Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][N:18]1[C:27](=[O:28])[CH2:26][C:21]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:20][C:19]1=[O:29]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][N:18]2[C:19](=[O:29])[CH2:20][C:21]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:26][C:27]2=[O:28])[CH2:13][CH2:14]1
Reactant: Fc1ccc(F)c(N2CCNCC2)c1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Solvent: CO
Product: O=C1CC2(CCCC2)CC(=O)N1CCN1CCN(c2cc(F)ccc2F)CC1
Temperature: 160 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(2,5-difluorophenyl)piperazine (100 mg, 0.51 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione (100 mg, 0.44 mmol) was heated with stirring at 160° C. for 5 hours. The residue was dissolved in methanol, transferred to a preparative thin layer chromatographic plate (silica gel), and eluted with ethyl acetate/hexane (1:1). A band at Rf=0.7 was removed and rinsed with chloroform/methanol (4:1). The solvent was removed, giving the title compound as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ6.99-6.89 (11-line m, 1H), 6.65-6.52 (m, 2H), 3.95 (t, 2H, J=6.5 Hz), 3.03 (t, 4H, J=4.7 Hz), 2.66 (t, 4H, J=4.7 Hz), 2.60 (s, 4H), 2.54 (t, 2H, J=6.6 Hz), 1.74-1.69 (m, 4H), 1.55-1.51 (m, 4H); ESI-MS m/z 392 (MH+). The title compound was dissolved in ether and precipitated by addition of 1N HCl in ether, giving a white solid (64.9 mg, 0.15 mmol, 35%): mp 237-239° C., Anal. Calcd. for C21H27N3F2O2·HCl: C, 58.94; H, 6.59; N, 9.82; F, 8.88. Found: C, 58.70; H, 6.46; N, 9.68; F, 9.00.
Reaction SMILES: [Br:1]Br.[O:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[CH2:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.BrBr.O1C2C(=CC=CC=2)C(=O)CC1C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:11]1[CH:12]=[C:13]2[C:8]([C:6](=[O:7])[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:3]2)=[CH:9][CH:10]=1
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cc(-c2ccccc2)oc2cc(Br)ccc12
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Bromine was added to a solution of flavanone in carbon tetrachloride at 0° C. The ratio of bromine/flavanone was 1.3 in molar terms. The temperature of the solution was raised to 30° C. and kept there for 1 hour. The temperature of the solution was then raised to 65° C. and kept there for 45 minutes.
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:11][N:12]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[N:13]2)[CH2:10][O:9][CH2:8]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:26][NH:27][CH3:28]>C(#N)C.C(Cl)Cl>[CH3:26][N:27]([CH3:28])[CH2:6][C:7]1([CH2:11][N:12]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[N:13]2)[CH2:10][O:9][CH2:8]1
Reactant: CS(=O)(=O)OCC1(Cn2cc([N+](=O)[O-])cn2)COC1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CN(C)CC1(Cn2cc([N+](=O)[O-])cn2)COC1
Temperature: 70 °C
Yield: 14.7 %

