Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[CH:27]=[C:28]([NH:33][CH3:34])[C:29]([NH2:32])=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C.[CH3:44][O:45][C:46]([CH:48]1[CH2:50][CH:49]1[C:51](O)=O)=[O:47]>CN(C=O)C.O>[Br:25][C:26]1[CH:31]=[CH:30][C:29]2[N:32]=[C:51]([CH:49]3[CH2:50][CH:48]3[C:46]([O:45][CH3:44])=[O:47])[N:33]([CH3:34])[C:28]=2[CH:27]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: COC(=O)C1CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1CC1c1nc2ccc(Br)cc2n1C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (554 mg) was added to a solution of 4-bromo-N2-methylbenzene-1,2-diamine (279 mg), diisopropylethylamine (0.727 mL) and (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (200 mg) in DMF (5 mL) at room temperature. The mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was dissolved in acetic acid (5 mL), and the mixture was stirred at 80° C. for 1 hr. After concentration of the reaction mixture, saturated sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (80 mg) as a pale brown solid.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C@@:4]12[C@H:13]3[CH2:14][CH:15]=[C:16]4[C@@H:21]5[CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH2:25][C@:20]5([C:28]([OH:30])=[O:29])[CH2:19][CH2:18][C@@:17]4([CH3:31])[C@:12]3([CH3:32])[CH2:11][CH2:10][C@H:9]1[C:8]([CH3:34])([CH3:33])[C@@H:7]([OH:35])[CH2:6][CH2:5]2.O.ClCCl>C(OCC)C>[CH3:3][C@@:4]12[C@H:13]3[CH2:14][CH:15]=[C:16]4[C@@H:21]5[CH2:22][C:23]([CH3:26])([CH3:27])[CH2:24][CH2:25][C@:20]5([C:28]([O-:30])=[O:29])[CH2:19][CH2:18][C@@:17]4([CH3:31])[C@:12]3([CH3:32])[CH2:11][CH2:10][C@H:9]1[C:8]([CH3:34])([CH3:33])[C@@H:7]([OH:35])[CH2:6][CH2:5]2.[Na+:2]
Reactant: CC1(C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CC[C@]2(C(=O)[O-])CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]2C1

Procedure:
A 10% aqueous solution of sodium hydroxide is added to an almost saturated solution of oleanolic acid in a water immiscible solvent, for example dichloromethane or diethyl ether. The volume of the sodium hydroxide solution is controlled by the amount of oleanolic acid taken; the final mixture should contain at least one, preferably 1,5 to 3, mole sodium hydroxide per mole oleanolic acid--a large excess of the sodium hydroxide solution may lower the yield. The mixture is mixed well (vigorous stirring or shaking) and the precipitated sodium oleanolate is separated. The sodium oleanolate can be recrystallised from aqueous organic solvents, preferably aqueous methanol or aqueous ethanol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[N:14]/[S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13])=[N:2]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccon1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C/c1ccon1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
In a round-bottomed flask, isoxazole-3-carbaldehyde (300 mg, 3.09 mmol) was dissolved in THF (7 ml) and 2-methylpropane-2-sulfinamide (450 mg, 3.71 mmol) and titanium(IV) ethoxide (1.3 ml, 6.18 mmol) were added. The reaction mixture was stirred at room temperature overnight then slowly quenched by dropwise addition of brine (2 ml) which resulted in the formation of a thick yellow precipitate. The reaction mixture was diluted with ethyl acetate and stirred vigorously at room temperature for 10 min. The suspension was filtered over Celite and rinsed with ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 585 mg (95%) of 2-methyl-propane-2-sulfinic acid 1-isoxazol-3-yl-meth-(E)-ylideneamide as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[F-:12].[Cs+].Cl[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]2[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17][CH:16]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:12][C:3]1[CH:4]=[C:5]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17][CH:16]=2)[CH:6]=[C:7]([F:8])[CH:2]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: [F-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cc(F)cc(F)c3)ccc12
Temperature: 100 °C
Yield: 90.8 %

