Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([N+:11]([O-:13])=[O:12])=[C:5](Cl)[N:4]=1>C(O)(=O)C>[Br:1][C:5]1[N:4]=[C:3]([CH3:2])[NH:8][C:7](=[O:9])[C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1nc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: Br
Solvent: CC(=O)O
Product: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 25 °C
Reaction time: 44 h
Yield: 68.9 %

Procedure:
56.6 ml (503 mmol) of hydrobromic acid solution (48% in water) were added dropwise to a solution of 20.5 g (101 mmol) of the 2-methyl-4-methoxy-5-nitro-6-chloro-pyrimidine [Helv. (1958), 41, 1806] in 450 ml of acetic acid and the reaction mixture was stirred at room temperature for 44 hours. It was then evaporated under reduced pressure and the residue formed poured into 500 ml of an ice/water mixture and extracted 3 times with 500 ml of dichloromethane. The combined dichloromethane phases were washed with 100 ml of water and evaporated under reduced pressure. There were thus obtained 16.3 g (69.6 mmol, yield 69%) of the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one as light yellow solid, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(OC(Cl)=O)C(C)C.CN1CCOCC1.Cl.[CH3:46][C:47]([CH3:51])([OH:50])[CH2:48][NH2:49]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([NH:49][CH2:48][C:47]([OH:50])([CH3:51])[CH3:46])=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)O)cn1
Reactant: CC(C)(O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)NCC(C)(C)O)cn1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a solution of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylic acid (0.42 g, 0.9 mmol) in DMF (3.0 mL) was added isobutylchloroformate (0.126 g, 0.13 mmol) followed by the addition of N-methylmorpholine (0.11 g, 1.1 mmol) and stirred at −10° C., under argon atmosphere. After 20 min, added a solution of 1,1 dimethyl-2-aminoethanol hydrochloride (0.135 g, 1.1 mmol) in DMF (2.0 mL) containing N-methylmorpholine (0.11 g, 1.1 mmol). The mixture was stirred at room temperature for 1 h, and concentrated to dryness in vacuo. The resulting residue was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=537 M+H) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHCO3 (10 mL) and EtOAc (15 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (0.35 g, 75%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 9.1 (d, 1H, J=1.6 Hz), 8.71 (d, 1H, J=1.6 Hz), 7.61 (m 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.54 (s, 2H), 5.30 (s, 2 h). 3.30 (s, 2 h), 2.55 (s, 3H), and 1.21 (s, 6H); 19F NMR (CD3OD/400 MHz) −111.67 (m) and −116.05 (m); ES-HRMS m/z 537.0948 (M+H calcd for C23H24BrF2N4O4 requires 537.0943).
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.P(Br)(Br)[Br:26]>COCCOC>[Br:26][CH2:2][C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2CO)c1
Reactant: BrP(Br)Br
Solvent: COCCOC
Product: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-[3-(2-hydroxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-propionic acid (˜0.30 mmol) in DME (5 mL) was added phosphorus tribromide (0.06 mL, 0.60 mmol), and the solution was stirred at room temperature for 3 hours. After cooling to 0° C., the reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C1(C)C=CC=CC=1.[Cu]Br>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 100 °C
Yield: 14.8 %

Procedure:
A mixture of N-methylpiperazine (216 mg, 2.15 mmol), 2-bromo-5-nitroanisole (1 g, 4.3 mmol), potassium carbonate (447 mg, 3.23 mmol), copper (I) bromide (86.6 mg, 0.30 mmol) in pyridine (0.5 ml) and toluene (2 ml) was heated at 100° C. overnight. After cooling, the mixture was partitioned between water and ether and the aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and evaporated under reduced pressure, to give the crude product. This was purified by chromatography on silica gel, eluting with methanol and dichloromethane, to give the title compound (D34) as a yellow/brown oil (80 mg, 15%) MH+=252.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=O.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([Cl:13])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1cccs1
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1cccs1

Procedure:
65 ml of benzene was added to 10 grams of 3-(2-thienyl)acrylic acid. 7.8 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 70° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=2)[CH:6]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@H:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1.Cl.N[C@H](C1C=CC(F)=CC=1)C1C=CC(P(C)(=O)OCC)=CC=1>CC#N>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([NH:48][C@H:49]([C:62]3[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=3)[C:50]3[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=3)=[O:16])=[CH:9][N:8]=2)[CH:6]=1
Reactant: O=C(O)c1cnc(-n2cc(F)cn2)nc1O
Reactant: CCOP(C)(=O)c1ccc([C@H](N)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cc(F)cn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.7 %

