Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH3:12])[CH2:5][NH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([CH3:12])[CH2:5][N:6]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C(C)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Yield: 101.3 %

Procedure:
Under an argon atmosphere, a solution of 26.86 g (0.145 mole) of (rac)-3-cyclopentylamino-2-methyl-propanoic acid methyl ester in 25 mL of ethyl acetate was added over 5 minutes to a cooled (5 degrees) and stirring mixture of 28.13 g (0.145 mole) of 2,4-dichloro-5-nitro-pyrimidine, 48.72 g (0.58 mole) of sodium bicarbonate and 300 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The mixture was concentrated under reduced pressure to give 50.37 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-propanoic acid methyl ester (IV-1) as a thick oil, which contained a small portion of a regioisomer. This material was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10]Br.[C:12]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][CH2:23]1
Reactant: Clc1cccc(Cl)c1CCBr
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCc2c(Cl)cccc2Cl)CC1)c1ccccc1
Yield: 41.1 %

Procedure:
2-(2,6-Dichlorophenyl)ethyl bromide (674 mg.) was reacted with 4-benzamidopiperidine (547 mg.) in the presence of anhydrous potassium carbonate (736 mg.) following the procedure of Example 12 to give the title compound as the hydrochloride (412 mg.) m.p. 285.7° C. after crystallisation from ethanolic hydrogen chloride and ether. (Found: C, 58.0; H, 5.6; N, 6.7. C20 22Cl2N2O. HCl requires C, 58.05; H, 5.6; N, 6.8%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1F
Yield: 86.2 %

Procedure:
The same procedures as in Example 2 were carried out from methyl D-tryptophanate hydrochloride (2.5 g), triethylamine (1.6 mL), 2-fluorocinnamic acid (2.0 g), WSC.HCl (2.3 g), and methylene chloride (80 mL), to give the captioned compound (3.1 g, 86%) as an oily product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Cl:37][CH2:38][C:39](Cl)=[O:40]>O>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]([C:39](=[O:40])[CH2:38][Cl:37])[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:21][CH:22]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCl)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1 g (2.3 mmol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [compound (A)] is dissolved in 170 ml of abs. DMF under argon. 110 mg (4.6 mmol) of sodium hydride are added, and the mixture is stirred at RT for 20 min. Then 3.5 g (31 mmol) of chloroacetyl chloride are added, keeping the reaction temperature at RT. After 30 min, 25 ml of water are added while cooling, and the mixture is left to stand at RT for two days. The solvent is then removed in vacuo, during which the temperature should not rise above +25° C. The residue is taken up in 500 ml of dichloromethane and extracted five times with 200 ml of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to a volume of about 50 ml. While stirring, 200 ml of diethyl ether are added, and the precipitate (mostly unreacted starting material) is then filtered off. The mother liquor is concentrated and the residue is purified by flash chromatography on silica gel with toluene/ethanol 10:1 as eluent. The appropriate fractions are combined, and the solvent is removed. The residue is lyophilized from dioxane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N+:16]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni].O.[H][H]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH2:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1cccc(F)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(F)c1N
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of the N-tert-Butyloxycarbonyl-3-fluoro-2-nitro aniline (950 mg, 2.5 mmol) in MeOH was added catalytic amount of Raney Nickel in water, hydrogen was applied at 40 psi and the mixture was stirred overnight. The mixture was filtered over Celite and the solvent was evaporated to give the desired product in 66% yield (550 mg). MS (ESI)=226 (MH+)
Reaction SMILES: C[Si]([CH:5]([Si](C)(C)C)[C:6]([NH2:8])=[O:7])(C)C.C([Li])CCC.[CH:18]([S:21]([N:24]1[C:28]2[CH:29]=[C:30]([C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[NH2:41])(=[O:23])=[O:22])([CH3:20])[CH3:19].C(C1NC2C=CC=CC=2N=1)(=O)C1C=CC=CC=1.Cl>O.O1CCCC1>[CH:18]([S:21]([N:24]1[C:28]2[CH:29]=[C:30]([C:33]([OH:40])([CH2:5][C:6]([NH2:8])=[O:7])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[NH2:41])(=[O:22])=[O:23])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: Cl
Agent: O=C(c1ccccc1)c1nc2ccccc2[nH]1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(O)(CC(N)=O)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 50 ml. of tetrahydrofuran containing 7.33 ml. of bistrimethylsilylacetamide (30 millimoles) and 18.75 ml. of a 1.6 Molar solution of n-butyl lithium (30 millimoles) was stirred at -78° C. for ten minutes. A solution of 1.03 g. (3 millimoles) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in 100 ml. of tetrahydrofuran was then added to the cold reaction mixture dropwise over one hour. The temperature of the reaction mixture was maintained at -78° C. throughout the addition, and the reaction mixture was stirred for four hours at -78° C. following complete addition of the benzoylbenzimidazole. The reaction mixture next was diluted with 75 ml. of water and 33 ml. of 1 N hydrochloric acid. The organic layer was separated and the aqueous acid layer was extracted several times with ethyl acetate. The organic layer and extracts were combined, washed with fresh water and dried. Removal of the solvent by evaporation under reduced pressure afforded a white solid product. Purification of the product by chromatography over silica gel afforded 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-aminocarbonylmethylbenzyl)benzimidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].C(N(C(C)C)CC)(C)C.[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>ClCCl>[C:23]([O:26][CH2:27][C:28]([NH:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1cc(C#N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.4 %

