Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]1[N:24]2[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:23]2=[N:22][CH:21]=1)CCC>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:20]2[N:24]3[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[N:28][C:23]3=[N:22][CH:21]=2)=[CH:7][C:6]=1[C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1
Reactant: Fc1ccc(Br)cc1-c1cnccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1cnccn1

Procedure:
2-(5-Bromo-2-fluorophenyl)pyrazine was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 4% methanol followed by crystallisation from hot toluene gave 3-[4-fluoro-3-(pyrazin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 9.31 (1H, d, J 7), 9.14 (1H, m), 8.85 (1H, dd, J 2 and 1.5), 8.73 (1H, d, J 2), 8.32 (1H, s), 8.27 (1H, dd, J 7 and 2), 7.96 (1H, m), 7.68 (1H, dd, J 11 and 9), 7.54 (1H, d, J 7); m/z (ES+) 360 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:21])([O-])=O.CC(O)=O>C1COCC1.[Zn]>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:21]
Reactant: O=[N+]([O-])c1cc(Oc2ccnc3ccccc23)ccc1O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccnc3ccccc23)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Nitro-4-(quinolin-4-yloxy)-phenol (Step A, 200 mg) was dissolved in THF (50 mL) at 0° C. and AcOH (0.88 mL) was added followed by zinc dust (2.3 g). The mixture was stirred at RT for 1.5 h and filtered through a Celite® pad. The solvent was evaporated, the residue was dissolved in CH2Cl2 and washed with 1M NaOH. The organic phases were dried, filtered and evaporated to give the title compound as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].OS(O)(=O)=O>>[C:12]([O:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cccc(Cl)c1O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1c(Cl)cccc1C(=O)O
Temperature: 100 °C
Yield: 94.6 %

Procedure:
To a mixture of 2-hydroxy-3-chloro-benzoic acid (5.0 g, 29.0 mmol) in acetic anhydride (9.0 mL, 95.6 mmol) was added conc. H2SO4 (0.44 mL) at rt. Resulting suspension was heated in a 100° C. oil bath for 40 min. After cooled to about 50° C., the reaction mixture was poured onto ice (100 g) with stirring. Liquid was decanted off and the gooey residue was dissolved in methylene chloride, washed with water and brine, and dried over MgSO4. It was then filtered, and concentrated to give the title compound (5.89 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.99 (dd, J=7.8, 1.6 Hz, 1H), 7.66 (dd, J=7.8, 1.6 Hz, 1H), 7.28 (m, 1H), 2.39 (s, 3H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 40.3 %

Procedure:
Using cyclohexyl{3-ethyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.55 g) synthesized in Example 3(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.39 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.35 g, 41%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:36][C:37]([Cl:42])([Cl:41])[C:38](Cl)=[O:39]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([C:38](=[O:39])[C:37]([Cl:42])([Cl:41])[Cl:36])[CH2:26][CH2:27]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCNCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCN(C(=O)C(Cl)(Cl)Cl)CC2)c1
Temperature: 22 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To an ice-water cooled solution of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-(piperidin-4-yloxy)-phenyl}-urea (390.6 mg, 1.0 mmol) and triethylamine (280 μL, mmol) in dichloromethane (5 mL) is added trichloroacetyl chloride (115 μL, 1.0 mmol). The reaction mixture is allowed to warm up to 22° C. and stirred for 1 hour. After removal of solvent, the residue is purified on a silica gel chromatography with hexanes and ethyl acetate to provide a white solid (520.0 mg, 97% yield, ES+(m/z) 535.9 [M+H]).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([OH:16])[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[N:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[C:17]([O:9][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:15]=1)=[C:7]([O:16][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(c1ccccn1)C(O)c1ccccn1
Reactant: CCCCCCCCCC(=O)Cl
Product: CCCCCCCCCC(=O)OC(=C(OC(=O)CCCCCCCCC)c1ccccn1)c1ccccn1
Yield: 9.9 %