Procedure:
645 mg of 3,4-difluorophenylboronic acid, 1.24 g of caesium fluoride, 13 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 25, in 30 cm3 of dioxane. The mixture is then heated at about 100° C. for 17 hours. The mixture is allowed to return to about 19° C. and then filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 75 cm3 of ethyl acetate and 50 cm3 of distilled water. The insoluble material is filtered off on a sinter funnel The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure under the conditions described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume) and collecting 35 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 1.1 g of N-[6-(3,5-difluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of an orange-coloured oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)cc1C1OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
A mixture of 5-bromo-2-fluoro-benzaldehyde (24.92 g, 123.2 mmol), ethylene glycol (21.0 mL, 369.6 mmol), toluene (650 mL), and TsOH (2.49 g, 12.4 mmol) were heated at reflux under a N2 atmosphere in a flask fitted with a Dean Stark trap and condenser. After 18 h, the mixture was cooled to rt, washed with a satd. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by FCC (EtOAc/hexanes) gave the desired product (28.74 g, 95%) as an oil. 1H NMR (CDCl3): 7.68-7.63 (m, 1H), 7.45-7.39 (m, 1H), 6.98-6.91 (m, 1H), 6.05-6.00 (m, 1H), 4.12 (br s, 2H), 4.02 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:22])([CH3:21])[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:5]=[C:4]([CH3:23])[C:3]=1[C:24]([OH:26])=[O:25].C([O-])(O)=O.[Na+:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:21])([CH3:22])[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:5]=[C:4]([CH3:23])[C:3]=1[C:24]([O-:26])=[O:25].[Na+:31]
Reactant: Cc1nc2cccc(OCC(C)(C)C(=O)NC(C)C)c2c(N)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2cccc(OCC(C)(C)C(=O)NC(C)C)c2c(N)c1C(=O)[O-]

Procedure:
Prepared as in Example G from 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylic acid (Example 1) and NaHCO3 as a white solid (100%). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.4 Hz, 6H), 1.23 (s, 6H), 2.56 (s, 3H), 3.86-3.94 (m, 1H), 4.07 (s, 2H), 6.66 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H). MS 360 (MH++H—Na).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:28]C(C)([O-])C.[K+].IC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH3:28])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(F)cc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To an ice-cold suspension of 0.07 g (0.17 mmol) 4-(2,5-dichloro-phenoxy)-N-(5-fluoro-2-methoxy-phenyl)-nicotinamide in 1 mL tetrahydrofuran were added 0.019 g (0.17 mmol) potassium tert-butoxide followed by 10 μl (0.18 mmol) iodomethane. The suspension was stirred at room temperature for 16 hours, poured onto 10% aqueous citric acid solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give 32 mg (44%) of the title compound as a white solid. MS (ESI): m/z=421.052 [M+H]+.
Reaction SMILES: [Mg].II.Br[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[C:12]1(=[O:32])[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=O)[C:15](=[O:27])[C:14]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:13]12.CC[O:35]CC>>[OH:35][CH:5]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:12](=[O:32])[C:13]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:14]2[C:15]1=[O:27]
Reactant: O=CCCCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CCOCC
Reactant: BrCc1ccncc1
Agent: II
Agent: [Mg]
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCC(O)c1ccncc1

Procedure:
Magnesium (1.2 equiv.) is stirred in anhydrous ether under a nitrogen atmosphere and a catalytic amount of iodine is added. The mixture is heated to reflux and 4-bromomethylpyridine (1 equiv.) is added. The reaction is stirred until formation of the Grignard reagent is complete and 9-phthalimidononanal (1.5 equiv.) is added. The reaction mixture is stirred until completion, quenched with ammonium chloride, extracted with brine and concentrated in vacuo. The crude product is purified by silica gel chromatography to give 1-hydroxy-1-(4-pyridinyl)-10-phthalimidodecane.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:25][CH2:26][CH:27]([NH:30][C:38](=[O:40])[CH3:39])[CH2:28][CH2:29]4)=[O:23])=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 0.67 h
Yield: 45.8 %

