Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:3]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:16])[CH:5]=[C:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)c1c[nH]c(=O)c(Br)c1
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CN(C)C(=O)c1cc(Br)c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-N,N-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (100 mg, 0.408 mmol) and iodomethane (57.9 mg, 0.408 mmol) in DMSO (3 mL) was added potassium carbonate (56.4 mg, 0.408 mmol). The mixture was stirred at room temperature overnight, filtered, and purified via preparative HPLC, eluting with a gradient of 10-90% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA). The product was dried under vacuum to give the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[C:19]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH3:19])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: CO
Product: COC1CCN(C)C(=O)N1c1nnc(C(F)(F)F)s1

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux heated The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxy-2(1H)-pyrimidinone.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=1)#[CH:14].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[F:23][C:17]1[CH:16]=[C:15]([C:13]#[C:14][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccc(OC)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#Cc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To the mixture of diisopropylamine (0.262 mL, 1.87 mmol) in tetrahydrofuran (5 mL) at −78° C. under nitrogen was added slowly the solution of n-butyllithium (1.17 mL, 1.87 mmol, 1.6M in hexanes). After stifling for 30 minutes, the solution of 4-ethynyl-2-fluoro-1-methoxybenzene (622) (0.180 g, 0.94 mmol) in tetrahydrofuran (1 mL) was added slowly into the reaction mixture. The mixture was allowed to reach 0° C. over 1 hour and ethyl chloroformate (0.134 mL, 1.4 mmol) was added. The resulting mixture was stirred to room temperature for 12 hours, quenched with saturated ammonium chloride and extracted with ethyl ether. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to provide ethyl 3-(3-fluoro-4-methoxyphenyl)propiolate (623) (0.070 g, 6.3%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH:19]([C:21]1[NH:22][C:23]([CH3:31])=[CH:24][C:25]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[CH:19][C:21]3[NH:22][C:23]([CH3:31])=[CH:24][C:25]=3[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)cc1CCC(=O)O

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (71 mg, 0.3 mmol) was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid (54 mg) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=[C:28](N1C=CN=C1)[N:29]1C=CN=[CH:30]1.CNC>ClCCl.O>[CH3:28][N:29]([CH3:30])[C:22]([C:21]1[CH:25]=[CH:26][C:18]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])[CH2:14][CH2:13]3)=[N:17]2)=[CH:19][CH:20]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. Dimethylamine (93 mg, 2.07 mmol) was added and stirring continued, under argon, at room temperature for 4 hours. The resulting crude mixture was diluted with water, and extracted with dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D41). MS (ES+) m/e 385 [M+H]+.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([N:20]=[C:21]=[O:22])=[CH:14][C:13]=2[O:12]1>C1C=CC=CC=1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:21]([NH:20][C:15]3[CH:16]=[CH:17][C:18]4[O:19][CH2:11][O:12][C:13]=4[CH:14]=3)=[O:22])=[CH:4][C:3]=2[O:2]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: O=C(Nc1ccc2c(c1)OCO2)Nc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-methylenedioxyaniline (0.35 g) and 3,4-methylenedioxyphenyl isocyanate (0.4 g) in benzene (25 ml) was refluxed for 1 hour. The precipitate formed was filtered, washed with benzene then dried to give pure DC-0076B (0.697 g, 95%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([F:21])=[CH:4][C:3]=1[F:22].ClC1[NH:28][C:27]2[CH:29]=[C:30]([C:42]([F:45])([F:44])[F:43])[CH:31]=[C:32]([C:33]3[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=3)[C:26]=2[N:25]=1>>[F:22][C:3]1[C:2]([NH2:1])=[N:7][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[NH:25][C:26]4[C:32]([C:33]5[CH:34]=[C:35]([F:41])[C:36]([F:40])=[C:37]([F:39])[CH:38]=5)=[CH:31][C:30]([C:42]([F:43])([F:44])[F:45])=[CH:29][C:27]=4[N:28]=3)[CH2:12][CH2:13]2)=[C:5]([F:21])[CH:4]=1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)c(F)cc2F)CC1
Product: Nc1nc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)CC2)c(F)cc1F

