Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5](/[CH:6]=[CH:7]/[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:4][CH:3]=1.BrC[CH:19]1[CH2:21][CH2:20]1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:10]2[CH2:11][CH:19]2[CH2:21][CH2:20]2)=[CH:15][CH:16]=1
Reactant: BrCC1CC1
Reactant: Fc1ccc(/C=C/CC2CCCCN2)cc1
Solvent: CC#N
Product: Fc1ccc(/C=C/CC2CCCN2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
In a reactor protected from moisture, there are introduced 2.3 g (0.010 mol) of (E)-2-(p-fluorocinnamyl)piperidine (Preparation 2B) dissolved in 25.2 ml acetonitrile, followed, during 2 min, by 1.56 g (1.1 ml-0.012 mol) bromomethylcyclopropane. The medium is kept stirring at ambient temperature for 1 h 30 min, is raised to 60° C. for 4 h, and is then lowered to 20°±3° C. for 16 h. The solvent is evaporated under vacuum and on a water bath. The oily residue is dissolved in water, acidified and extracted with ether. After decanting, the cooled aqueous phase is alkalinized with soda, extracted with ether and washed with saturated NaCl solution. The organic phase is dehydrated over Na2SO4 and the solvent is then removed by distillation. The residue is purified by the Chromatoflash technique, elution being carried out with a 90:10 v/v mixture of methylene chloride and 10% ammoniacal MeOH, and is then subjected to a second acid-alkali treatment. (E) -2-(p-fluorocinnamyl)-1-(cyclopropylmethyl)pyrrolidine is obtained in the form of a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([N:13]2[C:17]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:16](=[O:23])[NH:15][C:14]2=[O:24])=[CH:9][CH:8]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:15]1[C:16](=[O:23])[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH3:25])=[CH:12][CH:11]=2)[C:14]1=[O:24])[CH3:32]
Reactant: Cc1ccc(N2C(=O)NC(=O)C23CCCCC3)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)N(c2ccc(C)cc2)C2(CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
17.9 g (0.130 mol; 1.1 eq.) of potassium carbonate are added to a solution of 30.4 g (0.117 mol; 1 eq.) of 1-p-tolyl-1,3-diazaspiro[4.5]decane-2,4-dione in 150 ml of DMF, and 16 ml (0.141 mol; 1.2 eq.) of ethyl bromoacetate are then added dropwise to the reaction medium. The cream-coloured reaction medium suspension is stirred at room temperature for 18 hours. The reaction medium is poured into 300 ml of water and the white precipitate is filtered off, rinsed with water and then dried in an oven under vacuum at 40° C. for 48 hours. The product (2,4-dioxo-1-p-tolyl-1,3-diaza-spiro[4.5]dec-3-yl)acetic acid ethyl ester is obtained in the form of a white solid.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([O-:19])=[O:18])[CH:13]=[C:14]([Cl:16])[CH:15]=1.Br[C:21]1[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=1>O.CN(C)C=O>[Cl:16][C:14]1[CH:13]=[C:12]([S:17]([C:21]2[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)(=[O:19])=[O:18])[CH:11]=[C:10]([Cl:9])[CH:15]=1
Reactant: FC(F)(F)c1nnc(Br)s1
Reactant: O=S([O-])c1cc(Cl)cc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)c1nnc(C(F)(F)F)s1
Yield: 70 %

Procedure:
A solution of 75.6 g (0.6 mole) of analytically pure sodium sulfite in 300 ml of water was pre-warmed to 60°-70° C in a beaker. 122.8 g (0.5 mole) of 3,5-dichlorobenzenesulfochloride, and a solution of 40 g (1 mole) of sodium hydroxide in 200 ml of water were synchronously added dropwise from two dropping funnels in such a way that the pH value (measured with an electrode in the reaction solution) was always between 7 and 9; during the addition the mixture was stirred magnetically. The saline solution of the 3,5-dichlorobenzenesulfinate (about 600 ml) was then diluted with 1.8 liters of dimethylformamide and after adding 116.5 g (0.5 mole) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole the whole was stirred for 15 hours at 50° C. The sulfone was precipitated completely by adding ice water and was recrystallized from ethanol. 121 g (70% of theory) of 2-(3',5'-dichlorophenylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 123° C were obtained.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Na].[CH2:14](Br)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCBr
Reactant: OCCCCCCCCCCO
Agent: [Na]
Product: CCCCOCCCCCCCCCCO
Yield: 62 %