Procedure:
(3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methyl methanesulfonate (0.225 g, 0.935 mmol) was suspended in acetonitrile (6 mL) with K2CO3 (0.297 g, 2.15 mmol) and dimethylamine (2M in MeOH, 1.87 mL, 3.75 mmol) in a microwave vial and sealed under Nitrogen. This was heated at 70° C. for 36 h then diluted with DCM (20 mL), washed with water (20 mL) and brine (20 mL). The organics were dried over Na2SO4, filtered and the solvent removed under vacuum. The crude product was purified by prep HPLC to give N,N-dimethyl-1-(3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methanamine as a white solid (33 mg, 15% yield).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].[Li][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1>O>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: [Li]c1cccs1
Reactant: CC(C)CCBr
Solvent: O
Product: CC(C)CCc1cccs1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
Isopentyl bromide (Aldrich, 8 g, 53mmol) was added to 53 mL of an ice-cooled solution of lithiothiophene (1.0M in THF, 53 mmol). The reaction was stirred at 0° C. for 2 hours, at room temperature for 16 hours, and poured into water, then the mixture was extracted with hexane. The organic layer was dried and concentrated, and the residue was purified by column chromatography on silica gel, eluting with hexane, to give 7.2 g (88% yield) of the title compound as a colorless oil. NMR (CDCl3) δ:7.10 (dd, J=1, 6 Hz, 1H), 6.90 (dd, J=4, 6 Hz, 1H), 6.78 (dd, J=1, 4 Hz, 1H), 2.84 (t, J=8 Hz, 2H), 1.7-1.5 (m, 3H), 0.94 (d, J=6 Hz, 6H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([C:20]#[C:21][C:22]([OH:24])=[O:23])[O:19][C:14]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd]>[O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])[O:19][C:14]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C#Cc1cc(=O)c2ccc(OCCCOc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: O=C(O)C=Cc1cc(=O)c2ccc(OCCCOc3ccccc3)cc2o1

Procedure:
3-[7-(3-Phenoxypropyloxy)-4-oxo-4H-1-benzopyran-2-yl]propiolic acid (1 g) in ethanol was hydrogenated at atmospheric pressure in the presence of palladium on barium sulphate poisoned with quinoline. Isolation procedures yielded the title acrylic acid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](OC(=O)C)(=[O:7])[CH3:6].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>ClCCCl>[C:5]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([NH:21][C:22](=[O:30])[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH2:12]2)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NC1Cc2ccccc2C1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)CC(NC(=O)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.87 g (21.6 mmol) aluminum trichloride were suspended in 10 ml 1,2-dichloroethane, 500 mg (4.9 mmol) acetic anhydride and 1.0 g N-(indan-2-yl)-4-fluoro-benzamide added, and the whole was stirred for 2 h at RT. The resulting mixture was poured onto ice water/HCl, extracted with dichloromethane, the organic phase was dried with Na2SO4 and evaporated.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH:4]1[F:27].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH:4]1[F:27]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2F)CC1F
Solvent: CSC
Solvent: CC(=O)Cl
Product: NC(=O)CC[C@H]1CN(c2ccc(N3CCC(=O)C(F)C3)c(F)c2)C(=O)O1
Temperature: 40 °C
Reaction time: 96 h
Yield: 61 %

Procedure:
The mixture of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), freshly fused zinc chloride (3.1 mmol), dimethyl sulphide (5.1 mmol), acetyl chloride (3.1 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. The reaction mixture was extracted with ethyl acetate water mixture and the organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel to give title compound in 61% yield.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:18][NH2:19]>CN(C=O)C>[F:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([NH:19][CH3:18])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CN
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (15 g, 130 mmol) was added slowly to a solution of acid 2-fluoro-4-nitro-benzoic acid (20 g, 110 mmol) in DMF (20 mL) at −5° C. The mixture was stirred for an additional 1 h at −5° C. At 0° C., a methylamine solution (2M, 400 mL, 800 mmol) in tetrahydrafuran was added drop-wise to the solution. The reaction mixture was slowly warmed to 25° C. and then poured into ice-water (125 mL). The suspension was extracted with ethyl acetate (2×200 mL). Combined organic phase was washed with brine (1×200 mL), dried (MgSO4) and concentrated to dryness in vacuo. The title compound 21 was obtained as a yellow solid (20 g, 90% yield). MS: 163 (M+H)+. 1H NMR (acetone-d6, 500 MHz): δ 7.66 (1H, dd, J=8.5, 8.5 Hz), 6.41 (1H, dd, J=8.6, 2.1 Hz), 6.32 (1H, dd, J=13.6, 2.0 Hz), 3.05 (3H, d, J=4.4 Hz).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:30]=[C:31]([CH2:34][CH3:35])[N:32]([CH3:33])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N+:26]([O-:9])=[CH:25][C:24]3[N:30]=[C:31]([CH2:34][CH3:35])[N:32]([CH3:33])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1C
Reaction time: 5.5 h
Yield: 8.3 %

