Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1.IC>CO>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[NH:11][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=3[N:10]=2)=[CH:15][CH:14]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CO
Solvent: CI
Product: O=[N+]([O-])c1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of the 4-nitrobenzene-1,2-diamine in methanol was treated with 4-bromo phenyl isothiocyanate (1 eq) and stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature and iodomethane (1 eq) was added and stirred overnight at 60° C. The reaction was concentrated and purified on silica gel to yield (4-bromophenyl)(5-nitrobenzimidazol-2-yl)amine. The product was taken in methanol and hydrogenated with catalytic amount of 10% Pd/C to give ((5-aminobenzimidazol-2-yl)(4-bromophenylamine). MS: MH+=302.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[C:15]([O:20][CH3:21])[C:16]([NH2:19])=[N:17][CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1.[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]=1[C:13]1[CH:14]=[C:15]([O:20][CH3:21])[C:16]([NH2:19])=[N:17][CH:18]=1
Reactant: BrBr
Reactant: COc1cc(-c2csc(-c3ccc(F)cc3)n2)cnc1N
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(-c3ccc(F)cc3)sc2Br)cnc1N
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 76.6 %

Procedure:
To a solution of 5-(2-(4-fluorophenyl)thiazol-4-yl)-3-methoxypyridin-2-amine (68 mg, 0.23 mmol) in chloroform (3.6 mL) at 0° C. was added a solution of bromine (2.0 M in CHCl3, 0.17 mL, 0.34 mmol). The reaction was stirred at rt for 6-10 min and concentrated in vacuo. The resulting residue was azeotroped with 5% methanol in DCM solution (5 mL) and purified by prep TLC (SiO2, 1.0 mm, 95:5 DCM-methanol) to give 67 mg of 5-(5-bromo-2-(4-fluorophenyl)thiazol-4-yl)-3-methoxypyridin-2-amine was isolated as a tan solid: LCMS (m/z): 380.0 (MH+), tR=0.85 min.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:22](=[O:23])[CH2:21][CH:20]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:19][C:18]1=[O:29].[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[C:30]([O:23][C:22]1[CH2:21][CH:20]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:19][C:18](=[O:29])[C:17]=1[C:10]1[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8])(=[O:32])[CH3:31]
Reactant: Cc1cc(C)c(C2C(=O)CC(C3CCOC3)CC2=O)c(C)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)CC(C2CCOC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triethylamine (0.11 ml, 0.79 mmol) in dichloromethane (2 ml) is added dropwise to a chilled (ice-bath) solution of 2-(2,4,6-trimethylphenyl)-5-(tetrahydrofuran-3-yl)cyclohexane-1,3-dione (prepared by a method analogous to that described in Example 2) and acetyl chloride (0.056 ml, 0.79 mmol) in dichloromethane (4.5 ml). Once the addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane (35 ml) and washed with saturated aqueous sodium bicarbonate solution (20 ml). The organic phase is dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo. The residue is purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane to give 3-oxo-5-(tetrahydrofuran-3-yl)-2-(2,4,6-trimethylphenyl)cyclohex-1-enyl acetate.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([NH:7][C:8]1[N:13]=[C:12]([C:14](=O)[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)([CH3:6])[CH3:5].CO>O.[OH-].[Na+]>[CH:4]([NH:7][C:8]1[N:13]=[C:12]([C:14](=[N:2][OH:3])[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)([CH3:6])[CH3:5]
Reactant: NO
Reactant: CC(=O)c1cc(C)nc(NC(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NO)c1cc(C)nc(NC(C)C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of hydroxylamine hydrochloride (737 mg, 10.6 mmol) in water (3.0 mL) and 1 N aq. NaOH (11 mL) is added to 1-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-ethanone (1.71 g, 8.85 mmol). The solution is stirred at 80° C. for 2 h and MeOH is added to maintain homogeneity of the mixture. The mixture is cooled to rt and the precipitate that forms is collected, washed with water and dried in vacuo to give 1-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-ethanone oxime (1.54 g) as a yellow solid; LC-MS: tR=0.72 min, [M+H]+=209.52; 1H NMR (D6-DMSO): δ 1.15 (d, J=6.5 Hz, 6H), 2.10 (s, 3H), 2.25 (s, 3H), 4.07 (m, 1H), 6.80 (s, 1H), 6.86 (d, J=7.5 Hz, 1H), 11.62 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=[C:5]2O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1nc(O)c2cc(Cl)ccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc(Cl)c2cc(Cl)ccc2n1