Procedure:
Monosodium decane-1,10-diol is reacted with n-butyl bromide to give oily 10-n-butoxydecanol in a yield of 62% of theory. This is brominated with phosphorus tribromide in the presence of pyridine to give an oily product in a yield of 37% of theory. After reaction of this 10-n-butoxydecyl bromide with monosodium ethylene glycol, there is obtained oily 10-n-butoxydecyloxyethanol in a yield of 36% of theory, which is reacted with phosphorus tribromide in the presence of pyridine to give oily 10-n-butoxydecyloxyethyl bromide in a yield of 52% of theory. This is then reacted with methyl β-mercaptopropionate in the presence of sodium methylate to give a yield of 49% of theory of oily methyl β-(10-n-butoxydecyloxyethylthio)-propionate, reduction of which with lithium aluminium hydride gives a yield of 90% of theory of 3-(10-n-butoxydecyloxyethylthio]-propanol; m.p, 23°-27° C.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]([N:16]1[CH2:17][CH2:18][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:15]1)=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Temperature: 0 °C
Yield: 217.8 %

Procedure:
Triphosgene (25 g, 84.2 mmol) was taken into dichloromethane (200 mL) and the resulting solution cooled to 0° C. A solution of tert-butyl 1-piperazinecarboxylate (40 g, 214.8 mmol) and pyridine (35 mL, 432.7 mmol) in dichloromethane (100 mL) was then added dropwise to the triphosgene solution and the reaction mixture was allowed to warm to room temperature over 30 minutes. The mixture was then quenched by addition of aqueous hydrochloric acid (0.1N, 200 mL) and the aqueous phase washed with dichloromethane (50 mL) followed by drying the combined organic layers over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave tert-butyl 4-chlorocarbonyl-1-piperazinecarboxylate (45.6 g, 85%) as a yellow solid which may be used without further purification. The material can be purified further by crystallization from ethyl ether/hexane.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17](=[O:31])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[NH2:30])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[C:12]([O:16][C:17](=[O:31])[CH2:18][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[NH2:30])[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(Cc1ccc([N+](=O)[O-])cc1N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
Benzyl chloroformate (6.8 mL, 48 mmol) was added slowly to a solution of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (9.08 g, 32 mmol) and triethylamine (13.5 mL, 97 mmol) in dry methylene chloride (300 mL) at 0° C. The mixture was stirred for 2 h and warmed to room temperature for another 1 h. The mixture was concentrated and chromatograph with hexanes and ethyl acetate to give [(2-amino-4-nitro-benzyl)-benzyloxycarbonyl-amino]-acetic acid tert-butyl ester (8.39 g) as a yellow solid (62%): 1H NMR (300 MHz, CDCl3) δ 7.58 (br, 1H), 7.5 (d, 1H), 7.3 (br, 5H), 7.12 (d, 1H), 5.15 (s, 2H), 4.55 (s, 2H), 3.78 (s, 2H), 1.33 (s, 9H); MS (m/e): 416.3 (M+1).
Reaction SMILES: [OH-].[Li+].[C:3]([CH2:11][NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([NH:32][C:33]([CH3:43])=[CH:34][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.C1COCC1>[C:3]([CH2:11][NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([NH:32][C:33]([CH3:43])=[CH:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)NC(C)=CC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=CC(=O)c1ccccc1)N[C@@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)C(=O)O
Reaction time: 16 h
Yield: 16.6 %