Procedure:
A modification of the general method described in Part B of Example 3 was followed. mCPBA (60% pure, 1.39 g, 47.3 mmol) was added in portions to a solution of 8-benzyloxy-2-ethyl-1-methyl-1H-imidazo[4,5-c]quinoline (1.5 g, 47 mmol) in chloroform (75 mL), and the reaction was stirred for 5.5 hours. During the work-up, the combined aqueous washings were extracted with dichloromethane, and the product precipitated from solution. The combined dichloromethane and chloroform solutions were concentrated under reduced pressure until crystals formed and then allowed to stand overnight. The crystals were isolated by filtration. The aqueous solution was extracted with chloroform, and the combined extracts were washed with water (2×) and concentrated under reduced pressure to a small volume. Hexanes were added, and the resulting crystals were isolated by filtration. The mother liquor was concentrated under reduced pressure to afford a solid that was recrystallized from 2-propanol. The three batches of crystals were combined to yield 1.30 g of 8-benzyloxy-2-ethyl-1-methyl-5-oxido-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:12])[C:8]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[CH:9]=2)[NH:7][CH:20]=1)=[O:16])[CH3:19]
Reactant: CCc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2ccc(CC)cc2c1=O
Yield: 35.6 %

Procedure:
p-Ethylaniline (5.0 g) and diethyl ethoxymethylenemalonate (10.7 g) were reacted in the same manner as in Experimental Example 1 to give 3-ethoxycarbonyl-6-ethyl-4(1H)-quinolone (3.6 g). The compound (2.8 g) was N-ethylated with potassium carbonate (2.3 g) and ethyl iodide (2.1 g) in the same manner as in Experimental Example 9 to give 1,6-diethyl-3-ethoxycarbonyl-4(1H)-quinolone (compound 85, 1.55 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=1)=[O:39]>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[N:10]([CH2:37][C:38](=[O:39])[NH:40][C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(N4CCOCC4=O)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(N3CCOCC3=O)cc1)n2CC(=O)Nc1ccc(Cl)cn1
Reaction time: 4 h

Procedure:
72.0 mg (0.183 mmol) 2-[4-(3-Oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 7 mL DMF. Sequentially 37.8 mg (0.274 mmol) K2CO3 and 54.6 mg (0.219 mmol) 2-bromo-N-(5-Chloro-pyridin-2-yl-)-acetamide were added and the resulting mixture was stirred for 4 h at 80°. The mixture was diluted with 200 mL toluene and washed with 50 mL of a saturated NaHCO3-solution. The product was not completely soluble in toluene, so ethyl acetate had to be added. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester as a light brown amorphous solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:18]([N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCCBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of ethyl 4-bromobutyrate (2.0 g, 10.25 mmol), dibenzylamine (2.02 g, 10.25 mmol) and potassium carbonate (2.83 g, 20.5 mmol) in N,N-dimethylformamide (20 mL) was heated with stirring at 100° C. overnight. The resulting mixture was diluted with water (80 mL) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (80 mL×2), and then dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc:PE=1:4) to afford ethyl 4-(dibenzylamino)butanoate as a white solid (2.0 g, yield: 64%).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH2:12]([Mg]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.O1CCCC1>[NH2:11][C:10]1[CH:9]=[C:8]2[C:3](=[C:1]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:2]=1)[N:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Br[Mg]Cc1ccccc1
Reactant: N#CCc1cccnc1C#N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1cc2cccnc2c(Cc2ccccc2)n1

