Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(O)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCc4ccccc4)cc23)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89 %

Procedure:
To a solution of 6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (1.5 g, 4.7 mmol) and benzyl bromide (0.61 g, 5.1 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (0.71 g, 5.1 mmol), and the mixture was stirred at room temperature for 17 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (100 ml). The aqueous layer was separated and extracted with ethyl acetate (50 ml). The organic layer and the extract were combined and the mixture was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, and crystallized from n-hexane-ethyl acetate to give 6-(benzyloxy)-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (1.7 g, yield 91%) as pale-yellow crystals.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])C=C.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:10]1[CH:9]=[CH:8][C:7]([F:11])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cccc(F)c1-c1ccccc1Cl
Product: C=CCc1ccc(F)c(-c2ccccc2Cl)c1O
Yield: 81 %

Procedure:
A solution of 2-allyloxy-2′-chloro-6-fluorobiphenyl (9.0 g, 33.7 mmol) in mesitylene (100 mL) was refluxed for 24 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 7.0 g (81%) of 3-allyl-2′-chloro-6-fluorobiphenyl-2-ol as a colorless oil.
Reaction SMILES: [C:1]1([C:6]([NH:8][CH2:9][CH3:10])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([CH2:6][NH:8][CH2:9][CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNC(=O)C1=CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNCC1CCCC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
N-Cyclopentenoyl-ethylamine was prepared from cyclopentenoic acid (2 grams, 17.5 mmol) and oxallyl chloride (2.2 grams, 17.5 mmol) after stirring at 25-35° C. for 8-12 hours. To this was added a benzene solution of ethylamine (2.1 grams, 48.7 mmol) at 0° C., and this reaction mixture was stirred for 3 hours at 25-35° C., after which time the solvent was evaporated under vacuum to yield N-cyclopentenoyl-ethylamine (1.7 grams), yield: 68.9%. A solution of N-cyclopentenoyl-ethylamine (1.7 grams, 13.3 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) under a nitrogen atmosphere, and lithium aluminum hydride (LiAlH4; 1.3 grams, 36.1 mmol) was added to the solution. After being stirred for 1 hour at 25-35° C., the reaction mixture was gently refluxed for 8 hours. The reaction mixture was quenched with saturated sodium sulfate solution, filtered, and the precipitate washed with diethyl ether (Et2O). The filtrate was concentrated to afford N-cyclopentylmethyl ethylamine (0.6 g), yield: 40%.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH2:28][CH3:29])=[C:20]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[CH3:31][N:32]=[C:33]=[S:34]>>[CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH2:28][CH3:29])=[C:20]([S:23]([NH:24][C:33]([NH:32][CH3:31])=[S:34])(=[O:25])=[O:26])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2
Reactant: CN=C=S
Product: CCOc1cc2c(cc1S(=O)(=O)NC(=S)NC)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)methyl)-6-(methylaminothiocarbonyl aminosulfonyl)-7-ethoxychroman ##STR53## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-ethoxychroman is synthesized analogously to Example 14 from 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-ethoxychroman and methyl isothiocyanate. Melting point: 178° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:12][CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:12][CH:13]=[O:14])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)C[C@H]1CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)C[C@H]1CC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-(2-hydroxyethyl)cyclopropanecarboxylate (9.70 g, 35.5 mmol) in DCM (300 ml) at 0° C. was added Dess-Martin periodinane (18.06 g, 42.6 mmol). The formed slurry was stirred at room temperature overnight. The reaction mixture was filtered through celite. The resulting filtrated was concentrated and this process was repeated one more time. Residue was purified by a silica gel column, eluted with 8:1, 4:1, 3:1, then 2:1 heaxane-EtOAc to yield (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-(2-oxoethyl)cyclopropanecarboxylate (6.15 g, 22.67 mmol, 63.9% yield) as a colorless oil. 1H NMR (CDCl3) δ 1.24 (t, J=7 Hz, 3H), 1.40-1.45 (m, 11H), 1.65-1.69 (m, 1H), 2.75-2.80 (m, 2H), 4.09-4.19 (m, 2H), 5.17 (b, 1H), 9.76 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([OH:17])=O)[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C@@H:26]1[NH:31][CH2:30][CH2:29][N:28]([C:32]2[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:27]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:31]3[CH2:30][CH2:29][N:28]([C:32]4[C:37]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:27][C@@H:26]3[CH3:25])=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: C[C@H]1CN(c2ncccc2C(F)(F)F)CCN1
Product: C[C@H]1CN(c2ncccc2C(F)(F)F)CCN1C(=O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1