Procedure:
To a stirred solution of 28-g (2.8 g, 12 mmol) and Et3N (3.5 g, 34 mmol) in MeCN (30 ml) was added HATU (4.8 g, 12 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((R)-amino(4-fluoro phenyl)methyl)phenyl(methyl)phosphinate, 18-e, (3.5 g, 11 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=1/1) to provide the product, 29-a, (1 g, 15.7%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.OS(O)(=O)=O.O=S(=O)=O.[CH2:22]=O>>[C:6]([C:5]1[CH:9]=[C:10]2[C:2](=[CH:3][CH:4]=1)[C:1](=[O:12])[O:11][CH2:22]2)([OH:8])=[O:7]
Reactant: C=O
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 125 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
Terephthalic acid (10 kg) is charged into a reactor. Oleum (20% (18-24% SO3); 6 kg/kg terephthalic acid ) is added and then paraformaldehyde (1.33 equivalents, 0.24 kg/kg terephthalic acid) is added. The mixture is agitated at 125° C. for 17 hours. Water (13 kg/kg terephthalic acid and filter aid is added, the temperature is adjusted to about 70° C. The precipitate is filtered of, washed with water and suspended in water. The pH of the suspension is adjusted to about 7 with NaOH, activated carbon, 0.07 kg/kg terephthalic acid is added, and then the mixture is filtered, the precipitate is rinsed with water. The temperature of the filtrate is adjusted to about 65° C. and the pH is adjusted to about 2 with 50% sulfuric acid. The 5-carboxyphthalide precipitated is separated by filtration washed and dried. Yield 83%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8](=[O:10])[CH3:9].O>CN(C)C=O>[N:1]1([CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCCC(Br)C(C)=O
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(C(C)=O)n1ccnc1

Procedure:
30 g of imidazole was dissolved in 80 ml of N,N-dimethylformamide. To this solution, 30 g of 3-bromo-2-heptanone was gradually added under stirring, and stirred at a temperature of from 50° to 60° C. for 4 hours. Then, the mixture was poured into water and extracted with chloroform. The extraction solution was treated by a usual manner, and the obtained oily product was purified by distillation, whereby 3-(imidazole-1-yl)-2-heptanone was obtained. The boiling point was 116°-119° C./2 mmHg.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.[BH4-].[Na+].[OH-].[Na+]>CO>[Si:1]([O:8][CH2:9][CH2:10][NH:16][CH2:15][CH:12]1[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: NCC1CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(tert-Butyldimethylsilyloxy)acetaldehyde (0.98 g) was dissolved in dry methanol (40 ml) and then treated with cyclopropane methylamine (0.634 ml) followed by 4A° molecular sieves (1 g). The resultant mixture was stirred for 5 h at room temperature and then sodium borohydride (0.340 g) was added. After stirring for a further 18 h at room temperature, sodium hydroxide (2N) was added, the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was partitioned between sodium hydroxide (2N) and ethyl acetate. The separated aqueous layer was washed further with ethyl acetate. The combined organic components were dried (over magnesium sulphate), filtered and concentrated under reduced pressure to give the title compound (0.78 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[N:21]([CH2:22][CH3:23])[N:20]=[C:19]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[N:18]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][N:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:13]([C:10]1[O:9][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:17]3[N:21]([CH2:22][CH3:23])[N:20]=[C:19]([CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:18]=3)[N:6]=2)=[N:12][N:11]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CCn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
A suspension of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (3009.5 g, 6.05 mol) in DCM (9 L) was cooled to 5-10° C. under N2. TFA (9 L) was added portionwise to the suspension whilst maintaining the temperature <30° C. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, the resulting residue was dissolved in water (30 L) and added slowly to a 35% aqueous ammonia solution (12 L) at 0-5° C. The suspension was stirred for 30 min then the product was filtered off and washed with water (2×6 L). The product was dried at 50° C. in vacuo for 2 days to afford 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine ((2496 g): 1H NMR Spectrum: (DMSO-d6) 1.4-1.52 (12H, m), 1.57-1.73 (2H, m), 1.83-1.93 (2H, nm), 2.57-2.7 (2H, m), 2.71-2.84 (1H, m), 2.96-3.09 (2H, m), 4.58 (2H, q), 8.06 (2H, s), 8.84 (1H, s): Mass Spectrum [M+H]+=398.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: COc1ccnc2c(N)cccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 17.1 %