Procedure:
To 21.0 g (0.1 mole) of pulverized α-pyridoin (commercially available, e.g. from Aldrich Chemical Co.) was added 9.5 g (0.05 mole) decanoyl chloride. The reaction mixture was mixed for 30 minutes, after which it became solid. The solid was extracted with acetonitrile and the acetonitrile solution evaporated to yield an oily semisolid. Recrystallization from 70% cyclohexanone-30% acetone yielded 1.3 g (9.9%) white fine needles of compound NA-IV, m.p. 89°-90° C.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([CH2:19][O:20][C:21]2[CH:50]=[CH:49][C:24]([C:25]([N:27]4[CH2:48][CH2:47][C:30]5([NH:34]/[C:33](=[N:35]/[C:36]([C:38]6[C:43]([NH2:44])=[N:42][C:41]([NH2:45])=[C:40]([Cl:46])[N:39]=6)=[O:37])/[NH:32][CH2:31]5)[CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:22]=2)[CH:13]=[CH:12]3)[CH2:4][O:3]1>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][O:20][C:21]1[CH:50]=[CH:49][C:24]([C:25]([N:27]3[CH2:28][CH2:29][C:30]4([NH:34]/[C:33](=[N:35]/[C:36]([C:38]5[C:43]([NH2:44])=[N:42][C:41]([NH2:45])=[C:40]([Cl:46])[N:39]=5)=[O:37])/[NH:32][CH2:31]4)[CH2:47][CH2:48]3)=[O:26])=[CH:23][CH:22]=1)[CH:13]=[CH:12]2
Reactant: CC1(C)OC[C@@H](COc2ccc3cc(COc4ccc(C(=O)N5CCC6(CC5)CN/C(=N\C(=O)c5nc(Cl)c(N)nc5N)N6)cc4)ccc3c2)O1
Solvent: CO
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4ccc(OCc5ccc6cc(OC[C@@H](O)CO)ccc6c5)cc4)CC3)N2)nc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [8-{4-[6-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-ylmethoxy]-benzoyl}-1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide (0.16 g, 0.22 mmol) in MeOH (10 ml) is added SCX-2 resin (˜2 g), the resultant slurry is stirred for 0.5 hours and then the solvent is removed in vacuo. The slurry is loaded onto a column of SCX-2 resin (˜3 g) and eluted with MeOH and then with 2 M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and the residue is triturated with diethyl ether to obtain 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [8-{-4-[6-((S)-2,3-dihydroxy-propoxy)-naphthalen-2-ylmethoxy]-benzoyl}-1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide as yellow solid; [M+H]+ 675
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3C=O)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:45])[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: O=Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3O)CC2O)CCCCC1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-formylphenyl)piperidin-3-ol (1.38 g, 2.8 mmol) obtained in Step 1 of Example 61 in 50 ml of chloroform, was added 486 mg of m-chloroperbenzoic acid (5.6 mmol). The reaction mixture was stirred for about 2 hours at room temperature. The resulting organic layer was washed with the solutions of sulfurous acid and sodium bicarbonate, dried on sodium sulfate. The resulting ester residue was dissolved in 100 ml of methanol and was added a drop of concentrated hydrochloride thereto. The reaction mixture was stirred for about 1 hour, was added sodium bicarbonate (0.5 g) thereto. The reaction mixture was concentrated. The resulting residue was purified with column chromatography to give 1.0 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]([NH:21][C@@H:22]([C:26](O)=[O:27])[CH:23]([CH3:25])[CH3:24])(=[O:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[C:18]([NH:21][C@@H:22]([C:26]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])=[O:27])[CH:23]([CH3:25])[CH3:24])(=[O:20])[CH3:19]
Reactant: CC(=O)N[C@@H](C(=O)O)C(C)C
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)N[C@@H](C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O)C(C)C

Procedure:
To a solution of the active drug, preferably 2'-deoxy-5-fluorouridine, an N-protected amino acid, preferably N-acetyl-D-valine, and triphenylphosphine in an anhydrous polar aprotic solvent is added diisopropylazodicarboxylate. Upon completion of the reaction, the mixture is concentrated under reduced pressure. The prodrug, preferably a compound of Formula 11, most preferably, 2'-deoxy-5'-O-(N-acetyl-D-valinyl)-5-fluorouridine, may be isolated by conventional means.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)(=[O:5])[CH3:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)C>[CH3:11][C:8]1[S:7][C:6]([C:3](=[O:5])[CH:4]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C(=O)C=Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
A stirred solution of 2.2 grams (0.055 mole) of sodium hydroxide in 20 ml of ethanol was cooled to 0° C. and a mixture of 4.0 grams (0.03 mole) of 2-acetyl-5-methylthiophene and 3.1 grams (0.03 mole) of benzaldehyde in 5 ml of ethanol was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 16 hours. The reaction mixture was poured into aqueous 1N hydrochloric acid and extracted with methylene chloride. The extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 4.6 grams of 1-(5-methyl-2-thienyl)-3-phenyl-2-propen-1-one as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]=1[NH:6][C:7](=[O:10])[CH2:8][Cl:9])([O-:3])=[O:2].[CH3:18][O:19][CH2:20]Cl.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:9][CH2:8][C:7]([N:6]([CH2:18][O:19][CH3:20])[C:5]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2])=[O:10]
Reactant: COCCl
Reactant: O=C(CCl)Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCN(C(=O)CCl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 0.83 h
Yield: 80 %

