Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH3:39])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=4[S:23](=[O:37])(=[O:36])[N:22]=3)[C:11]2=[O:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:41]>O>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH3:39])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([O-:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=4[S:23](=[O:36])(=[O:37])[N:22]=3)[C:11]2=[O:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+:41]
Reactant: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A suspension of the product of Example 38C (0.339 g) in water (10 mL) was treated with 0.997N sodium hydroxide solution (0.595 mL, 0.593 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.334 g, 95%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.63 m, 3 H) 0.98 m, 8 H) 1.45 m, 7 H) 1.68 m, 1 H) 2.09 m, 1 H) 2.93 m, 3 H) 7.30 m, 3 H) 7.45 m, 3 H) 8.05 m, 1 H) 9.87 m, 1 H) 15.45 m, 1 H). MS (ESI−) m/z 570 (M−H)−.
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:41])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:27](=[O:39])[C:26]2=[O:40])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:41])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27](=[O:39])[C:26]2=[O:40])=[CH:18][CH:19]=1)(=[NH:11])[NH2:13]
Reactant: CC(C)(C)OC(=O)CN1CCN(CCCC(=O)Nc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)c1ccc(NC(=O)CCCN2CCN(CC(=O)O)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.1 %

Procedure:
To a solution of 0.28 g of tert-butyl [4-[4-(4-benzyloxycarbonylamidinophenylamino)-4-oxobutyl]-2,3-dioxopiperazin-1-yl]acetate in 2.8 ml of methylene chloride was added 1.4 ml of trifluoroacetic acid, and the resulting mixture was stirred at room temperature for 12 hours and then distilled under reduced pressure to remove the solvent. To the resulting residue were added 0.08 g of 5% palladium-carbon and 5.6 ml of N,N-dimethylformamide, followed by hydrogenation at ordinary temperature and atmospheric pressure for 3 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. To the resulting concentrate were added 5 ml of water and 0.042 g of sodium hydrogencarbonate to obtain a homogeneous solution. This solution was purified by a reversed phase column chromatography (eluent: a 10% aqueous acetonitrile solution) to obtain 0.08 g of [4-[4-(4-amidinophenylamino)-4-oxobutyl]-2,3-dioxopiperazin-1yl]acetic acid as colorless crystals.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:17]3[C:18]([O:22][CH3:23])=[N:19][CH:20]=[CH:21][C:16]=3[N:15]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:14]=2)[CH:8]=1)(=O)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[N:15]1[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[C:17]=2[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:8]=2)=[N:14]1
Reactant: C1CCNC1
Reactant: COc1nccc2c1c(-c1cccc(COS(C)(=O)=O)c1)nn2-c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1cccc(CN3CCCC3)c1)nn2-c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzyl methanesulfonate (100 mg) obtained in Step B of Example 258 and pyrrolidine (0.028 mL) in DMF (3 mL) was added triethylamine (0.047 mL) at room temperature, and the mixture was stirred at 60° C. for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (70 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]12.Br[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[N:3]1([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:7][CH2:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]12
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: c1cc2n(n1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN1CCn2nccc21
Temperature: 0 °C
Reaction time: 66 h
Yield: 30.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.3 g, 7.5 mmol) was added portion-wise to a stirred solution of 2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.68 g, 6.19 mmol) in anhydrous DMF (5 mL) at room temperature under a nitrogen atmosphere. The mixture was cooled to 0° C. and stirred for 15 min before a solution of tert-butyl 3-bromopropylcarbamate (1.47 g, 6.19 mmol) in DMF (5 mL) was added portionwise over 5 min. The reaction was warmed to room temperature and stirred for 66 hr at room temperature. Water (5 mL) was added dropwise and the mixture was concentrated under reduced pressure. More water was added and the mixture was extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 