Procedure:
To a solution of 2-cyano-3-pyridylacetonitrile (2 g, 0.014 mol) in toluene (20 ml) is added benzylmagnesium bromide 8.4 ml, 2N in tetrahydrofuran, 0.17 mol) at ambient temperature. After 1 h the reaction is quenched with a saturated solution of ammonium chloride. The product is extracted with ethyl acetate and the organic layer washed with 2N NaOH and water. The product is purified by flash column chromatography on silica gel (10:3 toluene/acetone) affording the title compound. Mass M+H 236; mp 113-116° C.
Reaction SMILES: CN1CCCC1=O.[CH:8]1[C:20]2[N:19]([NH2:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:21][N:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:20]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:28]=1
Reactant: Nn1c2ccccc2c2ccccc21
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cc(Nn2c3ccccc3c3ccccc32)ncn1
Temperature: 100 °C

Procedure:
To 150 ml of 1-methyl-2-pyrrolidinone was added 10.0 g of 9H-carbazol-9-amine, and 8.2 g of 4,6-dichloropyrimidine, and the mixture was heated to 100° C. and stirred for eleven hours. The mixture was then poured into water and extracted with toluene. The organic layer was washed with water and dried (sat. NaCl, anhydrous MgSO4).
Reaction SMILES: [CH:1]([N:4]([C:11]([C:13]1[N:22]=[C:21]2[N:15]([CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=32)[CH:14]=1)=O)[NH:5][C:6](=O)[CH2:7][O:8][CH3:9])([CH3:3])[CH3:2].C(O)(=O)C.[Cl-].[NH4+:33]>O(Cl)Cl.[P+5]>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:15]([CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1)[CH:14]=[C:13]([C:11]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH2:7][O:8][CH3:9])[N:33]=1)[N:22]=3
Reactant: COCC(=O)NN(C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)C(C)C
Reactant: [NH4+]
Agent: ClOCl
Agent: [Cl-]
Agent: [P+5]
Solvent: CC(=O)O
Product: COCc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-N′-(2-methoxy-acetyl)-hydrazide (1.00 g, 2.29 mmol) was suspended in phosphorus (V) oxychloride (23 mL) then stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue then azeotroped with toluene (×3) giving a brown solid. To the brown solid was added acetic acid (23 mL) and ammonium chloride (1.76 g, 22.9 mmol), the resultant mixture was stirred at 125° C. for 2.5 h then further ammonium chloride (0.88 g, 11.4 mmol) added, the reaction was stirred at 125° C. for 1 h, then concentrated in vacuo. The resultant residue was treated with water and extracted with DCM (×3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution then followed by brine then dried (Na2SO4) and concentrated in vacuo. The resultant solid was triturated with diethyl ether to give 8-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a light brown solid (0.73 g, 1.74 mmol, 76%). LCMS RT=4.95 min, [M+H]+=418/420. 1H NMR 400 MHz (DMSO-d6) δ: 8.29 (1H, d, J=8.65 Hz), 7.93 (1H, s), 7.31 (1H, dd, J=8.66, 2.05 Hz), 7.25 (1H, d, J=2.05 Hz), 5.79-5.78 (1H, m), 4.49 (4H, s), 4.33 (2H, s), 3.27 (3H, s), 1.43 (6H, d, J=6.60 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][NH:11][C:12](=[O:29])[C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC1C(O[C:46](=[O:64])[C@H:47]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([OH:63])=[CH:59][CH:58]=2)[NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=C(Cl)C(Cl)=C(Cl)C=1Cl>C(OCC)(=O)C.Cl>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][NH:11][C:12](=[O:29])[C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:14][C:46](=[O:64])[C@H:47]([CH2:56][C:57]1[CH:58]=[CH:59][C:60]([OH:63])=[CH:61][CH:62]=1)[NH:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
18.55 g (45 mmoles) of the protected dipeptide ester obtained in Step 1 above are dissolved in 60 ml of ethyl acetate containing 11-15% of hydrochloric acid. After 0.5 hours of standing the solution is evaporated, and the residue is dried in a vacuum desiccator above potassium hydroxide. The resulting substance, Rf3 =0.4-0.5, is dissolved in 40 ml of dimethyl formamide, and 5.0 ml (45 mmoles) of N-methylmorpholine and 26.2 g (49.5 mmoles) of tert.-butoxycarbonyl-L-tyrosine pentachlorophenyl ester are added. The reaction mixture is stirred for 16-20 hours. During the first two hours 5.5 ml (49.5 mmoles) of N-methylmorpholine are added to the mixture in five portions. The reaction mixture is evaporated under reduced pressure, the residue is dissolved in a mixture of 300 ml of ethyl acetate and 50 ml of water, the ethyl acetate phase is separated, washed twice with 50 ml of 1 n aqueous hydrochloric acid cooled with ice water and then twice with 50 ml of water, each, dried over sodium sulfate, decolourized with carbon, filtered, and the filtrate is evaporated under reduced pressure. The crystalline residue is suspended in diisopropyl ether, the solid is filtered off, washed with diisopropyl ether, and dried in a vacuum desiccator. 23.5 g (90.8%) of tert.-butoxycarbonyl-L-tyrosyl-D-phenylalanyl-glycine benzyl ester are obtained; m.p.: 169° C., Rf10 =0.45-0.55, [α]D20 +16.3° (c=1%, in dimethyl formamide).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[O:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=[O:5])[NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)(=[O:26])=[O:25]
Reactant: O=C(Nc1nccs1)c1ccccc1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.7 %

