Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:19]S(C(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].Cl.O1CCOCC1>CO>[NH2:19][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCC(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 5-(2,6-dimethoxyphenyl)-5-(1,1-dimethylethylsulfinamido)pentanoate (5.560 g; 14.96 mmol) in MeOH (115 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (7.5 ml; 30.00 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The obtained yellow solution was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate as a yellow oil. LC-MS (conditions B): tR=0.73 min.; [M+H]+: 268.01 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(F)cc1F
Yield: 96 %

Procedure:
2′,4′-difluoroacetophenone (5 g, 32 mmol) was reacted with sodium borohydride (1.21 g) in THF (20 mL) and methanol (10 mL) for 1 hr. The resultant mixture was evaporated to dryness and partitioned between methylene chloride and water. The organic layer was separated, dried, and evaporated to give 1-(2′,4′-difluorophenyl)-ethanol as a colorless oil (4.86 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 5.15 (q, 1H), 2.0 (s, 1H), 1.5 (d, 3H). 1-(2′,4′-difluorophenyl)-ethanol (5.384 g, 34 mmol), t-butyltrimethylsilyl chloride (6.148 g, 40.8 mmol) and imidazole (5.567 g, 81.8 mmol) in DMF (60 mL) were combined and stirred at rt overnight. The resultant mixture was evaporated to dryness in vacuo, and then the residue was partitioned between methylene chloride and water. The organic layer was separated, dried and evaporated to give 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether as a white solid (6.88 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.45 (q, 1H), 6.75 (m, 1H), 6.62 (m, 1H), 5.05 (q, 1H), 1.32 (d, 3H), 0.88 (s, 9H), 0.05 and 0.01 (each s, each 3H). A 1.6 M solution of n-butyl lithium in hexane (3.75 mL, 6 mmol) was added dropwise to a solution of 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether (1.362 g, 5 mmol) in THF (60 mL) at −50° C. and was stirred at the same temperature for 3 h. The reaction mixture was poured to dry ice; and then was evaporated to dryness. The residue was partitioned between methylene chloride and water, acidified with acetic acid. The organic layer was separated, dried, and evaporated to give 2,6-difluoro-3-(1-t-butyltrimethylsilyloxyethyl)-benzoic acid Compound 5A as white solid (1.57 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.70 (q, 1H), 7.00 (t, 1H), 6.00 (br, 1H), 5.15 (q, 1H), 1.40 (d, 3H), 0.90 (s, 9H), 0.12 and 0.05 (each s, each 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([O:33][CH3:34])[CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[CH2:37](OC(=O)C1C=CC(N)=CC=1OC)[CH3:38]>>[CH2:37]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:35][CH3:36])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:22])=[CH:25][C:26]=1[O:33][CH3:34])[CH3:38]
Reactant: COc1cc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)ccc1C(=O)O
Reactant: CCOC(=O)c1ccc(N)cc1OC
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1OC

Procedure:
4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methoxy-benzoic acid, MS (ISP): m/e=531.0 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using 4-amino-2-methoxy-benzoic acid ethyl ester and yielded 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methoxy-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:26][O:25][C:17]1[C:16]2[C:6]3[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24]
Reactant: COc1ccc(CCCCc2cc(OC)c(OC)c(OC)c2)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)-c1c(cc(OC)c(OC)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 24.4 %

Procedure:
In 1 ml of dichloromethane, 70 mg (0.194 mmol) of 1-(3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-butane were dissolved. The solution was added with 0.1 ml of trifluoroacetic acid and 180 mg (0.39 mmol) of ferric perchlorate, followed by stirring at room temperature for 40 minutes. The reaction mixture was dissolved in 20 ml of ethyl acetate. The resulting solution was washed with 2N-HCl and then with saturated NaCl. The organic layer was dried over anhydrous magnesium sulfate and the solvent was thereafter distilled off under reduced pressure, whereby brown oil was obtained. The oil thus obtained was purified by thin-film chromatography (silica gel: "MERCK #5744", eluent: 1:5 mixed solvent of ethyl acetate and hexane), whereby 17 mg of the title compound were obtained as colorless oil (yield: 24%). In addition, the starting material was recovered as colorless oil (15 mg, recovery: 21%).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-].