Procedure:
In analogy to example 73, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was converted to the acid chloride and subsequently reacted with (S)-3-methyl-1-(3-trifluoromethyl-pyridin-2-yl)-piperazine to give the title compound as a colorless solid. MS: 580.3 ([M+H]+)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:32]=[CH:31]1>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ag]=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:34]5[N:30]([CH3:29])[CH:31]=[N:32][CH:33]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: Cl[Pd]Cl
Agent: O=[Ag]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cncc1-c1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Yield: 20 %

Procedure:
(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.70 g, 1.81 mmol), 1-methyl-5-[tri(n-butyl)stannyl]imidazole (prepared according to the published method: K. Gaare et. al., Acta Chem. Scand., (1993), 47(1), p57-62) (2.2 g, 6 mmol), 1,4-bis(diphenylphosphino)-butane palladium (II) chloride (0.41 g, 0.7 mmol) and silver oxide (0.22 g, 1.8 mmol) were reacted in dry dioxane according to Procedure B. Purification by silica gel chromatography, eluting with 10%MeOH/EtOAc, gave the product as a pale brown solid (0.16 g, 0.37 mmol, 20%); δH CDCl310.62 (1H,s), 9.25 (1H,s), 8.75 (1H,s), 8.60 (1H,s), 8.13 (1H,s), 8.03 (1H,s), 7.20-7.78 (9H,m), 5.61 (2H,s), 3.96 (3H,s); m/z (M+1+) 433.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:16]([OH:18])=O)[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1)(=[O:5])=[O:4])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:31]([N:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38][NH2:39])[CH3:32]>O1CCCC1>[CH2:31]([N:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38][NH:39][C:16]([C:8]1[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:7]=1)=[O:18])[CH3:32]
Reactant: CCS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Reactant: CCN1CCCC1CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)CC)cc2c1OCCO2
Temperature: 25 °C
Yield: 76.7 %

Procedure:
13 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid, 300 ml of tetrahydrofuran and 13 g of carbonyldiimidazole were introduced into a balloon flask provided with an agitator, a thermometer and a condenser. The mixture was agitated at ambient temperature and then 9.5 g of 1-ethyl-2-aminomethylpyrrolidine was added. Agitation was maintained at ambient temperature and then the solvent was evaporated under vacuum. The crystals produced were washed with water and then dried. 14 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 118°-119° C.; yield: 73.8%)
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]([OH:5])=[O:4])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NC(CCCc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(CCCc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of (±)-2-amino-5-phenyl-pentanoic acid (0.188 g, 0.000973 mol), 4-fluoro-benzenesulfonyl chloride (0.189 g, 0.000971 mol), and sodium carbonate (0.208 g, 0.00196 mol) in water (4 mL) was stirred at room temperature for 4 days. The mixture was heated briefly on a steam bath to give a cloudy solution. The solution was gravity filtered hot, and the filtrate allowed to cool. The resulting solid that crystallized was filtered off, washed with water, and dried in vacuo; yield 0.131 g, (38%). 1H-NMR (DMSO-d6): δ 7.81 (m, 2H), 7.37 (t, 2H), 7.25 (t, 2H), 7.14 (m, 4H), 3.34 (br s, H2), 3.04 (t, 1H), 2.46 (m, 2H), 1.6-1.4 (m, 4H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH3:22])[CH:13]=3)[OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH3:22])[CH:13]=3)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CCOc1cc(C(O)c2ccc3occc3c2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc3occc3c2)ccc1OC