Procedure:
Stirred 4-aminopiperidyl 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl ketone hydrochloride (300 mg, 0.582 mmol) in 10 mL THF with triethylamine (0.293 mg, 2.91 mmol). Acetic anhydride (89 mg, 0.873 mmol) was added and the reaction was stirred for 40 minutes. The solution was concentrated down and purified by preparative HPLC to give N-{1-[(4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]-4-piperidyl}acetamide (0.120 g, 46% yield): HPLC Retention time; 6.92 min. (Method B) M+1; 450.4
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]([C:18]#[CH:19])([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:4][CH2:3]1.Cl.[C:21]1([O:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(Cl)Cl>[O:27]([C:28]([N:2]1[CH2:3][CH2:4][C:5]([C:18]#[CH:19])([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:7]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-4-ethynyl-4-(2-nitrophenoxy)piperidine (liberated from 10.0 g of the hydrochloride) in 45 ml of methylene chloride was added dropwise a solution of 5.8 g of phenylchloroformate in 45 ml of methylene chloride. The mixture was stirred at room temperature for 1 hr and at reflux, under nitrogen, for 16 hrs. The solution was allowed to cool to room temperature, poured into water, extracted with methylene chloride, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of solvent provided an oil (13.9 g). A 2.2 g sample of the oil was chromatographed on 150 g of alumina. The column was eluted with three 150 ml volume of ether. Evaporation of the solvent from the second fraction provided 1.36 g (65%) of product. Recrystallization from isopropyl alcohol provided the analytical sample, mp 76°-80°.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][NH2:18])=[N:15][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][NH:18][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])=[N:15][CH:16]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(Cl)N1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNc1ccc(F)cn1)N1CCCCC1
Yield: 84 %

Procedure:
1-Piperidine carbonyl chloride (348 mg, 0.30 mL, 2.36 mmol) was added dropwise to a solution of 5-fluoro-2-hydrazinyl-pyridine (see for reference WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol) and DIPEA (1.2 mL, 7.08 mmol) in DCM (10 mL) at RT under nitrogen and the mixture stirred for 2 h. The solution was washed with water (2×15 mL) and dried (Na2SO4). The solvent was evaporated and the residue triturated (diethyl ether) and filtered to afford the title compound as an off-white solid (475 mg, 84%). LCMS (Method 1): Rt 1.82 min, m/z 239 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 83.3 %

Procedure:
A suspension of 6-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (843 mg, 3 mmol), 5-chloromethyl-2-(trifluoromethyl)pyridine (704 mg, 3.6 mmol) and solid K2CO3 (830 mg, 6 mmol) in anhydrous DMF (10 mL) was stirred at 70° C. for 20 min. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the reaction was diluted with water and extracted with EtOAc (40 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by trituration with CH2Cl2-hexanes to afford 1.10 g (84%) of the title compound as a yellow solid. LC/MS (method A): retention time=3.50 min, (M+H)+=440.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][CH2:12][C:13]1[C:14]([CH3:19])=[N:15][NH:16][C:17]=1[CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][CH2:12][C:13]2[C:14]([CH3:19])=[N:15][NH:16][C:17]=2[CH3:18])=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: Cc1n[nH]c(C)c1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1n[nH]c(C)c1CCSc1ccc(Cl)cc1N
Yield: 74.5 %

Procedure:
Following General Procedure A, the title compound (517 mg, 74%) was prepared from 2-Amino-4-chloro-benzenethiol (590 mg, 3.693 mmol) and 4-(2-bromo-ethyl)-3,5-dimethyl-1H-pyrazole (500 mg, 2.462 mmol), K2CO3(1.7 g, 12.31 mmol) in DMF (20 ml).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[CH:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[C:9]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[N:8]=3)[CH:6]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.23) (0.966 g, 2.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.829 g, 2.4 mmol) according to the general procedure VI. Obtained as a white solid (0.158 g, 14%). MS (ISP) 575.2 [(M+H)+].
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([O:18]C)=[O:17])=[CH:14][C:13]([S:20][CH3:21])=[N:12]2)=[CH:7][CH:6]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([S:20][CH3:21])=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(SC)nn1-c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2nc(SC)cc2C(=O)O)cc1
Reaction time: 21 h
Yield: 98.9 %