Procedure:
A solution of 3-amino-5-(trifluoromethyl)benzonitrile (Intermediate 28, 2.20 g, 11.82 mmol) and di-isopropylethylamine (2.27 mL, 13.0 mmol) in dichloromethane (40 mL) was cooled in an ice-water bath before the addition of 2-chloro-2-oxoethyl acetate (1.40 mL, 13.0 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 4 hours. To the reaction was added 2-chloro-2-oxoethyl acetate (0.14 mL) and the reaction stirred at room temperature for a further 18 hours. The reaction was diluted with DCM (100 mL) and the solution washed with 2N HCl (75 mL) and NaHCO3 (75 mL), collected via a hydrophobic frit and the solvent removed to yield the title compound as an orange oil (3.7 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27]([NH:29][C:30](=[O:39])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[S:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][N:19]=3)[S:17][C:10]=12.[CH3:40][O:41][CH2:42][CH2:43]N.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27]([NH:29][C:30](=[O:39])[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[S:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH2:43][CH2:42][O:41][CH3:40])=[CH:20][N:19]=3)[S:17][C:10]=12
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCCOCc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a suspension of aldehyde 33 (17.06 g, 30.04 mmol) and 2-methoxyethylamine (13.25 ml, 152 mmol) in THF (300 ml) in a 1 L round-bottom flask was added AcOH (8.71 ml, 152 mmol)). After 1 h, NaBH(OAc)3 (32.2 g, 152 mmol) was added and the reaction mixture was stirred for 20 h at r.t. and was then quenched with HCl 2M (300 mL) After 1 h, NaOH 2N (350 mL) was added until pH 11 and the mixture was concentrated. The solid was subjected to chromatographic purification through a pad of silica gel, eluent 2%-10% MeOH/DCM, to give 15 (8.59 g, 13.86 mmol, 81% yield) as a white solid. MS (m/z): 620.2 (M+1)
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9](=[S:11])[NH:8][CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.[C:12](O)(=O)[CH3:13]>[OH-].[K+].O>[CH2:12]([S:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[NH:4][N:3]=[C:2]([I:1])[C:10]=12)[CH3:13]
Reactant: S=c1[nH]cnc2[nH]nc(I)c12
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCSc1ncnc2[nH]nc(I)c12
Temperature: 25 °C

Procedure:
Compound 5 (43.5 g, 157 mmol) was stirred in potassium hydroxide solution (38.6 g KOH in 350 mL of water) for 30 min. The mixture was filtered and the filtrate was acidified to pH 10 by addition of acetic acid and then diluted with 350 mL of absolute ethanol. Iodoethane (10 mL) was added and the solution was stirred at room temperature. Additional 10 mL aliquots of iodoethane were added after 30 min. and 1.0 h. The reaction was complete after a total of 90 min. Other runs required further addition of iodoethane to complete the reaction. The reaction solution was diluted with 700 mL of water and 20 mL of acetic acid. The mixture was cooled in an ice-bath and the solid was filtered, rinsed with water and dried. This crude product was dissolved in 300 of DMF and stirred at 90° C. for 15 min. Insoluble material was filtered away and the filtrate was diluted with 1 L of water and cooled in an ice-water bath. The solid was filtered, rinsed with water and dried: 19 g (40%) yield.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Product: CCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 34 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-butyl chloroformate. Yield: 34% of theory, C33H39N7O5 (613.7) ##EQU90##
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]=[N:8][C:9]=2[N:10]=1.ClC1N(C)C(=O)C2N(C3CCCC3)C=NC=2N=1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[OH:41].C(N(CC)CC)C>CC#N>[OH:41][C@@H:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[NH:35][C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: Cn1c(Br)nc2ncn(C3CCCC3)c2c1=O
Agent: Cn1c(Cl)nc2ncn(C3CCCC3)c2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2ncn(C3CCCC3)c2c1=O