Procedure:
2-hydroxy-N-1,3-thiazol-2-ylbenzamide (502, 267.1 mg, 1.21 mmol) was placed into a 10 mL round bottom flask equipped with a stirbar and a septum with a dry nitrogen inlet. Dichloromethane (5.0 mL) and triethylamine (500 μL, 3.59 mmol) were added to form a light pink solution. Methanesulfonyl chloride (100 μL, 1.3 mmol) in dichloromethane (ca. 1.0 mL) was added dropwise to the stirring solution over ca. 30 seconds, and the reaction was stirred at room temperature for ca. 20 minutes before being quenched into saturated NaHCO3, and extracted with dichloromethane. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was recrystallized from hexanes/ethyl acetate to yield (284 mg, 78%) of 11 as a colorless crystalline solid. Example 11 (2-thiazol-2-ylcarbamoyl)phenyl methanesulfonate) has the empirical formula C11H10N2O4S and a molecular weight of 298.34.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]1([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=2)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>CN(C=O)C>[N:1]([CH2:17][C:16]1[CH:19]=[CH:20][C:13]([C:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:12])=[CH:14][CH:15]=1)=[N+:2]=[N-:3]
Reactant: O=C(c1ccc(CBr)cc1)C1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
Add sodium azide (441 mg, 6.785 mmol) to a stirred solution of 4-(cyclohexanecarbonyl)-benzyl bromide (954 mg, 3.393 mmol) in anhydrous DMF (20 mL) and heat the mixture to 90° C. for 2 h. Cool the mixture to room temperature, add water and extract the aqueous solution with diethyl ether. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as oil (310 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].[N:12]([O-])=O.[Na+].[F:16][B-:17]([F:20])([F:19])[F:18].[H+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([N+:5]#[N:12])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: O=N[O-]
Reactant: Nc1cc(F)c(F)c(Br)c1Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cc(F)c(F)c(Br)c1Cl

Procedure:
To a suspension of 3-bromo-2-chloro-4,5-difluoroaniline (30.1 g) in 42% fluoroboric acid (180 ml) with stirring vigorously was added sodium nitrite (12 g) in water (30 ml) at -9° to 1° C. for 40 minutes. After stirred for 1.5 hours, the resulting precipitate was collected by filtration and washed with 42% fluoroboric acid and then with ether to give the title compound (35.6 g) as light yellow needles, mp 300° C.