[Na+].S(=O)(=O)(O)[OH:16]>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Temperature: 40 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1.77 kg (10 mol) of 2,3,4-trifluoronitrobenzene are added to 2 l of water, and the mixture is warmed to 40° C. and vigorously stirred. 1760 g (22 mol) of 31.7% strength sodium hydroxide solution are then added dropwise in such a way that the temperature does not rise above 60° C. After about 2 h, GC checking no longer shows any starting compound. The reaction mixture is brought to pH 2.5 using 70% strength sulfuric acid. Steam is then passed into the solution, the product passing over with the steam. The separated solution is cooled to 10° C. with stirring and the precipitated solid is filtered off with suction. The water having a residual content of about 0.1% of 2,3-difluoro-6-nitrophenol can be used in a subsequent batch. 1.48 kg of 2,3-difluoro-6-nitrophenol having a purity >99.9% (GC) are obtained after drying (melting point 64° C.), which corresponds to a yield of 85% of theory.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][N:14]([CH3:27])[C:15]3[N:19]([CH3:20])[C:18]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[N:17][N:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:27][N:14]([CH2:13][C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:28]#[N:29])[N:9]=1)[C:15]1[N:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:17][N:16]=1
Reactant: CN(C)C=O
Reactant: CN(Cc1nnn(-c2cccc(I)c2)n1)c1nnc(-c2ccncc2)n1C
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(Cc1nnn(-c2cccc(C#N)c2)n1)c1nnc(-c2ccncc2)n1C

Procedure:
The title compound is prepared from [2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.Cl>CCCCCC.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][C:6]([B:18]([OH:21])[OH:19])=[CH:5]2)=[CH:10][CH:11]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2ccc(Br)cc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccc(Br)cc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
First, 3.0 g of 2,7-dibromonaphthalene was placed into a 500-mL three-neck flask, and the air in the flask was replaced with nitrogen. To this compound was added 150 mL of tetrahydrofuran (THF), and this solution was stirred at −78° C. for 20 minutes. Then, 6.4 mL of a 1.7M hexane solution of n-butyllithium (n-BuLi) was dripped into this mixture solution, followed by stirring at −78° C. for 2 hours. After the predetermined time had elapsed, 2.4 mL of trimethyl borate was added to the mixture and this solution was stirred for 18 hours while the temperature was raised to room temperature. After the predetermined time had elapsed, 60 mL of 1.0M hydrochloric acid was poured into this solution, and the mixture was stirred for 1 hour. Then, this mixture solution was separated into an organic layer and an aqueous layer. Organic substances were extracted with ethyl acetate from the obtained aqueous layer. The solution of the extract was combined with the organic layer that had been first obtained, and the mixture was washed with saturated brine and dried by addition of anhydrous magnesium sulfate to the organic layer. Then, the filtrate obtained by gravity filtration was concentrated to give a white solid. The obtained white solid was washed with a mixed solvent of hexane and toluene, whereby 7-bromonaphthalene-2-boronic acid was obtained (as a white powder in 75% yield). The synthesis scheme of Step 1 is illustrated in the following (a-5).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH2:10][CH2:9][N:8]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:14]([N:12]([CH3:13])[C@@H:11]1[CH2:10][CH2:9][N:8]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:7][C@H:6]1[CH2:4][OH:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@@H]1CN(CCc2ccc(F)cc2)CC[C@H]1N(C)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.1 %

Procedure:
A solution of trans-4-(benzyl-methyl-amino)-1-[2-(4-fluorophenyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester (144 mg, 361 μmol) in tetrahydrofuran (1 mL) was treated with a solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 723 μL, 723 μmol). The mixture was stirred at room temperature for 2.5 hours, then was treated very slowly with 28 μL of water, followed by 28 μL of 15% aqueous sodium hydroxide, then by 84 μL of water. The mixture was filtered and the solid was washed with ether. The filtrate and washes were combined and concentrated under vacuum to provide a white solid (116 mg, 90%). 1H NMR (300 MHz, CDCl3) δ7.34 (m, 5H), 7.15 (m, 2H), 6.98 (t, J=9 Hz, 2H), 6.26 (bs, 1H), 3.78 (d, J=13 Hz, 1H), 3.60 (m, 2H), 3.50 (m, 1H), 3.10 (m, 1H), 2.87 (m, 1H), 2.78 (m, 2H), 2.54 (m, 2H), 2.28 (s, 3H), 2.20 (m, 1H), 1.88 (m, 2H), 1.75 (m, 1H), 1.58 (m, 1H). Mass spec (ES+) m/z 357.3 (M+H+).
