %

Procedure:
A sample of 47 g (0.29 mole) of ICl was added to a solution of 40 g (0.29 mole) of 4-hydroxybenzamide in 400 ml of MeOH and 800 ml of acetic acid in the absence of light. The mixture was stirred for 70 hr under N2 at 25° C. A precipitate was collected by filtration. The filtrate was diluted with water and a second crop of crystals collected by filtration. A third crop was obtained by evaporation of solvent from the second filtrate. The combined solids were recrystallized from 95% ethanol. The solid which precipitated and was collected (28 g). It was largely diiodinated material. The filtrate was evaporated in vacuo and the residue recrystallized from MeOH. The precipitated solid was collected by filtration (2.0 g). It was again diiodinated material. The filtrate was concentrated to dryness in vacuo to give 23 g (30% yield) of brownish crystalline 4-hydroxy-3-iodobenzamide, mp 90°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6](=[O:22])[C@H:7]([CH3:21])[NH:8][C:9](=[O:20])[C@H:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[S:19])[CH3:18])[NH2:11].[N:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6](=[O:22])[C@H:7]([CH3:21])[NH:8][C:9](=[O:20])[C@H:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[S:19])[CH3:18])[NH:11][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([N:25]=[N+:26]=[N-:27])=[CH:36][CH:35]=1
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCNC(C)=S
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(C)=S)NC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
To a solution of Nε-thioacetyl-lysinyl-alaninyl-alanine methyl ester (50 mg, 0.14 mmol) in 0.8 mL of THF was added a solution of 4-azidobenzoic acid (35 mg, 0.21 mmol) in 0.8 mL of THF. PyBOP (109 mg, 0.21 mmol) and DIPEA (59 mg, 0.42 mmol) were introduced into the reaction mixture. The reaction was stirred at room temperature for 6 h, and then solvent was removed under reduced pressure. Silica gel column chromatography (ethyl acetate: hexanes 10:1) afforded Nα-4-azidobenzoyl-Nε-thioacetyl-lysinyl-alaninyl-alanine methyl ester (58 mg, 0.115 mmol, 82%) as a pale yellow solid. 1H NMR (CD2Cl2, 500 MHz) δ (ppm): 1.39 (s, 3H), 1.40 (s, 3H), 1.47 (m, 2H), 1.67 (m, 2H), 1.88 (m, 2H), 2.87 (s, 3H), 3.57 (m, 2H), 3.68 (s, 3H), 4.41 (m, 1H), 4.46 (m, 1H), 4.64 (m, 1H), 7.05 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.2 Hz, 1H), 7.36 (d, J=6.8 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.86 (d, J=8.6 Hz, 2H), 8.32 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][C:22]1[CH:23]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)[NH:20][N:21]=1
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(-c3ccccc3)cc3ccccc23)[nH]n1

Procedure:
To a solution of 1-chloro-3-phenylisoquinoline (J. Het. Chem., 20, 1983, 121-128)(0.33 g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added 3-amino-5-methylpyrazole (0.27 g, 2.74 mmol) and potassium carbonate (0.57 g, 4.13 mmol) and the resulting mixture was heated at reflux for 6 hours. The reaction mixture was then cooled and solvent removed in vacuo. The residue was extracted twice with ethyl acetate and the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, gradient DCM-MeOH) to afford V-1 as a colourless oil; 1H NMR (MeOD) δ 2.23 (3H, s), 5.61 (1H, s), 7.41 (1H, m), 7.52(2H, m), 7.62(1H, m), 7.81(1H, m), 8.07(1H, d), 8.19(2H, m), 8.29(1H, s), 8.54 (1H, d); MS 301.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>CS(C)=O>[CH3:24][O:23][C:19]([C:20]1[S:21][C:4]2[CH:3]=[C:2]([Cl:1])[C:9]([O:10][CH3:11])=[CH:8][C:5]=2[CH:6]=1)=[O:22]
Reactant: COC(=O)CS
Reactant: COc1cc(C=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2cc(OC)c(Cl)cc2s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-2-fluoro-5-methoxybenzaldehyde (0.821 g, 4.35 mmol) in 8.7 mL of DMSO were successively added K2CO3 (1.81 g, 3 eq.) and methyl thioglycolate (0.474 mL, 1.2 eq.), and the mixture was vigorously stirred at 50° C. for 2 h. After cooling, the reaction mixture was poured onto crashed ice/HCl, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated. Flash chromatography (SiO2, hexane/AcOEt=85/15), followed by crystallization from heptane/AcOEt, yielded 0.300 g of the title compound as off-white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]([NH2:16])=[S:15]>CCO>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]([NH2:16])[S:15][CH:2]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(-c2csc(N)n2)cc1
Yield: 116.5 %