Procedure:
To a 500 ml. stirred flask was added 3.0 g. (0.012 moles) of 2',6'-dinitro-2-chloroacetanilide, 2.5 ml. of chloromethyl methyl ether, 1.0 g. of phase transfer catalyst and 150 ml. of methylene chloride. Thereafter, 75 ml. saturated sodium carbonate solution was added in one portion and stirring continued for 50 minutes. At the end of this period, water was added to aid separation and the aqueous/organic mixture was allowed to stand overnight. The product, 2-chloro-2',6'-dinitro-N-(methoxymethyl)acetanilide, 2.9 g. m.p. 105.5°-108° C. was obtained in 80% yield.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](OCC)=[N:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:27][NH2:28])=O>C(O)CCC>[CH:1]1([N:6]2[C:10]3[C:11]4[N:12]([C:25]([C:21]5[S:20][CH:24]=[CH:23][CH:22]=5)=[N:27][N:28]=4)[CH2:13][CH2:14][C:9]=3[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NNC(=O)c1cccs1
Reactant: CCOC1=NCCc2c(CC)nn(C3CCCC3)c21
Solvent: CCCCO
Product: CCc1nn(C2CCCC2)c2c1CCn1c(-c3cccs3)nnc1-2

Procedure:
A solution of 1cyclopentyl-7-ethoxy-3-ethyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine (3.739 kg, 14.3 moles) and 2thiophenecarboxylic hydrazide (2.237 kg, 15.8 moles) were heated in a solution in 1-butanol (37 L) to ˜90° C. in a 50 gal tank for 48 hours. At this point, some 1-butanol was distilled off to remove water azeotropically. The reaction was concentrated to a low volume and 4 gallons of methylene chloride (4 gal, 15 L) was added. The organics were washed twice with 1 N HCl (8 gal, 30.3 L) and concentrated by distillation to low volume. Isopropanol (16 L) was added to the concentrate and the resulting slurry was cooled and granulated. The product was collected by filtration and vacuum oven dried at 40° C. The yield was 3.25 kg (67%) of a white solid; mp 126° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC#N>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1I
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 2-iodophenol (1 g, 4.55 mmol) in CH3CN (20 mL) was added K2CO3 (0.93 g, 6.83 mmol) and ethyl 2-bromoacetate (0.835 g, 5.0 mmol). The reaction mixture was stirred at reflux for 2 h, cooled to room temperature, extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. (1.1 g, yield 79%) MS (ESI+) e/z: 307.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].[O-]CC.[Na+].[C:18](OC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>C(O)C>[CH3:22][C:20]1[N:7]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:12])([F:13])[F:1])[NH:6][C:18](=[O:23])[CH:19]=1
Reactant: N=C(N)c1ccccc1C(F)(F)F
Reactant: COC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Yield: 50.2 %

Procedure:
A mixture of 2-trifluoromethyl-benzamidine (2.13 g, 4 mmol) and sodium ethoxide (0.83 g, 12 mmol) in ethanol (20 mL) was treated with methyl acetoacetate (0.44 mL, 4 mmol) and heated at for 24 hours. The reaction was cooled, concentrated, diluted with water and acidified with 2 N hydrochloric acid. The resulting solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (3:97)] provided the title compound (0.51 g, 50% yield) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) δ 12.7 (br s, 1H), 7.9 (m, 1H), 7.8 (m, 2H), 7.7 (m, 1H), 6.3 (s, 1H), 2.21 (s, 3H) ppm; MS (FIA) 255.0 (M+H); Rt (Method A) 2.578 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCSCCCC(F)(F)C(F)(F)F)[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=2)[C:3]1=[O:41].CS(OCCCCC[CH2:53][CH2:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][CH2:60][C:61]([F:67])([F:66])[C:62]([F:65])([F:64])[F:63])(=O)=O>>[CH3:42][C:2]1([CH3:1])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:53][CH2:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][CH2:60][C:61]([F:67])([F:66])[C:62]([F:63])([F:65])[F:64])[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([C:37]([F:38])([F:40])[F:39])[CH:29]=2)[C:3]1=[O:41]
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Yield: 13 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 1, 10-[(4,4,5,5,5-pentafluoropentypthio]decyl methanesulphonate (prepared according to an experimental protocol similar to that described in WO 2005077968) replacing 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate. The expected compound is obtained in the form of a pale yellow oil with a yield of 13% (125 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:13]([Cl:12])[CH:14]=2)=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(Br)ccc1O
Reaction time: 18 h
Yield: 46.2 %