Procedure:
A mixture of 2-bromo-1-methyl-7-cyclopentylpurin-6-one and 2-chloro-1-methyl-7-cyclopentylpurin-6-one (11.4 g), (±) trans-2-aminocyclopentanol (1.2 g, 11 mmol), and triethylamine (1.2 ml) in CH3CN (20 ml) is heated to reflux for 12 hr. The resultant mixture is cooled, concentrated in vacuo, and partitioned between EtOAc/THF 1:1 and brine. The organic layers are concentrated in vacuo and the residue is purified by flash chromatography using 6% EtOH in CH2Cl2 to give 2-(trans-2-hydroxycyclopentylamino)-1-methyl-7-cyclopentylpurin-6-one, a colorless solid (1.4 gm, MS FAB: M+H=318). A mixture of 2-(trans-2-hydroxycyclopentylamino)-1-methyl-7-cyclopentylpurin-6-one (1.3 gm, 4.1 mm) and triphenylphosphine dibromide (prepared from triphenylphosphine (1.2 g) and 0.2 ml bromine) in DMF (20 ml) is stirred at room temperature for 18 hr and heated to 70° C. for 6 hr. Dilute NaOH is added to the cooled reaction mixture to adjust the pH to 10, and the resultant solution is extracted with EtOAC/THF (1:1). The organic layer is concentrated in vacuo and purified by flash chromatography using 15% EtOH in CH2Cl2 and recrystallized from CH2Cl2 /hexane to give the title compound, a solid, mp 133°-134° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[C:3]=1[CH2:4]O.S(Cl)([Cl:16])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[C:3]=1[CH2:4][Cl:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(NC(N)=O)c1CO
Solvent: ClCCl
Product: Cc1cccc(NC(N)=O)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 2-methyl-6-ureidobenzyl alcohol (1 g) and thionyl chloride (0.66 g) in methylene chloride (20 ml) was stirred for 2 hours at room temperature and evaporated in vacuo. The residue was washed with water and dried in a desiccator to give 2-methyl-6-ureidobenzyl chloride (0.66 g).
Reaction SMILES: CN(C)S([N:6]1[C:10]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH:20]3[O:24][CH2:23][CH2:22][O:21]3)[C:14]=2[F:25])=[CH:9][N:8]=[CH:7]1)(=O)=O.Cl.O1CCO[CH2:30][CH2:29]1>O1CCCC1>[O:24]1[CH2:23][CH2:22][O:21][CH:20]1[C:15]1[C:14]([F:25])=[C:13]([N:12]([CH2:29][CH3:30])[CH2:11][C:10]2[NH:6][CH:7]=[N:8][CH:9]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CN(C)S(=O)(=O)n1cncc1CNc1ccc(F)c(C2OCCO2)c1F
Reactant: C1COCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CCN(Cc1cnc[nH]1)c1ccc(F)c(C2OCCO2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
To a stirred solution of 5-[(3-[1,3]dioxolan-2-yl-2,4-difluoro-phenylamino)-methyl]-imidazole-1-sulfonic acid dimethylamide (0.53 g, 1.27 mmol) in tetrahydrofuran (10 ml) was added a 4 N solution of hydrogen chloride in dioxane (3.87 ml, 15.5 mmol) and the mixture was stirred at room temperature for 24 h. The mixture was then concentrated in vacuo and the residue taken up in dichloromethane/methanol (95:5) and washed with 1 N aq. sodium hydroxide solution. The layers were separated and the aqueous phase was back extracted twice with dichloromethane/methanol (95:5). The combined organic phases were washed with saturated brine, then dried over magensium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield a colourless gum (225 mg, 57%); MS (ISP): 310.3 ((M+H)+.).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=2)[O:3]1.OS(O)(=O)=O.[N+:25]([O-])([OH:27])=[O:26]>>[N+:25]([C:5]1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:19])([CH3:1])[CH2:11][C:10]2([CH3:12])[CH3:13])([O-:27])=[O:26]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2,2,4,4-tetramethyl-6-chromanoate (150 mg, 0.57 mmol) was slowly added to 0.3 ml of conc. H2SO4 at 0° C. To this mixture was added very slowly 0.03 ml of HNO3. The reaction mixture was stirred at 0° C. for 30 min and poured into ice-water. The product was extracted into 5 ml of ethyl acetate, washed with NaHCO3 (sat.), brine and dried over MgSO4. After concentration, the product was purified by column chromatography (ethyl acetate/hexane 1/10) to yield 74 mg of light-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6](=O)[CH:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])[CH3:8])=[O:4].C([O-])(=O)C.