Yield: 58.1 %

Procedure:
Preparation D10, Step 3: 6-Chloro-2-propylquinazolin-4-ol (810 mg, 3.64 mmol, 1 eq), phosphorus oxychloride (3.30 mL, 35.1 mmol, 9.64 eq) and triethylamine (1.63 mL, 11.7 mmol, 3.21 eq) were mixed at room temperature then refluxed for 2.5 hours. The reaction was stripped 3 times from methylene chloride. The residue was dissolved in methylene chloride (25 mL) and rinsed 3 times with saturated sodium bicarbonate (25 mL), 1× with water (25 mL). The organic layer was dried (sodium sulfate) and stripped to an amber oil. Purified over silica gel in 9:1 hexanes/ethyl acetate to give 4,6-dichloro-2-propylquinazoline (510 mg) as a light-amber solid. Yield=58%. 1H NMR (400 MHz) (CD3OD) □ 7.98 (s, 1H); 7.98 (d, 1H, J=7 Hz); 7.93 (d, 1H, J=7 Hz); 3.00 (t, 2H, J=7 Hz); 1.90 (t of q, 2 H, J=7 Hz); 1.00 (t, 3H, J=7 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[N:4]=1.[C-:41]#[N:42].[K+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=1)[N:4]=[C:3]2[CH2:2][C:41]#[N:42]
Reactant: [C-]#N
Reactant: COc1cc2c(CCl)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(CC#N)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Temperature: 25 °C
Yield: 67 %

Procedure:
In 1200 ml of dimethyl sulfoxide was suspended 165.0 g of 3-chloromethyl-5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazole, followed by stirring at room temperature. To the suspension was added 43.6 g of potassium cyanide, having been ground to powder in a mortar, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and poured into 15000 ml of water with vigorous stirring, followed by stirring for 1 hour. A precipitated solid was collected, washed with three 1000 ml portions of water, and dissolved in 5000 ml of chloroform. The solution was dried over sodium sulfate, filtered, and the solvent was evaporated. Silica gel column chromatography (ethyl acetate) of the residue yielded 108.7 g of a pale brown solid, which was used in the next reaction as such.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCOCCOCCC(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCOCCOCCOCCOCCOCCC(=O)O

Procedure:
A solution of 3-{2-[2-(2-{2-[2-(2-tert-Butoxycarbonyl-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-propionic acid tert-butyl ester (6 g, 18.6 mmol) in anisole (20 ml) was cooled in an ice bath and trifluoroacetic acid (65 g) was added. After 3 hrs at RT volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and 5% sodium bicarbonate solution. The aqueous layer was acidified with 1 N HCl, saturated with NaCl and then extracted with ethyl acetate (3×50 ml). Combined organic layers were washed with brine and dried over sodium sulfate. Removal of volatiles under the reduced pressure provided the product as colorless liquid which solidified upon refrigeration (3.8 g, 82%).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:12][C:7]=2[O:6][C:5]1=[O:19].C(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:12][C:7]2[O:6][C:5](=[O:19])[CH:4]([CH3:3])[C:8]=2[CH:9]=1
Reactant: BrBr
Reactant: CC1C(=O)Oc2cc(N3CCOCC3)ccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1C(=O)Oc2cc(N3CCOCC3)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 11 g (0.069 mole) of bromine in 50 ml of chloroform is added dropwise in the course of one hour, at from 0° to 5° C. while stirring, to a mixture of 15 g (0.064 mole) of 3-methyl-6-morpholinobenzofuran-2(3H)-one in 120 ml of chloroform. Subsequently the mixture is stirred at room temperature for 30 minutes. Methylene chloride is added to the reaction mixture, which is washed in succession with 10% strength sodium thiosulphate solution, dilute sodium bicarbonate solution and water. The crude product remaining after drying and concentrating by evaporation the organic phase is chromatographed over silica gel with petroleum ether/ether. Recrystallisation of the pure fractions from ether/petroleum ether yields 5-bromo-3-methyl-6-morpholinobenzofuran-2(3H)-one having a melting point of 99°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].O.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[S:33]([OH:36])(=[O:35])=[O:34]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[S:33]([O-:36])(=[O:35])=[O:34]