Procedure:
1.7 ml (1.70 mmol) of an aqueous 1M lithium hydroxide solution are added to a solution containing 620 mg (1.13 mmol) of methyl (S)-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-(1-methyl-3-oxo-3-phenyl-propenylamino)propionate in 10 ml of a methanol/THF mixture (3/1). After stirring for 16 h, the medium is acidified with 1N hydrochloric acid until pH=4, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on a column of silica and eluted with a heptane/ethyl acetate mixture. 100 mg of (S)-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-(1-methyl-3-oxo-3-phenylpropenylamino)propionic acid are isolated with a 17% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][CH:8]([C:10]1[C:19]([C:20](OCC)=[O:21])=[C:18]([OH:25])[C:17]2[C:12](=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:9].Cl>>[Cl:7][CH:8]([C:10]1[C:19]([C:20]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:21])=[C:18]([OH:25])[C:17]2[C:12](=[C:13]([C:26]([F:29])([F:27])[F:28])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:9]
Reactant: Nc1nccs1
Reactant: CCOC(=O)c1c(C(C)Cl)nc2c(C(F)(F)F)cccc2c1O
Agent: Cl
Product: CC(Cl)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1

Procedure:
Using the procedure of Example 4, 1.5 g of 2-aminothiazole and 1.041 g of the product of Step A were reacted and after the addition of N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with ethyl acetate to obtain 2-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide which after crystallization from ether melted at ≃190° C. (decomposition).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].[H][H]>N.C1(C)C=CC=CC=1.[Rh]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: [H][H]
Reactant: CCOC(=O)CCC(CC=Cc1cccnc1)CCCC#N
Agent: [Rh]
Agent: N
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(CCCCN)CCCc1cccnc1

Procedure:
A solution of 125 g of ethyl 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptenoate in 825 ml of 9.53% ethanolic ammonia is added to a slurry of 62.5 g of 5% rhodium on carbon (50% water wet) in 300 ml of 9.53% ethanolic ammonia. The mixture is hydrogenated at about 3 atmospheres pressure (50 psi=3.45 bar) until theoretical uptake of hydrogen (4 moles) for saturation of the nitrile and double bond is obtained (about 12 h). The catalyst is then filtered off, washed with methylene chloride and ethanol, and the filtrate is evaporated to dryness to yield a residue which is redissolved in toluene. Evaporation to dryness yields ethyl 8-amino-4-[3-(3-pyridyl)propyl]-octanoate.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:20][CH2:21][C:22](Br)=[O:23].Cl>ClCCl>[Br:20][CH2:21][C:22]([C:8]1[CH:9]=[CH:10][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:6][CH:7]=1)=[O:23]
Reactant: OCCCCCCCCc1ccccc1
Reactant: O=C(Br)CBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc(CCCCCCCCO)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (200 mg, 1.50 mmol, 3.0 eq.) was suspended in dry dichloromethane (8 mL) and cooled to 0° C. 8-phenyl-1-octanol (0.11 mL, 0.50 mmol) and bromo acetylbromide (53 μL, 0.60 mmol, 1.2 eq.) were added dropwise. After 20 min the mixture was warmed to r.t. and stirred overnight. The reaction was stopped by pouring the solution into a mixture of ice water (25 mL) and concentrated hydrochloric acid (10 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (1×10 mL) and brine (1×10 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 12×4 cm, cyclohexane/ethyl acetate, 8:1). The product was isolated as colourless oil. Yield: 120 mg (73%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[O:22])[CH2:12][CH2:11]1)=[O:7])(C)(C)C.[ClH:33].O1[CH2:39][CH2:38][O:37][CH2:36]C1>>[NH2:25][C:26]1[C:27]([Cl:33])=[CH:28][C:39]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH3:32])[CH:24]=3)=[O:22])[CH2:12][CH2:11]2)=[O:7])=[C:38]([O:37][CH3:36])[CH:31]=1
Reactant: C1COCCO1
Reactant: Cn1cc(C(=O)NCCCCN2CCC(CNC(=O)OC(C)(C)C)CC2)c2ccccc21
Reactant: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2cn(C)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
N-(4-(4-tert-Butoxycarbonylaminomethylpiperidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide (1.40 g) was dissolved in 4N hydrochloric acid-dioxane solution (50 ml) and the mixture was stood at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure. Dimethylformamide (30 ml) was added to the residue and the mixture was neutralized with triethylamine (1.45 ml). 4-Amino-5-chloro-2-methoxybenzoic acid (0.64 g) and 1-hydroxybenzotriazole (0.49 g) were added thereto, and the mixture was stirred at 0° C. for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.63 g of N-(4-(4-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)-piperidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20](C(Cl)=O)=[CH:19][CH:18]=1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][NH2:38]>>[C:26]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:27]=[CH:28][C:29]([C:6]([N:8]2[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]2[C:10]([NH:38][CH2:37][C:33]2[O:32][CH:36]=[CH:35][CH:34]=2)=[O:12])=[O:7])=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCc1ccco1
Product: C=C1C[C@@H](C(=O)NCc2ccco2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonyl chloride, and 2-furylmethylamine the title compound was obtained in 94% purity by LC/MS. MS(ESI+): m/z=387.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.[NH2:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16]>C(O)C>[ClH:12].[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16])[N:3]=1
Reactant: CC(C)(N)CN
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: CC(C)(N)CNc1nc(N)nc(O)c1[N+](=O)[O-]
Product: Cl
Reaction time: 8 h
Yield: 97 %