3-(2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propylcarbamate as an orange oil (0.51 g, 31%). To a solution of this oil in conc. H2SO4 at 0° C. was added conc. HNO3 portionwise over 5 min. The reaction was warmed to room temperature and the mixture was stirred for 18 h. The mixture was re-cooled to 0° C., poured into ice water with stirring and basified with 40% aq. NaOH. The product was extracted into DCM and the combined organics were dried over MgSO4 and concentrated under reduced pressure to afford 3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propan-1-amine as a brown gum. This gum was dissolved in DCM (30 mL) and DIPEA (1 mL) and di-tert-butyl dicarbonate (0.5 g, 2.3 mmol) were added. The mixture was stirred at room temperature for 2 hr. The solvents were removed under reduced pressure and the residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazol-1-yl)propylcarbamate as a pale yellow gum (100 mg, 17% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 4.82 (s br, 1H), 4.26-4.16 (m, 2H), 4.12-4.00 (m, 2H), 3.84-3.72 (m, 2H), 3.23 (q, J=6.6 Hz, 2H), 1.89-1.78 (m, 2H), 1.44 (s, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(NS(C)(=O)=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g, 2.49 mmol), in anhydrous CH2Cl2 (5 mL) under argon were added methane sulfonyl chloride (0.23 mL, 2.99 mmol) and pyridine (0.30 mL, 3.73 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.40 g, 58%) as a white solid. 1H NMR (CDCl3) δ: 1.52 (d, J=6.8 Hz, 3H), 2.67 (s, 3H), 4.61-4.72 (m, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H). ESIMS (MNa+): 279.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:14]([I:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[F:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([I:15])[C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8]
Reactant: CC(C)(C)NS(=O)(=O)c1c(F)cccc1I
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1c(F)cccc1I

Procedure:
30.00 g (99.64 mmol) of 2-fluoro-6-iodobenzenesulfonamide, obtained from the reaction of N-(tert-butyl)-2-fluoro-6-iodobenzenesulfonamide with trifluoroacetic acid in analogy to example A3, are introduced together with 15.15 g (109.61 mmol) of potassium carbonate in 250 ml of dimethylformamide. At room temperature 7.68 g (109.61 mmol) of sodium thiomethoxide are added in portions, after which the mixture is stirred at room temperature for 12 h. It is poured into 150 ml of ice-water, adjusted to a pH of 4-5 using 2 N hydrochloric acid, and extracted with ethyl acetate. The organic phase is dried and evaporated. Preparative HPLC (reversed phase, 0.05% trifluoroacetic acid in water/acetonitrile, gradient: in 30 min, 25% to 100% acetonitrile) gives 7.40 g (23% of theory) of 2-iodo-6-(methylthio)benzenesulfonamide.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=1.[Br:15][CH2:16][CH2:17]Br.C(OCC)(=O)C>CS(C)=O>[Br:15][CH2:16][CH2:17][N:6]([N:4]1[CH:3]=[N:2][N:1]=[CH:5]1)[C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCBr
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium-hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,2-dibromoethane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,2-dibromoethane; the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 628 mg (43%). 1H-NMR (400 MHz, d6-DMSO) δ=3.61, (t, J=6.2 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 6.64 (d, J=9.0 Hz), 7.74 (d, 9.0 Hz, 2H), 8.97 (s, 2H). LRMS (FAB+): 292.0 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(#N)C.C(N(CC)CC)C>[CH2:23]([NH:27][C:28]([O:21][CH:20]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN=C=O
Reactant: O=C1c2ncccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNC(=O)OC1c2cccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 0.5 h

Procedure:
A suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1 g.) in acetonitrile (100 cc.) containing n-butyl isocyanate (7.25 cc.) and triethylamine (0.5 cc.) is heated at the reflux temperature for 3 hours. n-Butyl isocyanate (2.9 cc.) and triethylamine (2 drops) are then added and heating at the reflux temperature is continued for a further 30 minutes. After concentrating the mixture to dryness under reduced pressure (40 mm.Hg), the residue is triturated with diisopropyl ether (10 cc.). The precipitate is filtered off and recrystallised from acetonitrile (41 cc.) to give 5-n-butylaminocarbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.8 g.) melting at 215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[N:14]#[C:15][NH2:16].[N+:17]([O-:20])([OH:19])=[O:18]>CO>[N+:17]([O-:20])([OH:19])=[O:18].[NH2:16][C:15]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)=[NH:14]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CO