Reactant: O=S(=O)(O)c1ccc2ccccc2c1
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)([O-])c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 g of clopidogrel free base having an optical purity of 99.3% ee which was prepared by the method similar to that disclosed in International Patent Publication No. WO 02/59128 was dissolved in 100 ml of ethyl acetate, and a solution containing 34.8 g of 2-naphthalenesulfonic acid monohydrate dissolved in a mixture of 150 ml of ethyl acetate and 5 ml of water was added thereto dropwise over a period of 30 minutes. Then, the mixture was stirred at room temperature for 12 hours, and then, at a temperature ranging from 0 to 5 for 4 hours. The precipitates formed were filtered, washed with 30 ml of ethyl acetate and dried at 50° C., to obtain 71.6 g of the title compound (yield: 87%) as an white crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)C(C)CNC1CCOCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCOCC1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a mixture of 2.05 g (0.0095 mole) of (rac)-2-methyl-3-(tetrahydro-pyran-4-ylamino)-propanoic acid ethyl ester, 1.85 g (0.0095 mole) of 2,4-dichloro-5-nitro-pyrimidine 50 mL of ethyl acetate and 25 mL of water was added 2.85 g (0.0286 mole) of potassium bicarbonate. The mixture was stirred for 3 hours and then diluted with 50 mL of ethyl acetate and 50 mL of water. The layers were separated, and the aqueous layer extracted with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (75:25) to give 3.48 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(tetrahydro-pyran-4-yl)-amino]-2-methyl-propanoic acid ethyl ester (IV-45) as pale yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(C)nc2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 6-methyl-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=62%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:36])[C:15]=1[OH:37].O[C@@H:39]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:40]([O:42][CH3:43])=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C1C=CC=CC=1>[CH3:43][O:42][C:40](=[O:41])[C@H:39]([O:37][C:15]1[C:16]([Br:36])=[CH:17][C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:19][C:14]=1[Br:13])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1Br
Temperature: 80 °C
Yield: 97.4 %

Procedure:
Diethylazodicarboxylate (0.262 mL, 1.67 mmol) was added dropwise to a stirred, room temperature solution of 2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.60 g, 1.11 mmol), and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.300 g, 1.67 mmol), triphenylphosphine (0.437 g, 1.67 mmol) and benzene (5 mL) and the solution was heated in an 80° C. oil bath for 6 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel (30 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.76 g, 97%): mp 174-175° C.: NMR (DMSO-d6); δ 8.21 (ddd, J=8,1,1 Hz, 1H), 7.74 (d, J=2 Hz, 1H), 7.73 (d, J=2 Hz, 1H),7.67 (ddd, J=8, 6, 1 Hz, 1H), 7.53 (ddd, J=8, 7, 1 Hz, 1H), 7,43 (d, J=8 Hz, 1H), 7.35-7.24 (m, 5H), 5.11 (dd, J=7, 6 Hz, 1H), 3.61 (s, 3H), 3.43 (dd, 13, 6 Hz, 1H), 3.40 (dd, 13, 7 Hz, 1H), 2.44 (d, J=1 Hz, 3H), 1.60 (d, J=1 Hz, 3H); MS (+FAB): 3 bromine isotope pattern 700(20%), 702 (70%), 704 (75%), 706 (25%); Anal. Calc. for C30H23Br3O3S: C, 51.23, H, 3.30, N, 0.00. Found: C, 51.52, H, 3.36, N, 0.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)[CH:11]=[C:4]2[N:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccc(N4CCOCC4)nc3)cc2n1
Reactant: C1COCCN1
Solvent: O
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccc(N4CCOCC4)nc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resulting 5,7-dichloro-2-(6-morpholin-4-yl-pyridin-3-yl)-pyrazolo[1,5-a]-pyrimidine was dissolved in 1,4-dioxane (4 mL), morpholine (500 μL, 5.74 mM) was added to the solution and then the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the residue obtained was diluted with water, the precipitated solid was recovered through filtration and then dried under reduced pressure to thus give the title compound (59.6 mg, overall yield of these three steps: 