Procedure:
To a stirred solution of benzofuran-5-yl-(3-ethoxy-4-methoxy-phenyl)-methanol (2.36 g crude, 6.8 mmol) in CH2Cl2 (15 mL) at room temperature was added activated MnO2 powder (6.0 g, 69 mmol) and kept adding 2˜3 equivalents of MnO2 every 3˜5 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give benzofuran-5-yl-(3-ethoxy-4-methoxy-phenyl)-methanone as an off-white solid (2.25 g, 111% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)=[O:22]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCc1ccc(N)cc1
Product: COc1ccc(Cl)cc1C(=O)Nc1ccc(CCC(=O)O)cc1

Procedure:
By the reaction of ethyl β-(4-aminophenyl)-propionate hydrocholoride with 5-chloro-2-methoxybenzoyl chloride, there is obtained β-[4-(5-chloro-2-methoxybenzamido)-phenyl]-propionic acid; m.p. 188°-190° C., after recrystallization from ethanol.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:26]=[CH:25][C:9]2[C:10]([CH3:24])([CH3:23])[C:11]3[NH:12][C:13]4[C:18]([C:19]=3[C:20](=[O:21])[C:8]=2[CH:7]=1)=[CH:17][CH:16]=[C:15]([Br:22])[CH:14]=4.COC(=O)CO.[OH-].[Na+].Cl>CO>[Br:22][C:15]1[CH:14]=[C:13]2[C:18]([C:19]3[C:20](=[O:21])[C:8]4[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])[CH:26]=[CH:25][C:9]=4[C:10]([CH3:24])([CH3:23])[C:11]=3[NH:12]2)=[CH:17][CH:16]=1
Reactant: COC(=O)COc1ccc2c(c1)C(=O)c1c([nH]c3cc(Br)ccc13)C2(C)C
Agent: COC(=O)CO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)c2ccc(OCC(=O)O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, (3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-acetic acid methyl ester was prepared from Compound JJ2 and hydroxy-acetic acid methyl ester. The resultant was dissolved in MeOH (0.35 ml), added with aqueous solution of sodium hydroxide (6 mol/l), and stirred at room temperature for 10 min. The reaction solution was added with hydrochloric acid (3 mol/l), extracted with diethyl ether and dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, white solid was obtained, which was then washed with methylene chloride to obtain the title compound (11.2 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.BrN1C(=O)CCC1=O.O.[NH2:21]/[C:22](/[C:27]#[N:28])=[C:23](\[NH2:26])/[C:24]#[N:25]>CS(C)=O.CC(O)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7](=[O:11])[C:6]3[C:5]([C:4]=2[CH:3]=1)=[N:21][C:22]([C:27]#[N:28])=[C:23]([C:24]#[N:25])[N:26]=3
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: N#C/C(N)=C(/N)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1nc2c(nc1C#N)-c1cc(Cl)ccc1C2=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 5-chloro-1-indanone (1.05 g, 6.28 mmol) and N-bromosuccinimide (2.23 g, 12.56 mmol) in DMSO (25 ml) was stirred overnight at 40° C. and 5 h at 80° C. under vacuum. Water (125 ml) was added and the mixture was extracted with CH2Cl2 (25 ml). The aqueous phase was saturated with brine and solid NaCl and extracted with CH2Cl2 (4×80 ml). The collected organic phases were dried over Na2SO4 and the solvent evaporated. The crude was dissolved in EtOH (63 ml), diaminomaleonitrile (678 mg, 6.28 mmol) and a catalytic amount of AcOH were added and the mixture stirred at 80° C. for 45 min. The precipitate was collected by filtration and washed with EtOH (464 mg). The filtered solution was evaporated and the crude purified by flash.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[CH3:33])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:27]1([C:25]([NH:24][C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]4[CH:30]=[CH:31][C:32]([CH3:33])=[C:11]([NH:10][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[S:3][CH:4]=5)=[O:9])[CH:12]=4)=[N:20][N:19]3[CH:21]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
A mixture of 2-methyl-1,3-thiazole-4-carboxylic acid (120 mg, 0.84 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol), 1-hydroxybenzotriazole (110 mg, 0.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.84 mmol), triethylamine (85 mg, 0.84 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0) to give the title compound (180 mg, 62%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40](=[O:43])[CH2:41][CH3:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([N:37]1[CH2:38][CH2:39][N:34]([C:40](=[O:43])[CH2:41][CH3:42])[CH2:35][CH2:36]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCC(=O)N1CCNCC1
Product: CCC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 16 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of 1-(piperazin-1-yl)propan-1-one as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31](OC(N1C[C@@H]2CC[C@H]1CN2)=O)(C)(C)[CH3:32].N1(CC2C=CC([C@@H]3OC4=NC=CC=C4OC3)=CC=2)CCNCC1>>[C@H:10]12[CH2:32][CH2:31][C@H:13]([NH:8][CH2:9]1)[CH2:12][N:11]2[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[O:30][C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[O:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H]1CN2
Agent: c1cnc2c(c1)OC[C@H](c1ccc(CN3CCNCC3)cc1)O2
Product: c1cnc2c(c1)OC[C@H](c1ccc(CN3C[C@@H]4CC[C@H]3CN4)cc1)O2