Procedure:
2-Amino-6-chloro-4-hydroxy-5-nitropyrimidine, 1.94 g, was finely powdered and dissolved in approximately 200 ml boiling absolute ethanol and filtered while hot to remove the insoluble 2-amino-4,6-dihydroxy-5-nitropyrimidine (sole contaminant), leaving a solution containing 9.0 mmoles of (IIa). This was taken again to reflux and 0.88 g (20 mmoles) 1,2-diamino-2-methylpropane (99% pure) added all at once with stirring. The progress of the reaction was monitored on Partisil SCX (25×0.46 cm) eluted with 0.1M ammonium hydroxide made to pH 3.3 with formic acid/methanol, 9:1, by absorbance at 254 and 330 nm. After 2 hrs stirring at reflux, greater than 99% of (IIa) had been consumed and the majority of product had fallen out of solution. After being kept at -15° C. overnight in order to complete this precipitation, the reaction filtered, washed with a few ml cold absolute ethanol and 40 ml ether, and vacuum dried over P2O5, gave 2.43 g of the monohydrochloride salt (97% yield): UV (0.1N HCl) εmax 331 nm, 285-290 nm sh, 233 nm sh; 1H-NMR (DMSO-D6) δ1.13 (6H, s, C(CH3)2), δ3.50 (2H, d, J=5Hz, --N--CH2 (singlet if D2O added). Greater than 99% of the UV330 and 98% of the UV254 absorbance in a chromatogram of this material resides in a single well-shaped peak. No evidence for the presence of any 2-amino-6-(2-amino-1,1-dimethylethylamino)-4-hydroxy-5-nitropyrimidine can be seen by ether HPLC or NMR.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5]C=C(C)C=1.[CH2:9]([O:13]CC1OC1)[CH:10]1[O:12][CH2:11]1.C1(CN)C=CC=C(CN)C=1.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>C(O)CO.C(C1OC1)Cl>[CH2:9]([O:13][CH2:5][CH2:6][CH2:1][CH3:8])[CH:10]1[O:12][CH2:11]1
Reactant: Cc1cccc(C)c1
Reactant: C(OCC1CO1)C1CO1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: NCc1cccc(CN)c1
Solvent: ClCC1CO1
Solvent: OCCO
Product: CCCCOCC1CO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 210 %

