Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C1COCC1.C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[Br:1])=[O:19]
Reactant: Brc1ccc[nH]1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)n1cccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To the stirred solution of 2-bromo-pyrrole (22.3 mmol) in 60 mL of dry THF and 120 mL of CH2Cl2 at -78° C. in an atmosphere of nitrogen, was added triethylamine (6.22 mL, 44.6 mmol) followed immediately by dropwise addition of a solution of 2-methoxybenzoyl chloride (5.0 mL, 33.6 mmol) in 40 mL CH2Cl2. The reaction mixture was stirred overnight while it was allowed to warm to room temperature. The mixture was washed with water and brine, dried (Na2SO4) and concentrated in vacuo at room temperature. The crude product was purified by chromatography on triethylamine-treated neutral silica, using EtOAc-Hex (5:95) as the eluent, to give 3.81 g of the title compound as a colorless oil. 1H NMR (CDCl3) δ: 7.58-7.36 (2 H, m), 7.10-6.86 (3 H, m), 6.36 (1 H, dd, J=3.5, 1.8), 6.16 (1 H, t, J=3.5), 3.78 (3 H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10](Cl)(Cl)=[O:11]>C(COC)OC>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([N:1]=[C:10]=[O:11])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: CSc1cccc(N)c1
Solvent: COCCOC
Product: CSc1cccc(N=C=O)c1

Procedure:
m-Aminothioanisole (27.8 g., 0.2 mole) in 100 ml dry dimethoxyethane is added to a saturated solution of phosgene in 200 ml dry dimethoxyethane. Phosgene is passed into the refluxing mixture for a further 4 hr. and then the mixture is heated under nitrogen for 21 hours. Solvent is removed in vacuo to afford m-methylthiophenyl isocyanate as an amber oil which is dissolved in benzene for use in the next step.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5][CH2:4]1)#[N:2].[CH:18]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([C:3]1([CH3:18])[CH2:4][CH2:5][CH:6]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)OC(=O)NCC1CCC(C#N)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a cooled (−78° C.) solution of tert-butyl (4-cyanocyclohexyl)methylcarbamate (500 mg) in tetrahydrofuran (10 mL) was added lithium diisopropylamide (2.0 mL, 2M in heptane). The mixture was stirred at −78° C. for 30 minutes before the addition of CH3I (1 mL). The mixture was then stirred and the temperature was allowed to warm to room temperature. The reaction was quenched with aqueous NH4Cl and the mixture was extracted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent and silica gel chromatography (40% ethyl acetate in hexane) of the crude material gave the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[OH:1])=[O:14])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc2ccccc2c1O
Yield: 65.5 %

Procedure:
Using 1-hydroxynaphthalene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=2)[N:3]=[N:2]1.Cl[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[OH-].[K+].[H-].[Na+]>CN(C)C=O.O>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[N:1]1[CH:5]=[C:4]([C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=2)[N:3]=[N:2]1
Reactant: Clc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]nn2)CC1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3cnccn3)nn2)CC1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
tert-butyl 4-(1H-[1,2,3]triazol-4-yl)-1,2,3,6-tetra-hydropyridine-1-carboxylate (10 mg) prepared in the above 3) was dissolved in 1 ml of N,N-dimethylformamide, 0.04 ml of 2-chloropyrazine, 11 mg of powdery potassium hydroxide and 10 mg of sodium hydride were added thereto and the mixture was stirred for 5 hours under heating at 120° C. The reaction solution was allowed to cool down to room temperature, water was added thereto, the mixture was extracted with ethyl acetate, the extract was dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was separated and purified by a thin-layer chromatography (ethyl acetate/hexane=1/2) to give 4.5 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:21])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CN1CCC(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Solvent: C1CCOC1
Product: CN1CCC(N(C)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.1 %

Procedure:
To a solution of (S)-3-(1-methyl-piperidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.35 mmol) and paraformaldehyde (21 mg, 0.71 mmol) in THF (3 mL) MP-(OAc)3BH resin (Argonaut; 2.55 mmol/g; 346 mg, 0.88 mmol) was added and the reaction mixture was agitated at room temperature for 96 hours. Then, the reaction mixture was filtered and concentrated in vacuo to afford (S)-3-[methyl-(1-methyl-piperidin-4-yl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 99%) as an orange oil. The residue was used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]=[CH:18][CH2:19]Br>C(COC)OC>[C:3]1([CH:9]([CH2:19][CH:18]=[CH:17][C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([CH3:13])[CH:15]=2)[C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(C=CCBr)c1
Reactant: CC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1cccc(C)c1)c1ccccc1