Procedure:
The title product JJ is prepared from compound JJ-1 (prepared from Intermediate C and (1S,4S)-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester according to General Method J) according to the procedure used to synthesize Intermediate S.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([NH:25][CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])([CH3:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(N)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNC(C)(C)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
2-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-2-amine (113 mg, 0.33 mmol, 1.0 eq.) and methyl acrylate (86 mg, 0.99 mmol, 3.0 eq.) was dissolved in MeOH (2 mL). The mixture was reflux for 16 h. The mixture was concentrated and purified by silica gel chromatography (DCM:MeOH−20:1) to give the title compound (100 mg, 71%) as a slight yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.73-7.68 (m, 3H), 7.60 (dd, 1H), 7.13-7.16 (m, 2H), 4.26-4.23 (m, 1H), 3.66 (s, 3H), 2.62 (t, 2H), 2.50 (t, 2H), 2.28-2.26 (m, 2H), 1.90-1.87 (m, 2H), 1.58 (s, 6H), 1.45-1.38 (m, 2H), 1.19-1.09 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16][CH2:17]Br.[OH-].[K+]>CCOCC.CS(C)=O.C1OCCOCCOCCOCCOCCOC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:12]#[N:13])[CH2:17][CH2:16][CH2:15]1
Reactant: BrCCCBr
Reactant: N#CCc1ccc2ccccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccc3ccccc3c2)CCC1
Temperature: 15 °C
Yield: 392.9 %

Procedure:
A solution of 2-naphthylacetonitrile (10 g) and 1,3-dibromopropane (144 g) in a mixture of ether (350 ml) and dimethylsulphoxide (150 ml) was added dropwise at 20-25° C. under nitrogen over 2 hours to a stirred mixture of finely-powdered potassium hydroxide (150 g), 18-Crown-6 (1.3 g) and dimethylsulphoxide (570 ml). After the addition was complete, the mixture was cooled to 15° C. and quenched by the slow addition of water (330 ml). Ether (330 ml) was added, and the mixture was filtered through Hyflo Supercel filtration aid. The filter pad was washed well with ether, then the aqueous layer of the filtrate was separated, diluted with water (500 ml), and washed well with ether. All of the ethereal solutions were combined, washed with water (3×100 ml), and the solvents were removed in vacua. The residue was triturated with ethanol (100 ml) and the resulting solid was collected by filtration and dried in vacua to give 1-(2-naphthyl)cyclobutanecarbonitrile as a white solid (48.7 g), which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].CN1CCOCC1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][NH2:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[C:15]1([CH2:14][O:21][C:22]([NH:24][CH2:25][CH2:26][NH:27][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: CN(C)C(=O)NCCNC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 49.6 %

Procedure:
A solution of dimethylcarbamoyl chloride (1.39 g) in diethyl ether (15 ml) was added dropwise to a stirred solution of NMM (1.57 g) and 2-benzyloxycarbonylaminoethylamine (3.02 g) in diethyl ether (110 ml). The mixture was stirred for four hours and allowed to stand for two days. After evaporation of the ether the residual solid was partitioned between 10% aqueous citric acid and ethyl acetate. The ethyl acetate extracts were washed with 10% aqueous citric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, and then dried (Na2SO4) and evaporated to give a solid (1.7 g). A sample crystallised from ethyl acetate/patroleum ether (bp 60°-80°) m.p. 81°-82°.