Reaction SMILES: [Cl:1]Cl.[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1>C(O)(=O)C>[Cl:1][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[OH:3])[CH:8]=[O:9]
Reactant: ClCl
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: O=Cc1ccc(O)c(Cl)c1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
Acetic acid (300 ml) was bubbled with chlorine gas to make 38.38 g (0.541 mol) of chlorine. 4-Hydroxybenzaldehyde (66.1 g, 0.541 mol) was dissolved in acetic acid (300 ml) and stirred, during which the acetic acid solution containing chlorine as prepared above was slowly added thereto over 2 hours. The resulting mixture was stirred for further 2 hours. After completion of reaction, the reaction solution was concentrated. To the residue was added water (1L), which was then filtered, washed with water (500 ml) and dried to give 63.16 g (0.403 mol, Yield 75%) of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[CH2:37]([N:44]=[C:45]=[S:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:37]([NH:44][C:45]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)=[S:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: S=C=NCc1ccccc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=S)NCc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.9 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), benzyl isothiocyanate (248 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→3:1→4:1 as the eluant to afford the title compound (291 mg, mp 174.8-177.2° C.).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[C:8]([CH:7]=1)[CH:9]=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
Fuming nitric acid (200 mL) was added to sulphuric acid (400 mL) at 0° C. and then 3-bromobenzaldehyde (100 g, 0.54 mol) was added dropwise in 15 minutes. After stirring for 10 minutes at the same temperature, the reaction mixture was poured into ice water and filtered to afford the mixture of products which was purified by flash column chromatography eluting with PE/EtOAc (100/1 to 20/1) to give 5-bromo-2-nitrobenzaldehyde as white solid (60 g, 48%). 1H-NMR (CDCl3, 400 MHz) δ 10.41 (s, 1H), 8.02˜8.06 (m, 2H), 7.88 (s, 1H). MS (M+H)+: 230/232.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:8][CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)[CH:5]([CH3:7])[CH3:6])[CH3:3].O.NN.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:36].Cl>C(O)C.CO>[ClH:36].[ClH:36].[CH3:1][CH:2]([N:4]([CH:5]([CH3:7])[CH3:6])[CH2:8][CH2:9][NH2:10])[CH3:3]
Reactant: CC(C)N(CCN1C(=O)c2ccccc2C1=O)C(C)C
Agent: Cl
Agent: NN
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(C)N(CCN)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 40.54 g (0.148 mole) of 2-[2-[[N,N-bis(1-methylethyl)amino]ethyl]-2H-isoindole-1,3-dione and hydrazine hydrate (85%, 11.8 g, 0.2 mole) in 400 ml of 95% ethanol was heated at reflux for 5 hours. The reaction mixture was allowed to cool to room temperature while standing overnight. A white solid formed. The reaction mixture was concentrated almost to dryness on the rotary evaporator. The residue was dissolved in chloroform and extracted with 10% sodium hydroxide. After removing chloroform, a brown oil was obtained. A portion of the oil was dissolved in methanol and converted to the dihydrochloride salt. After recrystallization from methanol-diethyl ether, 1.50 g (20%) of white crystalline product, m.p. 178°-182° C. (decomposition) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.I.[NH2:31][C:32]1[C:33]([C:40]([NH:42][C:43](=[NH:46])SC)=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1>C(O)C>[NH2:31][C:32]1[C:33]([C:40]([N:42]=[C:43]([NH2:46])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:8][CH:7]=2)=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1
