Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]([O:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:4]=1>O1CCOCC1.CO>[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:4]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)OC(C)(C)C)CC3)CC4)nc(N)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 mL of 4 N HCl in 1,4-dioxane was added to a solution of 1-(tert-butoxycarbonyl)piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.10 g, 0.18 mmol) in methanol (1.0 mL). The reaction mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford the product as an HCl salt. Analytic LCMS (M+H)+: m/z=452.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:13]3=[N:14][C:15]([C:18]4[O:22][C:21]([NH2:23])=[N:20][N:19]=4)=[CH:16][CH:17]=[C:12]3[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=2)[CH:6]=[N:7][CH:8]=1.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:13]3=[N:14][C:15]([C:18]4[O:22][C:21]([NH2:23])=[N:20][N:19]=4)=[CH:16][CH:17]=[C:12]3[NH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(N)o4)nc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cncc(-c2c[nH]c3ccc(-c4nnc(N)o4)nc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
A mixture of 5-(3-(5-methoxypyridin-3-yl)-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)-1,3,4-oxadiazol-2-amine (0.022 g, 0.048 mmol) and 1 M NaOH (aq.) (0.095 mL, 0.095 mmol) in 4 mL of EtOH was stirred overnight at RT. The reaction was then concentrated and the residue taken up in H2O and EtOAc. The EtOAc layer was put aside and the aqueous layer was acidified with 2 M HCl (aq.) and extracted with DCM and 3/1 CHCl3/i-PrOH (2×). The aqueous layer was concentrated to give an orange solid, which was washed with MeOH and the MeOH washes were dried over Na2SO4, filtered and concentrated to give an orange solid. The solid was triturated with DCM and the orange solid (20 mg) was collected by filtration. This material was purified by reverse phase HPLC (5-100% MeCN in H2O with 0.1% TFA) followed by silica gel chromatography (0-10% MeOH in DCM) to afford 5-(3-(5-methoxypyridin-3-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)-1,3,4-oxadiazol-2-amine (0.0022 g, 7.14 μmol, 15.00%) as a white solid. MS (ESI, pos. ion) m/z: 309.0 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 4.01 (3H, s), 7.92-7.99 (2H, m), 8.11 (1H, d, J=2.93 Hz), 8.23 (1H, s), 8.43-8.47 (1H, m), 9.03 (1H, d, J=1.76 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]1([C:14]2[C:22]3[C:17](=[CH:18][C:19]([CH:23]=O)=[CH:20][CH:21]=3)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:15]=2)[CH2:13][CH2:12]1>>[CH:11]1([C:14]2[C:22]3[C:17](=[CH:18][C:19](/[CH:23]=[C:3]4/[C:2](=[O:10])[NH:1][C:9]5[C:4]/4=[CH:5][CH:6]=[CH:7][CH:8]=5)=[CH:20][CH:21]=3)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[N:15]=2)[CH2:12][CH2:13]1
Reactant: C[Si](C)(C)CCOCn1nc(C2CC2)c2ccc(C=O)cc21
Reactant: O=C1Cc2ccccc2N1
Product: C[Si](C)(C)CCOCn1nc(C2CC2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Yield: 85.5 %

Procedure:
According to the method of Example A19, indolin-2-one (17 mg, 0.13 mmol) and 3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (40 mg, 0.13 mmol) were reacted to obtain crude product. The crude mixture was purified by prepTLC (SiO2 2% MeOH in DCM) to provide the title compound as a yellow solid (48 mg, 88%). MS ESI 432.2 [M+H]+, calcd for [C25H29N3O2Si+H]+ 432.6.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][O:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[CH:3][CH:2]=1.NN>CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][O:12][NH2:13])=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccnc2ccccc12
Agent: NN
Solvent: CCO
Product: NOCc1ccnc2ccccc12
Reaction time: 3 h
Yield: 125.8 %

Procedure:
N-(4-quinolyl)methoxy phthalimide (2.00 g) was suspended in 95% EtOH and hydrazine (0.30 mL) was added. The reaction mixture was stirred for 3 h and then filtered. The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.44 g) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([Br:21])[CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>O1CCCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)([C:9]2[CH:10]=[C:11]3[C:6](=[C:7]([Br:21])[CH:8]=2)[N:5]=[C:4]([O:22][CH3:23])[CH:3]=[C:2]3[Br:1])[OH:13])=[CH:19][CH:18]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)cc(Br)c2n1
Solvent: C1CCOC1
Product: COc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 4,8-dibromo-6-[(4-chlorophenyl)carbonyl]-2-methoxyquinoline (1.5 g, 3.29 mmol, 1.00 equip) in tetrahydrofuran (30 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (9.87 mL, 3.00 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (100 mL). The solids were filtered out and washed with ethyl acetate (100 mL), and the ethyl acetate was combined with the filtrate. The resulting solution was extracted with ethyl acetate (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield bis(4-chlorophenyl)(4,8-dibromo-2-methoxyquinolin-6-yl)methanol as a yellow solid. LCMS (ES, m/z) 568 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=O)[CH2:7]Cl)#[N:2].[C:13]([NH:16][C:17]([NH2:19])=[S:18])(=[NH:15])[NH2:14]>CCO>[NH:16]([C:17]1[S:18][CH:7]=[C:6]([C:5]2[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=2)[C:1]#[N:2])[N:19]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N=C(N)NC(N)=S
Reactant: N#Cc1cccc(C(=O)CCl)c1
Solvent: CCO
Product: N#Cc1cccc(-c2csc(NC(=N)N)n2)c1

Procedure:
A mixture of 3-cyanophenacyl chloride (1.78 g.) and amidinothiourea (1.2 g.) in EtOH (40 ml.) was heated under reflux for 1 hour. The solid precipitate was filtered off, dissolved in hot water (100 ml.) and the solution basified with sodium bicarbonate. The precipitated solid was filtered off and dried to give 3-[2-guanidinothiazol-4-yl]benzonitrile which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[NH:8]1[CH2:13][CH2:12][C:11](=[C:14]2[C:23]3[CH:24]=[C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][C:22]=3[O:21][CH2:20][C:19]3[CH:18]=[CH:17][S:16][C:15]2=3)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[O:7]=[C:5]([CH3:6])[CH2:4][CH2:3][CH2:2][N:8]1[CH2:13][CH2:12][C:11](=[C:14]2[C:23]3[CH:24]=[C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][C:22]=3[O:21][CH2:20][C:19]3[CH:18]=[CH:17][S:16][C:15]2=3)[CH2:10][CH2:9]1
Reactant: CC(=O)CCCCl
Reactant: COC(=O)Cc1ccc2c(c1)C(=C1CCNCC1)c1sccc1CO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc2c(c1)C(=C1CCN(CCCC(C)=O)CC1)c1sccc1CO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
5-Chloro-2-pentanone (2.4 mL, 20.9 mmol) was added to a DMF (50 mL) solution of methyl (4-piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl)acetate (2.50 g, 7.0 mmol), anhydrous potassium carbonate (2.15 g, 15.6 mmol), and potassium iodide (1.41 g, 8.5 mmol), and the mixture was stirred overnight at 80° C. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvents were then distilled off under a reduced pressure. The residue was purified by column chromatography (chloroform:methanol=19:1), to give 2.40 g (78%) of the captioned compound in the form of an oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([CH3:24])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH3:24])[N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Yield: 89 %

Procedure:
Stir a mixture of 4-(6-methyl-5-nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (2.69 g, 8.0 mmol) and 10% palladium on carbon (1.0 g) in ethanol (60 mL) at 22° C. under hydrogen for 2 hours. Filter off the palladium catalyst. Concentrate the filtrate to give a colorless oil. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to give the title compound. (2.19 g, 89% yield). MS(ES): m/z=308.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][C:10]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:11]=3[CH:12]=[CH:13][CH:14]=[N:15]4)=[N:20][C:21]#[N:22])=[CH:23][CH:24]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#CN=C(NCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1)Nc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (50 mg, 0.16 mmol) and 4-chloro-benzenesulfonyl chloride (41 mg, 0.19 mmol) were added to pyridine (1 mL). An exothermic reaction occurred and the suspension became homogeneous. This solution was shaken at room temperature for 12 hours. The reaction mixture was then diluted with ethyl acetate (8 mL) and washed with water (5 mL×3). The organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was triturated with diethyl ether to give a solid product in 76% yield. 1H NMR (DMSO-d6, ppm): 10.37 (s, 1H), 9.39 (s, 1H), 8.96 (m, 1H), 8.12 (m, 1H), 8.02 (d, 1H), 7.69 (m, 3H), 7.63 (d, 2H), 7.49 (m, 2H), 7.39 (m, 1H), 7.08 (m, 4H), 4.21 (d, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[N:11][OH:12].C[O-].[Na+].Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.O>CO>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[O:19][CH2:18][CH2:17][O:12][N:11]=[C:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: O=C1C(=NO)Oc2ccccc21
Reactant: BrCCOC1CCCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(=NOCCOC2CCCCO2)Oc2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
5 g (0.03 mol) of benzofuran-2,3-dione 2-oxime (XI-1) are dissolved in 30 ml of methanol, and at 20° C. 15 ml of a 2 molar solution of sodium methoxide in methanol are added dropwise. The solvent is distilled off under reduced pressure. The crystalline residue is dissolved in 30 ml of N-methyl-2-pyrrolidinone and treated with 6.27 g (0.03 mol) of 2-(2-bromoethoxy)-tetrahydropyran at 20° C. The reaction mixture is stirred for 16 hours at 20° C., poured into 100 ml of water and the resulting mixture is extracted twice with 100 ml of dichloromethane each time. The solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel using a mixture of diethyl ether/dichloromethane/petroleum ether (1:1:2). 5.55 g (62.1% of theory) of benzofuran-2,3-dione 2-{O-[2-(tetrahydropyran-2-yloxy)-ethyl]-oxime} (XIV-2) are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:14](O)=O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[C:13]2[C:12]([N:11]=[C:3]3[C:4]=1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]3[CH3:1])=[CH:20][CH:19]=[C:18]([O:21][CH3:22])[CH:17]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Nc2cc([N+](=O)[O-])ccc2C)c(C(=O)O)c1
Product: COc1ccc2nc3c(C)ccc([N+](=O)[O-])c3c(Cl)c2c1
Yield: 68 %

Procedure:
N-(2′-methyl-5′-nitrophenyl)-5-methoxyanthranilic acid (7.2 g) is heated in phosphorous oxychloride (60 ml) at 120° C. for 1 hour. Excess phosphorous oxychloride is distilled off under reduced pressure, and the residue poured slowly into a stirred mixture of chloroform, concentrated ammonium hydroxide and ice. The separated chloroformic layer is washed with water and dried using magnesium sulfate. Chloroform is evaporated to dryness, and the residue is crystallized from benzene to give 9-chloro-7-methoxy-4-methyl-1-nitroacridine (6.1 g, 68% yield), m.p. 227-228° C. 1H NMR (d6 DMSO): δ8.23 (d, 1 H, J=9.3 Hz), 8.13 (d, 1 H, J=7.3 Hz), 7.79 (bd, 1 H, J=8.3 Hz), 7.71 (dd, 1H, J1=9.3 Hz, J2=2.9 Hz), 7.58 (d, 1 H, J=2.9 Hz), 4.02 (s, 3 H), 2.85 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9]C)[C:5]([NH2:6])=[CH:4][C:3]=1[Cl:11].B(Br)(Br)Br>C(Cl)Cl>[NH2:6][C:5]1[CH:4]=[C:3]([Cl:11])[C:2]([Br:1])=[CH:8][C:7]=1[OH:9]
Reactant: COc1cc(Br)c(Cl)cc1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cc(Cl)c(Br)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a suspension of 4-bromo-3-chloro-6-methoxyaniline (28) (944 mg, 4 mmol) in 10 ml DCM was added 1 M BBr3 in DCM (8 ml, 8 mmol). The reaction mixture was stirred at r.t. for 2 h, which turned to a brown solution and back to a brown suspension. After quenched with aq. sodium bicarbonate solution, the mixture was extracted with EA. The org. phase was washed with brine, dried over sodium sulfate, concentrated to dryness to give 865 mg of 29 as a brown solid. Yield: 97.2%, purity>95%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[Na+].[Na+]>CO.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(F)cccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(F)cccc1Br