Procedure:
A slurry of 5-bromosalicylic acid (15 g, 69 mmol) and 3,4-dichloroaniline (19.85 g, 73 mmol) and phosphorous trichloride (4.74 g 34.5 mmol) in 300 ml of chlorobenzene was refluxed for 3 hr. The hot solution was filtered through a glasswool plug and allowed to stand at room temperature for 18 hr. The crystals which deposited were collected by filtration and washed with fresh chlorobenzene and then methylene chloride to give after drying 19 g (76%) of product mp 230-233°. HPLC tr 19.25 min (Vydac HS5215 C18 ODS, 2.1×150 mm, 0.2 mL/min, gradient, A: water−0.1% trifluoroacetic acid B: acetonitrile−0.1% trifluoroacetic acid, 90-10% A during 20 min, UV detection at 214 nm). Recrystallization from chlorobenzene and then acetone gave 11.5 g of crystals, mp 237-2380°. The structure was verified by X-ray crystallography.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])([CH3:5])([CH3:4])[CH3:3].[N:13]([O-])=O.[Na+]>Cl.O>[C:2]([C:6]1[CH:7]=[C:8]([NH:9][NH2:13])[CH:10]=[CH:11][CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1cccc(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cccc(NN)c1
Reaction time: 1 h

Procedure:
3-t-Butylaniline hydrochloride (5 g) in concentrated hydrochloric acid (8 ml) was stirred at 0° whilst a solution of sodium nitrite (1.86 g) in water (2.4 ml) was slowly added. The mixture was kept at 0° for 1 hour and, after filtering (at 0°), it was treated dropwise with a solution of stannous chloride dihydrate (18.2 g) in concentrated hydrochloric acid (18.8 ml). A pink-coloured solid separated. After 1 hour, this solid was filtered off and washed with saturated aqueous sodium chloride. The resulting salt was converted into base in the usual way to give 3-t-butylphenylhydrazine, b.p. 88°-90°/0.25 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:16][C:17]#[CH:18])[N:3]=[CH:4][N:5]=1
Reactant: C#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 96 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 26 mg of 2-propyn-1-ol, to which 19 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 42 mg of 4-(2,3-difluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (82)).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][S:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]2[CH3:19])[C:5]2[CH2:10][S:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CSC2
Reactant: C[C@H]1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CSC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 2,4-dichloro-5,7-dihydrothieno[3,4-d]pyrimidine (300 mg, 1.45 mmol) and Et3N (294 mg, 2.9 mmol) in DMF (5.0 mL) at 0° C. was added 3-(S)-methylmorpholine (161 mg, 1.59 mmol) dropwise. After the addition was complete, the mixture was stirred overnight at rt. The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give the crude product which was purified by preparative TLC (Eluent: petroleum ether/ethyl acetate=2/1) to provide 2-chloro-5,7-dihydro-4-((S)-3-methylmorpholino)thieno[3,4-d]pyrimidine as a light yellow solid (283 mg, 72%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:10][C:8]1[CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=[CH:6][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 24 h
Yield: 98 %

Procedure:
3-Hydroxyacetophenone (136.15 g, 1 mol), potassium carbonate (414.63 g, 2 mol), KI (33.2 g, 0.2 mol), and benzyl bromide (171.04 g, 1 mol) were dissolved in acetone and the reaction mixture was refluxed while stirring for 24 hours, followed by washing with brine. The reaction mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 1-(3-benzyloxyphenyl)ethanone (221.8 g, yield 98%) in an oil state.