Reactant: NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N-phenylacetamide 19 (100 mg, 0.35 mmol) and triethylamine (0.14 mL, 1.00 mmol) in absolute ethanol (2 mL) was stirred at 60° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methyl-isothiourea hydriodide (140 mg, 0.37 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 4 h, cooled to room temperature, and concentrated by rotary evaporation. The crude residue was triturated with water and filtered. The filter cake was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (500:10:0, 500:10:1, 200:10:1, v/v) to give 2-(4-{4-[N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-phenyl acetamide (20, PSA 17482) as a yellow solid (120 mg, 67% yield). mp 168-170° C. 1H NMR (300 MHz, DMSO-d6) δ 1.55 (m, 4H), 2.55 (m, 2H), 3.16 (m, 2H), 4.65 (s, 2H), 6.60 (br s, 2H), 6.90 (d, 2H), 7.08 (m, 2H), 7.15 (d, 2H), 7.30 (m, 5H), 7.60 (d, 2H), 9.00 ( br s, 1H), 10.00 (br s, 1H). m/z (ESI): 511 [C24H27ClN8O3+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CC(C)(O)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)O)n2)c(C(N)=O)nn1
Temperature: 120 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
A dry 50 mL round bottom flask was charged with 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (241 mg, 783 μmol) dissolved in NMP (2.00 mL) To this solution was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (168 mg, 783 μmol) and the reaction mixture was heated in an oil bath with stirring at 120° C. for 18 h. After that, it was added more tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (168 mg, 783 μmol) in small portions during 7 hours. After last addition, the reaction was continued for 18 h. After cooling to room temperature, the solvent was distilled off under high vacuum, the residue was dissolved in dichloromethane containing few drops of methanol and then purified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to yield tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (179 mg, 47.1% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 11.54 (br. s., 1H), 8.16 (br. s., 1H), 8.04 (s, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 6.53-6.70 (m, 1H), 5.81 (d, J=3.4 Hz, 1H), 5.43 (br. s., 1H), 3.71-4.14 (m, 3H), 1.23-1.90 (m, 23H); LC-MS 486.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.Cl.[CH3:50][NH:51][O:52][CH3:53]>ClCCl>[CH3:53][O:52][N:51]([CH3:50])[C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNOC
Reactant: O=C(O)c1ccccc1CCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1CCc1ccccc1

Procedure:
A mixture of 3 g (13.2 mmol) of 2-phenethylbenzoic acid, 3.8 g (19.8 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 2.7 g (20.0 mmol) of 1-hydroxybenzotriazole hydrate, 3 ml (23 mmol) of N-ethylmorpholine and 1.94 g (19.9 mmol) of N,O-dimethylhydroxylamine hydrochloride was stirred in 50 ml of dichloromethane at room temperature for 2 hours. The solution was diluted with dichloromethane and washed sequentially with saturated aqueous citric acid solution and saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated to afford N-methoxy-N-methyl-2-phenethylbenzamide as a colorless oil. To a solution of 1 g (3.7 mmol) of this oil in 10 ml tetrahydrofuran at 0° C. was added 2.2 ml of a 1M solution of lithium aluminium hydride in tetrahydrofuran. The solution was stirred at 0° C. for 25 minutes and saturated aqueous potassium hydrogensulphate and ether were then added and the mixture stirred at room temperature for 30 minutes. The layers were separated and the organic layer washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated to afford 2-phenethyl-benzaldehyde as a colorless oil which was used directly without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2cccc(OC)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 75.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.18 g of 3-methoxyphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.23 g of 4-(3-methoxyphenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (30)).