Temperature: 80 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
2-Bromo-6-fluorobenzoic acid (1, 12.50 g, 57 mmol) was dissolved in a mixture of methanol (60 mL) and conc. sulfuric acid (65 mL). The solution was heated to 80° C. and stirred for 12 h. The reaction mixture was cooled and 20% sodium carbonate solution (500 mL) was added slowly to reach pH=8. The mixture was extracted with dichloromethane (3×180 mL), and the combined organic layers were dried over magnesium sulfate and evaporated. The title compound (11.29 g, 48.5 mmol, 85%) was obtained as a brown oil.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.O.[NH2:13][NH2:14]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:13][NH2:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NN
Reactant: Fc1ccc2ncc(Br)n2n1
Solvent: O
Product: NNc1ccc2ncc(Br)n2n1
Temperature: 70 °C

Procedure:
A suspension of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (2.16 g, 10 mmol) in hydrazine monohydrate (10 mL) was heated at 70° C. for 30 minutes. The mixture was cooled to room temperature, and the titled compound (1.78 g) was collected by filtration. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.27 (br. s., 2H) 6.78 (d, J=9.60 Hz, 1H) 7.51 (s, 1H) 7.73 (dd, J=9.60, 1.52 Hz, 1H) 8.20 (br. s., 1H).
Reaction SMILES: C1C2C(COC([N:18]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@H:19]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=3)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[OH:57][C:58]1[C:67]2[C:62](=[C:63]([OH:68])[CH:64]=[CH:65][CH:66]=2)[N:61]=[C:60]([C:69]([OH:71])=O)[CH:59]=1>>[OH:57][C:58]1[C:67]2[C:62](=[C:63]([OH:68])[CH:64]=[CH:65][CH:66]=2)[N:61]=[C:60]([C:69]([N:18]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:19]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=2)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=[O:71])[CH:59]=1
Reactant: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(O)c2cccc(O)c2n1
Product: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)c1cc(O)c2cccc(O)c2n1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-methyltrityl-L-glutaminyl]-3,4-dihydroxybenzylamine (1.0 g, 1.4 mmol, example 26, step A) as described for example 26 using 4,8-dihydroxyquinoline-2-carboxylic acid (435 mg, 2.1 mmol) instead of4-hydroxy-3-nitrobenzoic acid. The crude material was purified by flash chromatography using a solvent gradient from 30% to 60% EtOAc/CH2Cl2/1% AcOH. The title compound was obtained as yellow crystals (100 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]([NH:12][C:13](=[O:17])OCC)[CH3:11])[CH:5]=[CH:6][C:7]=1[OH:8].O.[NH2:20][NH2:21].O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:11])[NH:12][C:13](=[O:17])[NH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: NN
Reactant: CCOC(=O)NC(C)C(=O)c1ccc(O)c(Cl)c1
Solvent: O
Solvent: CCCCO
Product: CC1NC(=O)NN=C1c1ccc(O)c(Cl)c1
Yield: 51.1 %

Procedure:
32.64 g of ethyl N-[2-(3-chloro-4-hydroxyphenyl)-1-methyl-2-oxoethyl]carbamate [prepared as described in Example 1(b)] and 75.20 g of 80% hydrazine hydrate (i.e. a grade of hydrazine hydrate containing 20% w/w water) were added to 240 ml of butanol, and the mixture was heated under reflux for 18 hours. The butanol used as the solvent was distilled off under reduced pressure, and then 10% w/v aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The residue was collected by filtration, washed with ethyl acetate and dried, to give 14.71 g of the title compound as a yellow powder melting at 218°-222° C. (with decomposition). The filtrate was purified by column chromatography through silica gel eluted with a 10:1 by volume mixture of chloroform and methanol, to give a further 5.64 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1](C1NC(C(OCC)=O)=CC=1)C.[Cl:13][C:14]1[C:18]([Cl:19])=[C:17]([CH3:20])[NH:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:13][C:14]1[C:18]([Cl:19])=[C:17]([CH2:20][CH3:1])[NH:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1[nH]c(C)c(Cl)c1Cl