Procedure:
In a similar fashion using route 14 general procedure 26, 4-methoxy-quinolin-8-ylamine (Intermediate 71) (71 mg, 0.41 mmol), benzenesulfonyl chloride (79 mg, 0.44 mmol) gave the title compound (22 mg, 17%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]([CH3:24])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[N:13]=[CH:12][N:11]=1)=[O:8])C.[Li+].[OH-]>C1COCC1.O>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:13]=[CH:12][N:11]=[C:10]([NH:9][C:7](=[O:8])[N:6]([CH2:5][C:4]([OH:25])=[O:3])[CH3:24])[CH:15]=1
Reactant: CCOC(=O)CN(C)C(=O)Nc1cc(-c2ccccc2OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(NC(=O)N(C)CC(=O)O)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-1-methyl-ureido}-acetic acid ethyl ester (LVIII) (370 mg, 1.03 mmol) in a mixture of THF and water (1:1) was added a solution of LiOH (87.0 mg, 2.06 mmol) in water at ice bath temperature over 10 min and then allowed to stir for two hours at room temperature. THF was evaporated and the aqueous solution was acidified with 2N HCl. This aqueous phase was then extracted with ethyl acetate (2×100 ml), the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor to give {3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-1-methyl-ureido}-acetic acid as a brown coloured solid. Yield: 34 mg, 10.4%.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([CH3:13])[C:3]=1[CH:4]=[O:5].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([CH3:13])[C:3]=1[CH:4]1[O:16][CH2:15][CH2:14][O:5]1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(C)c1C1OCCO1
Temperature: 25 °C

Procedure:
A solution of 2.8 g of 2,6-dimethyl-3-nitrobenzaldehyde in 150 ml of toluene was treated with 5 ml of ethylene glycol and 20 mg of p-toluenesulphonic acid. The mixture was heated to reflux for 18 hours, with the water being separated using a separator. The mixture was left to cool to room temperature and was washed twice with water. After drying over anhydrous magnesium sulphate the solvent was evaporated and the crystalline residue was crystallized from hexane. 3.0 g of 2-(2,6-dimethyl-3-nitrophenyl)-1,3-dioxolane, m.p. 69-71° C., were obtained.
Reaction SMILES: [CH3:1][N:2]([C:4]([F:9])([F:8])[C:5](Cl)=[O:6])[CH3:3].[CH3:10][O:11][C:12]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:13]=1[CH:14]=[CH:15][CH:16]([S:26]([CH:29]([CH:39]=[CH:40][C:41]1[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH2:38])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH2:25])[CH:18]=1>O1CCCC1>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:12]([O:11][CH3:10])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=1[O:47][CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:5](=[O:6])[C:4]([F:9])([F:8])[N:2]([CH3:3])[CH3:1])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])([F:9])[F:8])[CH:18]=1
Reactant: CN(C)C(F)(F)C(=O)Cl
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(F)(F)N(C)C)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(F)(F)N(C)C)c2)c(OC)c1
Reaction time: 8 h

Procedure:
To a solution of dimethylamino-α,α-difluoroacetyl chloride (10 mmol) in tetrahydrofuran (40 mL) is added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution is stirred overnight and the reaction progress is monitored by TLC. The solvent is removed and the residue is taken up in dichloromethane and washed with water. The organic layer is dried over anhydrous sodium sulfate and evaporated to give the desired amide product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([CH2:37][NH2:38])[OH:36].CO>C1(C)C=CC=CC=1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][CH2:37][CH2:35][OH:36])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: NCCO
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(NCCO)n2)c1F)c1ccoc1
Temperature: 140 °C
Yield: 46 %