Procedure:
Sodium hydride (6 g., 0.14 mole, oil dispersion) is suspended in glyme (250 ml.) and phenyl acetone (18.6 g., 0.14 mole) in glyme (50 ml.) is added dropwise with stirring. After complete addition the mixture is heated to reflux for one hour. The mixture is cooled in a cold water bath and a solution of m-methylcinnamyl bromide (29.16 g., 0.14 mole) in glyme (50 ml.) is added dropwise. When addition is complete the mixture is refluxed for 20 hours. The cooled mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in ether and washed with dilute hydrochloric acid, water and saturated brine. After drying (MgSO4) and evaporation of ether the residue is vacuum distilled and the product is collected at 161°-164°/0.4 mm; 25.24 g.
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+:14].[Na+].[Na+].OCl.[Zr:19]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Zr+4:19].[Na+:14]
Reactant: [Zr]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: OCl
Agent: [Na+]
Product: [Zr+4]

Procedure:
The above sodium citrate solution was added to 500 gm of zirconium hydroxychloride solution which contains 20.0% ZrO2. The reaction batch was mixed continuously while the sodium citrate was being added. A clear solution of sodium zirconium citrate was obtained after the addition of sodium citrate solution was completed. The pH of the solution product was 6.2.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=4[O:28][CH3:29])=[N:17][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:63][CH:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH:63][CH:64]5[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]5)=[O:25])=[CH:21][C:20]=4[O:28][CH3:29])=[N:17][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2
Reaction time: 0.08 h
Yield: 70.9 %

Procedure:
A mixture of 0.04 g (0.0001 mole) of 4-(9-cyclopentyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid, 0.042 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.061 mL (0.00035 mole) of ethyldiisopropyl amine and 2.0 mL of dimethylformamide was stirred for 5 minutes and then 0.019 g (0.00015 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.035 g of 4-(9-cyclopentyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-21) as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>O>[CH3:27][S:1][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(S)c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(SC)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 3.85 g. of ethyl 3-mercapto-4-cyclohexylphenylglyoxylate in 40 ml. of water containing 0.65 g. of sodium hydroxide is added 2 ml. of dimethyl sulfate with stirring. The reaction mixture is gradually warmed to 40° C. and stirred for 2 hours. The mixture is cooled and extracted with ether which is washed with water, dried and evaporated in vacuo. The residue is distilled to obtain ethyl 3-methylthio-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC(C2C(C3C=CC4C(=CC=C(C5N(C6CCCCC6)C6C=CC(C(NC(CC7C8C(=CC=C(O)C=8)NC=7)C(O)=O)=O)=CC=6N=5)C=4)N=3)=CC(C(N3CCCC3)=O)=CC=2)=CC=1.C[O:99][C:100](=[O:109])[C@H:101]([CH2:103][CH2:104][C:105]([O:107]C)=[O:106])[NH2:102].[OH-].[Na+]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:102][CH:101]([CH2:103][CH2:104][C:105]([OH:107])=[O:106])[C:100]([OH:99])=[O:109])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Agent: O=C(NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCC(NC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1)C(=O)O
Yield: 15 %

Procedure:
Compound 237 was synthesized from Compound 201 as described for Compound 235, using L-glutamic acid dimethylester in place of L-5-hydroxytryptophane. In the 3rd step the protected intermediate was treated with aqueous sodium hydroxide for a 15% yield of the title compound
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH2:7])=O)[CH2:4][CH2:3]1.C1([C:11]2[N:15](C)[C:14]([CH:17]=[O:18])=[CH:13]N=2)CC1>>[CH3:11][N:15]1[C:14]([CH:17]=[O:18])=[CH:13][N:7]=[C:5]1[C:2]1([CH3:1])[CH2:4][CH2:3]1
Reactant: CC1(C(N)=O)CC1
Reactant: Cn1c(C=O)cnc1C1CC1
Product: Cn1c(C=O)cnc1C1(C)CC1