Reactant: CCOC(=O)c1ccc(CC)[nH]1
Product: CCOC(=O)c1[nH]c(CC)c(Cl)c1Cl

Procedure:
Title compound was synthesized from ethyl 5-ethyl-1H-pyrrole-2-carboxylate (Intermediate 12) by an analogous method to Intermediate 4.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:10][CH2:11][C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[SH:10][CH2:11][C:12]([O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: O=C(O)CS
Reactant: OC1CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CS)OC1CCCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 32 grams of cyclooctanol; 9.2 grams of mercaptoacetic acid and 0.5 grams paratoluene sulfonic acid.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][CH2:38][C:39](O)=[O:40])=[CH:29]1>ClCCl>[CH3:1][CH:2]1[N:6]([C:39](=[O:40])[CH2:38][CH2:37][C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:28][CH:29]=2)[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1
Reactant: CC1NCC2(CCN(C)CC2)S1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1SC2(CCN(C)CC2)CN1C(=O)CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (2.18 g, 11.7 mmol) in dichloromethane (230 ml) at room temperature was added dicyclohexylcarbodiimide (DCC) (3.24 g, 15.7 mmol) followed by addition of 3-indolepropionic acid (2.87 g, 15.2 mmol). The resulting solution was stirred at room temperature overnight. During the reaction a white solid precipitated. After filtration the solvent was evaporated and the crude product was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 90/10/1) to give AF710 (2.5 g, 100% chemical purity) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 8.17 (br s, 1H, NH-indole), 7.60 (d, J=7.81 Hz, 1H, CHC arom), 7.35 (d, J=8.08 Hz, 1H, CHC arom), 7.19 (app t, J=7.53 Hz, 1H, CHCH arom), 7.12 (app t, J=7.45 Hz, 1H, CHCH arom), 7.02 (d, J=1.86 Hz, 1H, CHNH arom), 5.52, 5.09 (2q, J=6.15 and J=6.22 Hz, 1H, CHCH3), 4.62, 3.66 (2d, J=11.76 and J=11.5 Hz, 1H, CHHNCO), 3.29, 3.08 (2d, J=11.48 and J=12.0 Hz, 1H, CHHNCO), 3.18-3.11 (m, 2H), 2.72-2.66 (m, 2H), 2.64-2.46 (m, 2H), 2.26, 2.25 (2s, 3H, NCH3), 2.32-2.19, 2.12-2.02 (2m, 2H), 1.87-1.80, 1.68-1.51 (2m, 4H), 1.48, 1.43 (2d, J=6.21 and J=6.19 Hz, 3H, CH3—CH) ppm; 13C NMR (CDCl3, 500 MHz) δ 170.58 (C), 136.39 (C), 127.25 (C), 122.19 (CH), 121.80 (CH), 119.52 (CH), 118.73 (CH), 115.17 (C), 111.31 (CH), 57.48, 57.19 (CH), 55.46 (C), 54.55, 54.12 (CH2), 53.11, 52.86 (CH2), 46.21, 46.15 (CH3), 38.05, 37.32 (CH2), 36.82, 36.31 (CH2), 34.41 (CH2), 25.44, 23.47 (CH3), 21.04, 20.96 (CH2) ppm.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:9]#[N:10])=[N:6][NH:7][CH:8]=1.[CH3:11]I>CN(C=O)C>[Br:3][C:4]1[C:5]([C:9]#[N:10])=[N:6][N:7]([CH3:11])[CH:8]=1
Reactant: CI
Reactant: N#Cc1n[nH]cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(C#N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Add sodium hydride (60 wt % oil dispersion, 700 mg, 17.5 mmol) in several portions under a nitrogen purge to a solution of 4-bromo-1H-pyrazole-3-carbonitrile (2.0 g, 11.6 mmol) in 15 mL of anhydrous DMF at 0° C. Stir the reaction at 0° C. for one hour. Add methyl iodide (0.9 mL, 14.5 mmol) to the mixture and allow to stir and come to room temperature over 1 hour. Pour into 100 mL of ice-water and stir for 15 minutes. Filter off the resulting solid and rinse with 20 mL of water. Dry the solid overnight. Chromatograph (1/9-1/3 EtOAc/hexanes) over silica gel to give the title compound as a white solid (1.38 g, 63%), along with a small amount (100 mg) of the regioisomeric bromide.