[NH4+:29]>C(O)C>[NH2:29][C:6](=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])[CH3:8]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: COC(=O)C=C(N)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of biphenyl-4-carboxylic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester (1275 g, 3.9 mol, 1 eq) and ammonium acetate (640 g, 8.3 mol) in ethanol (10 L) was heated with stirring at 70-75° C. until the keto ester compound is completely consumed (1-2 h). The mixture was then kept at 0-5° C. for 1.5 h. The precipitated solid was collected by filtration and washed with hexanes (2.5 L). The product was dried overnight under vacuum at 50° C. to obtain 1244 g (90% yield, 98% HPLC purity) of the title compound.
Reaction SMILES: C1[CH2:5][O:4][CH2:3]C1.[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18].[H-].[Na+].COCCl>O>[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]([CH3:15])([CH3:17])[CH3:16])[C:8]=1[O:18][CH2:3][O:4][CH3:5]
Reactant: C1CCOC1
Reactant: Cc1cc(Br)c(O)c(C(C)(C)C)c1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOc1c(Br)cc(C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, a THF 50 ml solution of 2-bromo-4-methyl-6-tert-butylphenol(23.41 g, 100 mmol) was added dropwise at 0° C. with stirring to a 100 ml THF suspension of sodium hydride (60%, 5.20 g, 130 mmol). After 2 hours, a THF 20 ml solution of methoxymethyl chloride (95%, 12.71 g, 150 mmol) was added dropwise to the mixture obtained above, the resulting mixture was brought up to room temperature and stirred for 10 hours. The reaction liquid thus obtained was cooled to 0° C., 100 ml of water was added thereto, and the aqueous layer was extracted with toluene (extracted twice with 200 ml of toluene). The organic solution layers were combined, washed with 100 ml of saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel column chromatography to obtain a colorless oil. The 1H-NMR spectrum data of the oil are shown below. The NMR data were determined by using EX-270 (mfd. by JEOL).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([CH2:13][CH3:14])=[N:7][C:6]=2[N:5]([CH3:15])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:15])[C:6]=4[N:7]=[C:8]3[CH2:13][CH3:14])=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CCc1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(c(=O)n(C)c(=O)n2C)n1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 66.9 %

Procedure:
To a solution of 1,3-dimethyl-8-ethylxanthine (416 mg) in DMF (10 ml) were added potassium carbonate (332 mg) and 4-(4-chlorobenzoyl)benzyl bromide (619 mg) and the mixture was stirred at room temperature for 21 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized (ethyl acetate-ether) to provide the title compound as white powder (584 mg, 67%). 1H-NMR (CDCl3) δ: 1.30(3H,t,J=7.6Hz), 2.72(2H,q,J=7.6Hz), 3.40(3H,s), 3.61(3H,s), 5.64(2H,s), 7.21-7.80(8H,m).
Reaction SMILES: C[O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[C:13]([NH2:15])=[NH:14].N(C1SC=C(CSCCNC2C(OC)=NSN=2)N=1)C(N)=N.[OH-].[Na+]>>[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:7]2[C:3]([OH:2])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=2)[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: COc1nsnc1NCCSCc1csc(NC(=N)N)n1
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)(=O)N=C2O)cs1

Procedure:
When 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with one equivalent of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine and the resultant 3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole, 1,1-dioxide is reacted with sodium hydroxide according to the procedure described in Example 17, Step B, the title compound is produced.