Procedure:
In the same reaction vessel as in Example 1 was fed 270 g of the modified polyamine synthesized in Production Example 1 (corresponding to the modified polyamine based on 1 mol of metaxylene, 0.125 mol of methoxypolyethylene glycol and 0.14 mol of epichlorohydrin), and then 186 g (1 mol) of 2-ethylehexyl glycidyl ether (epoxy equivalent of 186, produced by NOF Corporation, the trademark "Epiol EH") was added dropwise thereto over one hour at 80° C. in an atmosphere of nitrogen under stirring. After the completion of the dropwise addition, the reaction was carried out for one hour at a reaction temperature raised 100° C. Then, the vessel interior was cooled to 80° C., and then 231 g (1.70 mol) of metaxylylenediamine was added thereto. Then, a mixture of 307 g (0.807 mol) of epoxy resin in a liquid form of bisphenol A type (epoxy equivalent 190, produced by Yuka Shell Epoxy Co., Ltd., the trademark "Epicoat 828) with 278 g (2.1 mol) of butyl glycidyl ether (epoxy equivalent of 132, produced by NOF Corporation, the tradmark "Epiol B") was added dropwise thereto over one hour at 80° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:18])=[O:17])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:11]([O:35][CH3:36])[N:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C(N(C(C)C)C(C)C)C.Cl.[NH2:47][OH:48].Cl>O1CCOCC1>[OH:48][NH:47][C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([O:35][CH3:36])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:17])=[O:18])[N:14]=2)[CH:6]=[CH:5][N:4]=1)=[NH:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C#N)c2)nc1OC
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=N)NO)c2)nc1OC

Procedure:
A suspension of 100 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-cyano-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 19, in dioxane (10 ml) was treated at RT with 0.17 ml of N-etyldiisopropylamine then with 69 mg of hydroxylamine hydrochloride and refluxed 12 h until the reaction was complete according to TLC analysis. The mixture was poured into cold diluted HCl and the product extracted into AcOEt. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The solid residue was crystallised from CH2Cl2/Et2O to afford N-hydroxy-4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxamidine as off-white crystals. ISN mass spectrum, m/e 536.2 (M−1 calculated for C24H23N7O6S: 536).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:3]2[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]3/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/3)[CH2:5][CH2:4]2)=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=1
Reactant: O=Cc1ccc(Br)cc1C(F)(F)F
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)thiazol-2(5H)-one dihydrochloride (1.50 g) in DMF (23.3 mL) were added 4-bromo-2-(trifluoromethyl)benzaldehyde (1.99 g) and triethylamine (2.93 mL). The reaction mixture was stirred at room temperature for 1.5 hr, and sodium triacetoxyborohydride (3.34 g) was added. The reaction mixture was stirred at room temperature for 1 hr and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g).
Reaction SMILES: [CH3:1]O.[Cl:3][C:4]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O>C1C=CC=CC=1>[Cl:3][C:4]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:1])=[O:7]
Reactant: COc1ccc(C(=O)O)c(Cl)c1C
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OC)c(C)c1Cl
Reaction time: 18 h
Yield: 76 %

Procedure:
To 150 ml methanol, was dissolved 2-chloro-4-methoxy-3-methylbenzoic acid in an amount of 16.6 g (0.0832 mole), and the resulting solution was stirred for 18 hours under reflux and heating following to the addition of concentrated sulfuric acid in an amount of 1.0 g into the solution. The residue obtained by distillating out the solvent under reduced pressure was dissolved in benzene, washed with 3% aqueous solution of sodium hydrogencarbonate and subsequently with saturated saline solution and dried with anhydrous magnesium sulfate. After distillating out the solvent in the solution under reduced pressure, the crystals remained were washed with methanol to obtain methyl 2-chloro-4-methoxy-3-methylbenzoate in an amount of 13.5 g. The yield was 76.0%.