Procedure:
A mixture of 2-bromo-1-(4-methoxyphenyl)ethanone (5.00 g, 21.8 mmol) and thiourea (1.72 g, 22.6 mmol) in 95% EtOH (40 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-methoxyphenyl)thiazol-2-amine (5.24 g) as yellow solids in >99% yield: 1H NMR (500 MHz, DMSO-d6) δ 7.72 (d, 2H), 6.99 (s, 2H), 6.92-6.91 (m, 2H), 6.82 (s, 1H), 3.76 (s, 3H).
Reaction SMILES: C(NC([NH:8][CH2:9][C:10]#[C:11][CH2:12][NH:13][C:14]([NH:16][C:17]1[S:18][C:19]2[C:25]3[N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=[CH:28][C:24]=3[CH2:23][CH2:22][C:20]=2[N:21]=1)=[O:15])=O)(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]#[C:11][CH2:12][NH:13][C:14]([NH:16][C:17]1[S:18][C:19]2[C:25]3[N:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:27]=[CH:28][C:24]=3[CH2:23][CH2:22][C:20]=2[N:21]=1)=[O:15]
Reactant: CC(C)(C)NC(=O)NCC#CCNC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccccc1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC#CCNC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccccc1)CC2

Procedure:
0.1 g (0.2 mmol) of the compound obtained in Example 11 are suspended in 0.5 ml trifluoroacetic acid and 2 ml dichloromethane and stirred overnight at ambient temperature. The reaction mixture is evaporated down, the residue taken up in acetone and the product is precipitated by the addition of ethereal hydrochloric acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5]Br.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5][N:15]=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CN=[N+]=[N-])cc(C(Cl)=C(Cl)Cl)c1
Yield: 95.6 %

Procedure:
A solution of 3-methyl-5-(trichlorovinyl)benzyl bromide (3.14 g) and sodium azide (1.0 g) in 25 ml of ethanol was heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting oil triturated with 50 ml of hexane. The mixture was filtered and the filtrate concentrated to give 2.64 g of azide.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CN(C)C=O>[CH2:18]([N:20]([CH2:21][CH3:22])[C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19]
Reactant: CCNCC
Reactant: CC(C)c1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2ccccc2n2c(C(C)C)nnc12
Yield: 75 %

Procedure:
4-Chloro-1-isopropyl-[1,2,4]-triazolo[4,3-a]quinoxaline (1.0 g., 0.004 mole), the product of Example 6, and 900 mg. (0.012 mole) of diethylamine in N,N-dimethylformamide (15 ml.) were stirred at room temperature for 4 hours. The reaction mixture was poured over ice and the precipitate was separated by means of filtration, washed with water and placed on a column of silica gel (175 ml.) and finally eluted with chloroform. The eluant was evaporated in vacuo to afford 850 mg. (75% yield) of pure 4-diethylamino-1-isopropyl-[1,2,4]triazolo[4,3-a]quinoxaline as a white solid (m.p. 93°-95° C.). Mass spectrum: m/e, 283 (P). The pure product (100 mg.) was then distilled in vacuo (0.1 mm) at 140° to 150° C. to afford the analytical sample (80 mg.), m.p. 94°-96° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[CH:33]=O)([CH3:27])[C:23]([F:26])([F:25])[F:24].C(OC(N1CCC[C@H](NCC2C=C(C(F)(F)C)C=CC=2OC(F)(F)F)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:32]2[CH:35]=[C:28]([C:22]([CH3:27])([CH3:21])[C:23]([F:26])([F:24])[F:25])[CH:29]=[CH:30][C:31]=2[O:36][CH3:37])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(C(C)(C)C(F)(F)F)cc1C=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 12 and Compound 71 in the same manner of Compound 26.