Procedure:
A solution of lithium hydroxide (4.5 mL, 1.0 M, 4.5 mmol) was added to a suspension of methyl 1-(4-methoxyphenyl)-3-methylthio-1H-pyrazole-5-carboxylate (840 mg, 3.0 mmol) in MeOH (30 mL) and stirred at room temperatureerature for 21 hours. The resulting mixture was concentrated and partitioned between EtOAc and H2O. The organic layer was removed, and the aqueous layer was acidified with 1M HCl and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and evaporated to yield clean product (784 mg, 98%). 1H NMR (CDCl3): δ7.33 (d, 2H, J=8.4), 6.97 (s, 1H), 6.95 (d, 2H, J=8.4), 3.85 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH2:28])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.N1C=CC(N)=NC=1N>>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH:28][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[C:5]([F:16])=[CH:4][N:3]=3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: NCc1ccc2c(c1)OCCO2
Agent: Nc1ccnc(N)n1
Product: Oc1cccc(Nc2nc(NCc3ccc4c(c3)OCCO4)ncc2F)c1

Procedure:
In a manner analogous to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-6-ylmethylamine gave N2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4:pyrimidinediamine. 1H NMR (CDCl3) δ 4.24 (s, 4H), 4.45 (d, J=6.0 Hz, 2H), 6.55 (ddd, J=0.9, 2.4 and 8.4 Hz, 1H), 6.66 (d, 1H), 6.84 (m, 4H), 6.90 (m, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.30 (m, 1H), 7.86 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3) δ −170.44; LCMS: ret. time: 18.33 min.; purity: 96.75%; MS (m/e): 369.03 (MH+).
Reaction SMILES: [OH-:1].[K+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:15](O)(=[O:17])C.[C:19](O)(=O)C.IC1C=CC=CC=1.C(OCC)(=O)C>CO>[OH:1][CH:9]1[C:4]([O:17][CH3:15])([O:3][CH3:19])[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8]1
Reactant: [OH-]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CC(=O)O
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(OC)(OC)C(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a stirred solution of potassium hydroxide (42 g, 752 mmol) in dry methanol (100 mL), at 0° C. and under an atmosphere of N2, was added a solution of ethyl 4-oxopiperidine-1-carboxylate (26.4 mL, 29.96 g, 175 mmol) in dry methanol (75 mL) via syringe. The resulting solution was stirred for an additional 30 minutes under an atmosphere of N2 at 0° C. To it, in small portions over approximately 90 minutes, was added iodobenzene diacetate (84.6 g, 262 mmol). Temperature was kept near 0° C. throughout this time. The reaction was stirred overnight under an atmosphere of N2, gradually reaching room temperature. Complete conversion was suggested by TLC (50% ethyl acetate in hexanes; Hanessian's stain; Rf˜0.25) in the morning. The reaction was concentrated under vacuum. To the residue was added approximately 50 mL water; from this mixture was extracted the crude product with ethyl acetate (3×200 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated. The crude product was purified using column chromatography (silica gel; 10-65% ethyl acetate in hexanes), yielding 26.74 g (66%) of a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16]([SH:22])=[CH:15][CH:14]=1
Reactant: Cc1[nH]cnc1CSCCNC(=N)c1ccc(O)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1[nH]cnc1CSCCNC(=N)c1ccc(S)cc1

Procedure:
N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]-4-hydroxybenzamidine and a slight excess of phosphorus pentasulphide were refluxed in pyridine for 45 minutes to give the title compound.