Product: COC(=O)c1ccc(NC(=N)N)cc1OC
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
Into a reactor at room temperature was added methyl 4-amino-2-methoxybenzoate (4, 38 kg, 210 mol) and methanol (224 L). The mixture was stirred at 25 to 30° C. for 30 min. Aqueous cyanamide (50% w/w, 43 kg, 512 mol) was added over a minimum of 30min at 20 to 25° C. The reaction mixture was heated to reflux using a maximum jacket temperature of 75° C. Concentrated nitric acid (45 kg, 499 mol) was added over a minimum of 60 min. The resulting mixture was heated at reflux for 2 h. A suspension of seed crystals (16 g in 600 mL methanol) was added and the mixture was stirred using a 75° C. jacket temperature for 60 to 90 min. The mixture was cooled to 20 to 25° C. over at least 2 h and stirred for an additional 2 h. The mixture was filtered and washed with methanol (180 L) while stirring for 1 h. The wet cake was washed a second time with methanol (180 L) while stirring for 1 h. The resulting wet cake was dried under vacuum at 25° C. to provide 30.0 kg (50% yield) of 5. 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.57 (s, 4H), 6.97 (d, J=2.3 Hz, 1H), 6.84 (dd, J=2.3, 8.2 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H); MS (ESI) m/z 224.4 (M+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>N1C=CC=CC=1>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Nc1cnc(-c2ccc(O)cc2)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2ccc(O)cc2)cn1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-(4-hydroxyphenyl)pyrazine (283 mg) in pyridine (20 mL) was added under ice-cooling phenyl chloroformate (199 μL) and the mixture was stirred for 1 hour. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with diethyl ether (10 mL) to give the subject compound (314 mg).
Reaction SMILES: [CH3:1]C(C)=O.[S:5]([O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[CH:12][C:11]=1[CH3:20])(=[O:8])(=[O:7])[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>O>[S:5]([O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:19][CH3:1])=[CH:12][C:11]=1[CH3:20])(=[O:7])(=[O:8])[CH3:6]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1OS(C)(=O)=O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cc(C)c(OS(C)(=O)=O)cc1[N+](=O)[O-]
Yield: 77 %

Procedure:
To 200 ml of acetone, were added 19.1 g (77.3 mmol) of 2-methyl-4-hydroxy-5-nitrophenyl mesylate, 31.2 g of sodium carbonate and 19.2 g of dimethyl sulfate. The obtained mixture was heated under reflux for 3 hours. The reaction mixture was cooled and 700 ml of water was poured thereto. Then the mixture was extracted with 700 ml of chloroform, and the extract was washed with water and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, the residue was recrystallized from a solvent mixture (hexane/acetone (2:1, by volume)) to thereby give 15.4 g (59.1 mmol) of 2-methyl-4-methoxy-5-nitrophenyl mesylate. The yield was 77%.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH2:15]=[C:16]([CH2:19][OH:20])[CH2:17][OH:18]>>[OH:18][CH2:17][C:16](=[CH2:15])[CH2:19][O:20][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C=C(CO)CO
Product: C=C(CO)COc1cccc([N+](=O)[O-])c1C#N
Yield: 55 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and 2-methylenepropane-1,3-diol in 55% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.93 (dd, J=8.4 Hz, J=0.8 Hz, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.73 (dd, J=7.6 Hz, J=0.8 Hz, 1H), 5.23-5.29 (m, 2H), 5.03 (t, J=5.6 Hz, 1H), 4.85 (s, 2H), 4.06 (d, J=5.2 Hz, 2H). |ΠατAππ1009—Λ1|ZZMΠTAΓ|