Procedure:
3-Methyl-2-(1-methyl-cyclopropyl)-3H-imidazole-4-carbaldehyde was prepared from 1-methyl-cyclopropyl carboxamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([CH3:39])[CH:35]=5)[N:30]([CH3:40])[C:29]4=[O:41])[CH2:24][CH2:23]3)=[N:11][C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:13]2)=[CH:8][C:7]=1[O:42][CH2:43][CH3:44])(O)=[O:2].[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH2:43]([O:42][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][C:1]([N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:2])[N:13]=[C:12]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:11]=[C:10]2[N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([CH3:39])[CH:35]=3)[N:30]([CH3:40])[C:29]2=[O:41])[CH2:24][CH2:23]1)[CH3:44]
Reactant: C1CCNC1
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCC(=O)O
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCC(=O)N1CCCC1
Yield: 15 %

Procedure:
The same procedure as in Example 57 was repeated, using 300 mg (0.50 mmol) of Compound 56 obtained in Example 56, except that pyrrolidine was used in place of isopropylamine, to give 48 mg (yield: 15%) of Compound 58 as white crystals.
Reaction SMILES: Cl[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.C1C[O:29]CC1.C[Si](C)(C)[O-].[K+].Cl>O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[C:5](=[O:29])[NH:10][N:9]3[C:8](=[O:11])[NH:6][N:7]=[C:2]3[C:3]=2[C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[CH:17][CH:16]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: C1CCOC1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]n2c(=O)[nH]nc2c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a r.b. flask was added 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.256 mmol), prepared as described in Example 1F, THF (5 ml) and potassium trimethylsilanolate (132 mg, 1.026 mmol). The reaction mixture was stirred at 85° C. for 1.5 hrs. After this time, the solution was cooled to RT and the reaction was diluted with water (25 ml). The pH of the solution was adjusted to 4 with 1N HCl. The resultant solution was extracted with EtOAc (3×20 ml). The combined organic layers were washed with water (20 ml), saturated NaCl (20 ml). The organic layers was dried (MgSO4), filtered and concentrated to give the title compound, 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione (90 mg, 95% yield) as yellow solid. MS (M+H)=372.9.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)(=[O:29])=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:29])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNS(=O)(=O)c1cccs1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNS(=O)(=O)c3cccs3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.105 g, 0.379 mmol) was reacted with N-(2-azidoethyl)thiophene-2-sulfonamide (0.099 g, 0.379 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(thiophene-2-sulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.49 (s, 3H), δ 7.39 (s, 1H), δ 6.99 (s, 1H), δ 6.41 (bm, 3H), δ 4.43 (s, 2H), δ 3.42 (s, 2H), δ 2.54 (s, 2H), δ 2.09 (s, 2H), δ 1.51 (m, 13H), δ 1.19 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 150.8, 149.4, 148.1, 141.1, 138.3, 132.2, 132.1, 127.7, 122.6, 85.2, 53.8, 50.2, 43.2, 31.2, 29.9, 29.2, 28.8, 28.1, 25.5 ppm; HRMS (ESI) calcd for C21H31N7O4S2(M+) 509.1879. found 509.1879, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)thiophene-2-sulfonamide hydrochloride (0.098 g, 58% yield). 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), δ 7.76 (s, 1H), δ 7.57 (s, 1H), δ 7.11 (s, 1H), δ 6.46 (s, 1H), δ 4.79 (s, 2H), δ 3.55 (s, 2H), δ 2.50 (s, 2H), δ 1.66-1.18 (bm, 8H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.6, 155.6, 147.2, 140.9, 132.7, 132.3, 127.8, 127.7, 108.8, 53.1, 42.2, 36.8, 28.1, 27.8, 27.5, 24.9, 24.3, 23.8 ppm; HRMS (ESI) calcd for C16H23N7O2S2(M+) 409.1355. found 409.1354.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][N:4]=1.[Cl:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([Cl:30])[C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[Cl:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:25])=[O:26])=[CH:21][CH:20]=[C:19]([Cl:30])[C:15]=1[C:16]([NH:12][C:9]1[CH:10]=[C:11]2[C:3]([O:2][CH3:1])=[N:4][NH:5][C:6]2=[N:7][CH:8]=1)=[O:17]
Reactant: COc1n[nH]c2ncc(N)cc12
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1Cl
Temperature: 60 °C
Reaction time: 72 h
Yield: 17.2 %