Procedure:
The piperazine from step (a) above (74 mg, 0.35 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (87 mg, 0.25 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 529 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:18]COCC>CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH3:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Reactant: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.071 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 mL) and the solution was treated with methyl alcohol (0.075. mol, 3 mL) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was extracted with saturated solution of sodium bicarbonate until alkaline. The combined extracts were washed with ether and the aqueous layer acidified with 5N HCl to pH 1. The precipitated oil was extracted with CH2Cl2 (50 ml×3). The combined extracts were washed with water (50 mL×4) and dried over anhydrous MgSO4. The oily product crystallized on standing.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].CN(C)CCCN>C1(C)C(C)=CC=CC=1.O>[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([C:6]1[N:2]([CH3:1])[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:5]=1[CH3:7])=[O:18]
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: CN(C)CCCN
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2Cl)n1C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A solution of 50 g (0.276 mole) of ethyl 1,4-dimethyl-1H-pyrrole-2-acetate and 64 g (0.303 mole) of 2,4-dichlorobenzoyl chloride in 310 mL of xylene was heated under reflux for 4 h under argon. After cooling, a 20% solution of 3-dimethylaminopropylamine in H2O was added and stirred one hour. The organic layer was washed twice with 1N HCl, water, brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a solid which was recrystallized from methanol to give 79.39 g of product: mp 90-92° C.; mass spectrum (Cl—CH4) m/z=354 (M+1); NMR 300 MHz (CDCl3) d 7.5 (s, 1H); 7.3 (dd, 2H); 6.0 (s, 1H); 4.2 (q, 2H); 3.9 (s, 3H); 3.65 (s, 2H); 1.6 (s, 3H); 1.25 (t, 3H). Anal Calcd for C17H17Cl2NO3: C, 57.64; H, 4.84; N, 3.95. Found: C, 57.52; H, 4.60; N, 3.80.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:5])[OH:4])[CH3:2].[CH3:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29]Cl)=[O:27].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:4])[O:5][CH2:29][O:28][C:26](=[O:27])[C:25]([CH3:32])([CH3:31])[CH3:24])[CH3:2]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCP(=O)(O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCP(=O)(OCOC(=O)C(C)(C)C)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedures of Example 1, P-ethyl-2-nitro-5-(2,4-dichlorophenoxy)phenylphosphinic acid (0.30 g, 0.80 mmol) and chloromethyl 2,2-dimethylpropanoate (0.24 g, 1.6 mmol) are reacted together in the presence of triethylamine (0.23 ml) and DMF (3 ml) to give 2,2-dimethylpropionyloxymethyl P-ethyl-2-nitro-5-(2,4-dichlorophenoxy)phenylphosphinate.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][N+:12]=1[O-:20].O>C1COCC1>[N+:17]([C:15]1[CH:14]=[CH:13][N+:12]([O-:20])=[C:11]([O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc[n+]([O-])c(Oc2cccnc2)c1
Yield: 83 %

Procedure:
Sodium hydride (0.27 g of an 80% dispersion in oil, 9 mmol) was added to a solution of 3-hydroxypyridine (0.854 g, 9 mmol) in THF (3 ml) at 0° C. The mixture was then stirred for 1 h at room temperature before 2-chloro-4-nitropyridine-N-oxide* (2 g, 9 mmol) was added. The resulting solution was heated at reflux for 16 h, cooled, poured into water (100 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using ethyl acetate as eluant to afford the title compound (1.74 g, 83%) as a solid.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]2[C:11]1=[CH:12][C:13](=[O:39])[CH:14]([CH3:38])[CH:15]2[CH2:27][CH2:28][C:29](=[O:37])[CH2:30][CH:31]([OH:36])[CH2:32][C:33]([OH:35])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:41]>O1CCOCC1.O>[CH2:1]([O:8][N:9]=[C:10]1[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]2[C:11]1=[CH:12][C:13](=[O:39])[CH:14]([CH3:38])[CH:15]2[CH2:27][CH2:28][C:29](=[O:37])[CH2:30][CH:31]([OH:36])[CH2:32][C:33]([O-:35])=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:41]
Reactant: CCC(C)C(=O)OC1CCC(=NOCc2ccccc2)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)O)C21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)C(=O)OC1CCC(=NOCc2ccccc2)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)[O-])C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
103 mg of 7-[5-benzyloxyimino-2-methyl-8-(2-methylbutyryloxy)-3-oxo-1,2,3,5,6,7,8,8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoic acid (prepared as described in Example 1b) were dissolved in 2 ml of a 1:1 by volume mixture of dioxane and water. 1.8 ml of a 0.1N aqueous solution of sodium hydroxide were then added dropwise to the solution over a period of 5 minutes at 0° C., after which the solution was stirred for 1 hour at room temperature. At the end of this time, the solution was freeze-dried, to obtain 107 mg of the title compound as a colorless moisture sensitive powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH:13]([F:15])[F:14])[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:19][C:20]([F:29])([F:30])[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]([NH:11][CH2:12][CH:13]([F:15])[F:14])=[CH:10][C:2]=2[Cl:1])=[CH:27][CH:28]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl

Procedure:
The sub-title compound is prepared in analogy to 1b from 2-chloro-4-(2,2-difluoro-ethylamino)-5-nitro-benzoic acid (2.00 g, 7.1 mmol), 4-trifluoromethoxyaniline (0.96 mL, 7.1 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (1.13 mL, 8.5 mmol), DIPEA (2.85 mL, 16 mmol) and DCM (40 mL).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].O.Cl>C(O)C.[Fe]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]([CH3:21])=[N:8][CH:9]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)cnc1C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(N)cc2)cnc1C
Yield: 68.7 %

Procedure:
3-Ethoxycarbonyl-2-methyl-5-(p-nitrophenyl)pyridine (2 g) was dissolved in warm ethanol (70 ml). Iron powder (4 g) was added to the solution followed by water (7 ml) containing 2 drops of 11.5 N-hydrochloric acid. The mixture was refluxed for 1.5 hours, cooled and filtered. The filtrate was concentrated and the residue dissolved in methylene dichloride. The solution was washed with water, dried and concentrated. The crude product was recrystallised from methylene dichloride-petroleum ether (b.p. 30°-40°) to give the title compound (1.23 g), m.p. 137°-8°.
Reaction SMILES: CS(O[C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[O:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[N:20]=[N+:21]=[N-:22])=[CH:14][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Temperature: 120 °C

Procedure:
To a solution of (1R,2R)-2-(4-bromophenoxy)cyclohexyl methanesulfonate (3.55 g, 10.2 mmol) in dimethylformamide (21.8 mL) and water (2.43 mL) was added sodium azide (95%, 2.09 mg, 30.5 mmol) and the reaction was heated at 120° C. for 23 hours. The reaction was cooled to room temperature, diluted with water (400 mL) and extracted with ethyl acetate (4×400 mL). The combined organic layers were washed with aqueous lithium chloride solution (1N, 400 mL), washed with water (400 mL), and dried over magnesium sulfate. Filtration and removal of solvents in vacuo afforded (1R,2S)-2-azidocyclohexyl 4-bromophenyl ether as an orange oil, which was used in the next step without additional purification. Yield: 2.85 g, 9.62 mmol, 94%. 1H NMR (400 MHz, CDCl3) δ 1.36-1.48 (m, 2H), 1.62-1.76 (m, 4H), 1.96-2.07 (m, 2H), 3.63 (m, 1H), 4.43 (m, 1H), 6.85 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.9 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5]1([CH2:15][N:16]2[C:25](=[O:26])[C:24]3[N:23]([CH2:27][C:28]#[C:29][CH3:30])[C:22]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]4)=[N:21][C:20]=3[NH:19][C:17]2=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:5]1([CH2:15][N:16]2[C:25](=[O:26])[C:24]3[N:23]([CH2:27][C:28]#[C:29][CH3:30])[C:22]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]4)=[N:21][C:20]=3[N:19]([CH2:2][C:3]#[N:4])[C:17]2=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2[nH]c(=O)n(Cc3cccc4ccccc34)c(=O)c21
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1cccc3ccccc13)c(=O)n2CC#N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
30 μl of bromoacetonitrile are added to a mixture of 0.20 g 1-(naphth-1-ylmethyl)-7-(but-2-ynyl)-8-(3-tert-butoxycarbonylamino-piperidin-1-yl)-xanthine and 0.10 g potassium carbonate in 3 ml of dimethylformamide. The reaction mixture is stirred for 3 h at 60° C. and then cooled to ambient temperature. Water is added and the precipitate is separated off and dried at 60° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:18]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccco1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccco2)sc2ccccc12
Yield: 18.9 %