Procedure:
To the solution of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol) in toluene (2 ml) was added ethanol amine (64.5 mg, 1.056 mmol) and the reaction mixture heated in MW for 30 min at 140° C. Methanol (1 ml) was added and solution was purified by chromatography (100% EtOAc to 20% MeOH:EtOAc). N-{2-fluoro-3-[5-{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (53 mg, 43.7%) was isolated as white powder. 1H NMR (400 MHz, DMSO-d6) ppm 1.74 (qd, J=12.19, 4.48 Hz, 2H), 2.01 (dd, J=12.66, 2.12 Hz, 2H), 3.21-3.34 (m, 4H), 3.42-3.57 (m, 4H), 3.93 (dt, J=9.58, 2.22 Hz, 2H), 4.67 (t, J=6.00 Hz, 1H), 6.66 (t, J=1.29 Hz, 1H), 7.17 (t, J=5.75 Hz, 1H), 7.24-7.40 (m, 2H), 7.46 (td, J=7.69, 1.99 Hz, 1H), 7.82 (t, J=1.80 Hz, 1H), 8.08 (d, J=5.18 Hz, 1H), 8.28 (t, J=1.20 Hz, 1H), 10.31 (s, 1H); MS (ESI): 546.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18](O)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][C:37]([CH3:42])([CH3:41])[CH2:36]1)(=[O:34])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:41][C:37]1([CH3:42])[CH2:36][N:35]([S:32]([CH3:31])(=[O:33])=[O:34])[CH2:40][CH2:39][N:38]1[C:18]([C:13]1[N:14]([CH3:17])[C:15]2[C:11]([N:12]=1)=[C:10]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[N:9]=[C:8]([N:7]1[C:6]3[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=3[N:4]=[C:3]1[CH2:1][CH3:2])[N:16]=2)=[O:19]
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCN(S(C)(=O)=O)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (117 mg, 0.26 mmol), 1-methanesulfonyl-3,3-dimethylpiperazine (51 mg, 0.26 mmol) and HATU (100 mg, 0.26 mmol) in DMF (1 mL) was added NEt3 (720 μL, 5.18 mmol). The resulting mixture was allowed to stir at r.t. for 16 h then partitioned between EtOAc and H2O. The organic phase was dried (MgSO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%). The resulting solid was recrystallised from EtOAc and Et2O affording 715 (50 mg, 33%). LCMS (method I): RT 3.68 min, [M+H]+ 582.2. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.03 (1 H, m), 7.76-7.75 (1 H, m), 7.31-7.27 (2 H, m), 4.35 (4 H, brd s), 4.03 (2 H, t, J=5.39 Hz), 3.95 (3 H, s), 3.87 (4 H, t, J=4.70 Hz), 3.50 (2 H, t, J=5.40 Hz), 3.37 (2 H, q, J=7.47 Hz), 3.31 (2 H, s), 2.90 (3 H, s), 1.68 (6 H, s), 1.45 (3 H, t, J=7.47 Hz)
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:11].[N:12](OCCC(C)C)=[O:13]>C(O)C.C(OCC)C>[C:8](/[C:7](=[N:12]\[O-:13])/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)#[N:9].[Na+:11]
Reactant: N#CCc1ccccc1
Reactant: CC(C)CCON=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: N#C/C(=N\[O-])c1ccccc1
Reaction time: 2 h
Yield: 56.6 %

Procedure:
Phenylacetonitrile (9.72 g, 82.97 mmol) was metered into a suspension of 3.31 g (82.97 mmol) of NaOH in 60 ml of ethanol. Following the complete addition, 11.66 g (99.56 mmol) of isopentyl nitrite were metered in dropwise at temperatures of 15° C. The mixture was then stirred for a further 2 hours at this temperature. The reaction mixture was diluted with 300 ml of diethyl ether, and the precipitated solid was filtered off and washed twice with in each case 50 ml of diethyl ether. The white salt sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide (7.89 g, 56% yield) can be dried in vacuo or be further used directly. 1.49 g (6.24 mmol) of but-3-yn-1-yl[6-(chloromethyl)pyridin-2-yl]carbamate and 103 mg (0.624 mmol) of potassium iodide were added to a solution of 1.05 g (6.24 mmol) of sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide in 25 ml of acetonitrile and 10 ml of DMF. The reaction mixture was stirred for 7 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in 100 ml of ethyl acetate. The organic phase was washed with water and dried over MgSO4. After removing the solvent, 2.21 g (99% yield, only 1 oxime isomer) of but-3-yn-1-yl{6-[({[(Z)-cyano(phenyl)methylene]-amino}oxy)methyl]pyridin-2-yl}carbamate were isolated as a colourless solid.