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].Cl.[NH2:19][C@@H:20]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH:31]=[O:32])[CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(Cl)Cl>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([NH:19][C@@H:20]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:34])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH:31]=[O:32])[CH:23]=1)=[O:10])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a solution of Boc-Gln-OH (2.10 g), HCl.H-D-Trp(CHO)-Phe-OBzl (4.70 g) and HOBT (1.15 g) in a mixed solvent of methylene chloride (60 ml) and DMF (10 ml), was added WSC (1.41 g) under ice cooling. The reaction mixture was stirred for 1.5 hours at the same temperature and for additional 1.5 hours at room temperature and concentrated under reduced pressure. Water was added to the residue and the resulting precipitates were collected and washed successively with water, diluted sodium hydrogencarbonate solution and water. After drying, the crude product (5.84 g) was stirred in hot ethyl acetate (60 ml) in water bath. After cooling, the precipitates were collected by filtration and dried to give Boc-Gln-D-Trp(CHO)-Phe-OBzl (5.70 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3=[N:13][C:14]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=4)=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[CH2:31](O)[CH3:32]>>[CH2:31]([O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([C:14]2[N:13]=[C:11]3[N:10]([CH:15]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[S:12]3)=[CH:17][CH:18]=1)[CH3:32]
Reactant: CCO
Reactant: O=C(O)c1ccc(-c2cn3nc(-c4ccc(O)cc4)sc3n2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(-c2cn3nc(-c4ccc(O)cc4)sc3n2)cc1
Temperature: 80 °C
Reaction time: 9 h

Procedure:
To a suspension of 4-[2-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (4.0 g) in ethanol (50 ml) was added sulfuric acid (1.0 ml) and the mixture was stirred at 80° C. for 9 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration, washed with water, acetonitrile and diisopropyl ether and dried to give 4-[2-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester (2.09 g).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[N:3]1
Reactant: Cn1nnc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nnc(-c2cccc(CCOCCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3-(3-(2-methyl-2H-tetrazol-5-yl)phenethoxy)propanoate [Example 7, Step iii)] (500 mg), DCM (4 mL) and TFA (4 mL) was stirred at 25° C. for 30 min and concentrated under vacuum to give the subtitled compound as a gum (612 mg). 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.93 (dt, J=7.8, 1.4 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.31 (dt, J=1.4 and 7.7 Hz, 1H), 4.42 (s, 3H), 3.78 (t, J=5.9 Hz, 2H), 3.77 (t, J=6.3 Hz, 2H), 2.97 (t, J=6.3 Hz, 2H), 2.64 (t, J=6.1 Hz, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:21].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:21]
Reactant: CCOC(=O)CC1CCn2c1cc1c(C)c(OC)ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1CCn2c1cc1c(C)c(O)ccc12
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a stirred solution of ethyl 2-(7-methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (320 mg, 1.114 mmol) in anhydrous DCM (8 mL) was added a 1 M solution of boron tribromide in DCM (3341 μL, 3.34 mmol) at 0° C. under nitrogen protection. The reaction mixture was stirred at this temperature for 1 h, neutralized by addition of saturated NaHCO3 solution. The organic layer was separated and washed with water and dried over anhydrous Na2SO4. The solvent was evaporated, and the residue was purified by column chromatography to give the title compound (200 mg) as a light yellow oil. LCMS m/z=274.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 2.25-2.32 (m, 1H), 2.40 (s, 3H), 2.58 (dd, J=16.0, 8.5 Hz, 1H), 2.82-2.90 (m, 2H), 3.73-3.80 (m, 1H), 3.95-4.02 (m, 1H), 4.05-4.13 (m, 1H), 4.20-4.27 (m, 2H), 4.58 (s, 1H), 6.09 (s, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.[BH4-].ClCCl>CO>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:1][C@@H:2]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN[C@H](Cc2c[nH]c3ccccc23)c2nc(-c3ccccc3)c[nH]2)cc1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
2-{(R)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (36.3 mg, 0.12 mmol) and p-anisaldehyde (12 μL, 0.1 mmol) in 1 mL of methanol were shaken for about 2 hours at about 22° C. Borohydride resin (76 mg, 2.5 mmol/g, AMBERLITE® IRA-400) was then added and the slurry was stirred overnight before addition of dichloromethane (1 mL) and aldehyde Wang resin (31 mg, 3.22 mmol/g, Novabiochem). After about 8 hours of stirring, the slurry was then filtered and evaporated in vacuo to give a yellow solid (32.2 mg, 76%). 1H-NMR (CDCl3, 100 MHz) δ: 8.86 (br s, 1H); 7.73-6.68 (m, 15H); 4.62 (s, 1H); 4.33 (dd, J=4.7 and 8.5 Hz, 1H); 3.81 (s, 2H); 3.74 (s, 3H); 3.27 (ABX system, 2H); 2.26 (s, 1H). LC/MS: m/z=423 (M+H).