5.1%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[N+:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[C-:13].C(N(CC)CC)C>O1CCCC1>[CH3:18][O:17][C:15]([C:14]1[N:12]=[CH:13][O:5][C:4]=1[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:16]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: [C-]#[N+]CC(=O)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 500 ml three neck flask fitted with mechanical stirrer under nitrogen is added 2,4-difluorobenzoyl chloride (141 mmol, 25 g), methyl isocyanoacetate (143 mmol, 13 mL), triethylamine (424 mmol, 60 mL) and tetrahydrofuran (200 mL). The mixture is stirred for 72 hours at room temperature. The reaction is concentrated to a thick slurry and then transferred to a separatory funnel using 500 mls of distilled water. The aqueous mixture is extracted with ethyl acetate (4×250 mL). The ethyl acetate washes are combined and washed with brine. The organics are dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue is disolved in hot ethanol (400 mL) and treated with decolorizing carbon and magnesium sulfate. After 15 minutes, the mixture is filtered to remove the insolubles. To the filtrate is added to one liter of distilled water. A precipitate forms and the resultant mixture is allowed to stand. The resulting solid is collected by filtration and is washed with copious amounts of water. The resulting solid is dried under vacuum to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH4+].[Cl-].O>CCO.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=[N+]([O-])c1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 47.3 %

Procedure:
To a solution of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene (50.1) (0.980 g) and NH4Cl (1.64 g) in EtOH(50 mL)—H2O (5 mL), was added iron powder (1.92 g). The mixture was heated to reflux for 1 h. After cooling the reaction mixture was filtered through short celite pad. The filtrate was concentrated, diluted with sat.NaHCO3 and extracted with AcOEt (30 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. Concentration of solvent afford crude product, which was purified by column chromatography (silica gel, AcOEt:hexane=1:3) to provide aniline 50.2 (0.420 g) as a colorless solid.
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[OH-].[Na+]>CCCCCC.C(OCC)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]([NH2:6])=[NH:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Product: N=C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
380 mL 1N LiHMDS-solution in n-hexane was added to 20 g 4-fluoro-benzonitrile in 1 L diethylether. The reaction was stirred for 2 h at RT and decomposed with 1 L 4 NHCL-solution at 0° C. 4 N sodium hydroxide was added until pH 12 was reached and the water layer was extracted with chloroform. The organic layer was dried and evaporated to give 6.6 g of the desired product. Rt: 0.30 min (method B), (M+H)+: 139
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[CH2:23]1
Reactant: BrCC1COc2ccccc2O1
Reactant: COc1ccccc1C1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1C1CCCN(CC2COc3ccccc3O2)C1
Temperature: 130 °C
Yield: 23.6 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (34 mg, 0.15 mmol), 3-(2-methoxyphenyl)piperidine HCl (38 mg, 0.165 mmol) and triethylamine (41 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 110-150° C. for 90 min. After evaporation to dryness, the crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 12 mg of the title compound.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)[C:15]([O:17]CC)=[O:16])(=O)C1C=CC=CC=1.[OH-].[Na+].CO.Cl>O1CCCC1>[OH:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCCO)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-2-(2-aminothiazol-4-yl)acetate (syn isomer) (8.5 g.), 1N aqueous sodium hydroxide (35 ml.), methanol (40 ml.) and tetrahydrofuran (40 ml.) was stirred at 35° to 40° C. for 9 hours and at ambient temperature for 12 hours. After adjusting the resultant solution to pH 6.5 with conc. hydrochloric acid, the solution was concentrated to about 2/3 volume of the initial. The concentrate was adjusted to pH 3.5 with conc. hydrochloric acid under ice-cooling, and the precipitates were collected by filtration, washed with water and acetone in turn and then dried over phosphorus pentoxide under reduced pressure to give 2-(2-hydroxyethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (3.3 g.).