Procedure:
3-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine (50 mg, 0.305 mmol) in N,N-dimethylformamide (3.0 mL) was sequentially treated with 2,6-dichloro-3-(propylsulfonamido)benzoic acid (356 mg, 1.14 mmol), EDCI (117 mg, 0.609 mmol), and HOBt (82.3 mg, 0.609 mmol) and heated to 60° C. After 72 hours, the reaction mixture was allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate, washed with water (4×), sodium bicarbonate (2×), and brine (1×), dried over sodium sulfate, and concentrated. The crude product was applied directly to a silica gel column and eluted with a gradient (30% to 100%) of ethyl acetate-hexanes to provide 2,6-dichloro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (67.8 mg, 0.0524 mmol, 35.4% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.63-12.59 (s, 1H), 11.04-11.00 (s, 1H), 9.83-9.79 (s, 1H), 8.59-8.570 (d, 1H), 8.47-8.45 (d, 1H), 7.60-7.57 (m, 2H), 4.03-4.01 (s, 3H), 3.21-3.13 (m, 2H), 1.83-1.73 (m, 2H), 1.02-0.97 (t, 3H); MS (APCI-neg) m/z=456.1 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13](Br)[CH3:14])[CH:9]=2)[CH:4]=1>N1C(C)=CC(C)=CC=1C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13]=[CH2:14])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2cc(C(C)Br)ccc2c1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOCC
Product: C=Cc1ccc2cc(OC)ccc2c1

Procedure:
The 2-methoxy-6-(1-bromoethyl) naphthalene prepared in Example 9 was dissolved in 8.0 grams of collidine (2,4,6-trimethylpyridine) and the mixture was refluxed for 45 minutes. The product mixture was cooled, diluted with diethylether, and washed with dilute hydrochloric acid. The ether solution was dried over anhydrous magnesium sulfate, filtered and the diethylether removed by evaporation. The structure of the resulting product was verified as 2-methoxy-6-vinylnaphthalene by 1H and 13C nuclear magnetic resonance spectroscopic analysis.
Reaction SMILES: C([N:8]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:14]1([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC1CCCCC1)C(=O)O

Procedure:
1 g (0.41 mmol/g) of Boc-cyclohexylalanine-BAH resin was suspended and shaken in TFA/CH2Cl2 (1:1) by volume (3×40 mL) 10 min each time to remove the Boc group. The product was isolated by filtration and washed (3×50 mL each) with CH2Cl2, 8% DIEA in CH2Cl2 and CH2Cl2 to give the free base of cyclohexylalanine-BHA resin. This was subjected to sequential solid phase peptide synthesis using the Fmoc-protocol. All couplings except the last residue were performed using DCC/HOBt procedure. At step 7 the Fmoc amino acid, DCC and HOBt were added with the corresponding times as follows: Fmoc-Asp(OtBu)-OH (615 mg, 1.5 mmol), DCC (310 mg, 1.5 mmol) and HOBt (270 mg, 2 mmol) were dissolved in 20 mL of 1:1 by volume DMF/CH2Cl2 and allowed to couple for 60 min at room temperature. Fmoc-Met-OH (550 mg, 1.5 mmol), DCC (310 mg, 1.5 mmol) and HOBt (270 mg, 2 mmol) were dissolved in 20 mL of 1:1 by volume DMF/CH2Cl2 and allowed to couple for 60 min at room temperature. Fmoc-Trp-OH (650 mg, 1.5 mmol), DCC (310 mg, 1.5 mmol) and HOBt (270 mg, 2 mmol) were dissolved in 20 mL of 1:1 by volume DMF/CH2Cl2 and allowed to couple for 60 min at room temperature.
Reaction SMILES: [C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15](S)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC2[N:32]=[N:33]C(Cl)=CC=2C1)(=O)C1C=CC=CC=1.NC(N)=S>>[C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15]([NH:32][NH2:33])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2nnc(S)cc2C1
Reactant: O=C(c1ccccc1)N1CCc2nnc(Cl)cc2C1
Agent: NC(N)=S
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
The 6-benzoyl-5,6,7,8-tetrahydro-3-mercaptopyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 41(a), from 27.4 g of 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 8.4 g of thiourea. After cooling the reaction mixture with ice, the compound precipitates. M.P. 225°-228° (decomp., from glacial acetic acid).