Procedure:
A mixture of methyl thiosalicylate (1.01 g, 6.0 mmol), 2-furonitrile (0.57 g, 6.0 mmol), triethylamine (1.5 ml, 10.7 mmol) and toluene (20 ml) was refluxed for 24 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (0.26 g, 19%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([OH:16])[C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC(C)=O>[Cl:1][C:2]1[C:3]([C:10]2[C:11]([Cl:18])=[CH:12][C:13]([Cl:17])=[C:14]([CH:15]=2)[O:16][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8]
Reactant: CCOC(=O)C(C)Br
Reactant: CSc1c(Cl)c(-c2cc(O)c(Cl)cc2Cl)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1cc(-c2nn(C)c(SC)c2Cl)c(Cl)cc1Cl

Procedure:
A mixture of 4-chloro-3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-5-methylthio-1H-pyrazole (3.50 g, 10.8 mmoles), 50 ml acetone, anhydrous K2CO3, and ethyl 2-bromopropionate (2.06 g, 11.4 mmoles) was subjected to reaction under reflux for 2 hours. Then the resulting solution was filtered to remove acetone-insoluble matter, and the filtrate was concentrated and purified by silica gel column chromatography, give the title compound as oily substance; Yield 70.0 nD(28.8° C.): 1.5763.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH2:22])=[N:3]1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].CN(C)C=O>O>[CH3:20][N:19]([CH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([NH:22][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:5]=1)[CH3:21]
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Reaction time: 12 h
Yield: 84.9 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-[(dimethylamino) methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (2.0 g), ethyl chloroformate (0.72 g) and dimethylformamide (30 ml) was stirred at 25° for 12 h. The suspension was diluted with water (100 ml) and extracted with ethyl acetate. The organic extracts were evaporated to leave the title compound as a pale yellow oil (2.1 g). TLC silica, methanol/0.88 amonia 80:1, Rf 0.61. NMR (D2O 2.52 t (1H); 2.8-3 m (3H); 5.42 s (2H); 5.6-6 m (6H); 6.48 t (2H); 6.5 s (3H); 7.09 s (6H); 7.88 m (2H); 8.67 t (3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>>[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:34]
Reactant: CNCCOC
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Yield: 55 %

Procedure:
Conversion of 4-cloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (84 mg, 0.20 mmol) with N-(2-methoxyethyl)-methylamin (178 mg, 2.0 mmol) using the general procedure C affords the product as white solid in 55% yield.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5](=[O:11])[NH:4][NH:3]1.ClOC(C)(C)C.[C:18]([OH:24])(=[O:23])[CH:19]=[CH:20][CH:21]=[CH2:22]>O1CCOCC1>[C:18]([CH:19]1[CH:20]=[CH:21][CH2:22][N:4]2[C:5](=[O:11])[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:2](=[O:1])[N:3]12)([OH:24])=[O:23]
Reactant: O=C(O)Cn1c(=O)[nH][nH]c1=O
Reactant: C=CC=CC(=O)O
Agent: CC(C)(C)OCl
Solvent: C1COCCO1
Product: O=C(O)Cn1c(=O)n2n(c1=O)C(C(=O)O)C=CC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41.7 %

Procedure:
1.69 g (0.011 mol) of 3,5-dioxo-1,2,4-triazolidine-4-acetic acid were suspended in 20 ml of dry dioxan and the suspension was stirred at room temperature under a stream of nitrogen. A solution of 1.32 g (0.012 mol) of tert.butyl hypochlorite in 4 ml of dry dioxan was added dropwise over a period of 15 minutes. Stirring was continued for 45 minutes, the resulting red solution was filtered and the filtrate was evaporated in vacuo to give a red solid. This red solid was dissolved in 30 ml of dioxan and added portionwise to a stirred solution of 1.25 g (0.013 mol) of penta-2,4-dienoic acid in 20 ml of dioxan. The red colour was allowed to fade between the additions. After completion of the addition and when no red colour persisted, the solution was stirred at room temperature for 1 hour and evaporated in vacuo to give a colourless solid. This solid was recrystallized from acetonitrile to give 1.17 g (43%) of 5-carboxy-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo-[1,2-a]pyridazine-2-acetic acid of melting point 209°-211° C. (decomposition).