Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:19])[CH2:14][CH2:13]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reaction time: 1 h

Procedure:
To 3,5-dichlorobenzyl 4-(3-(tert-butoxycarbonylamino)propyl)piperazine-1-carboxylate (step 1) (438 mg, 0.981 mmol) in DCM (6 ml) was added TFA (3 ml, 38.9 mmol). The resulting solution was stirred for 1 hr and then concentrated under reduced pressure. The residue was basified with saturated sodium bicarbonate solution (50 ml) and extracted with EtOAc (2×100 ml). The combined extracts were dried (MgSO4) and concentrated to give 3,5-dichlorobenzyl 4-(3-aminopropyl)piperazine-1-carboxylate as a tan crystalline solid;
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:13]=1)(=[O:3])[CH3:2].[CH2:35]([N:37]([CH2:41][CH3:42])[C:38](Cl)=[O:39])[CH3:36]>C1COCC1>[C:1]([O:4][C@@H:5]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:38]([N:37]([CH2:41][CH3:42])[CH2:35][CH3:36])=[O:39])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cncc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1
Temperature: 110 °C

Procedure:
1 g (2.02 mM) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 0.5 ml (3.95 mM) of diethylcarbamoyl chloride, 50 mg (0.06 mM) of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane and 15 ml of THF are placed under an argon atmosphere in a reactor adapted for microwaves. The mixture is heated at 110° C. for 30 minutes by microwaves. The cooled reaction mixture is filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using pure dichloromethane and then a dichloromethane/methanol mixture (9/1; v/v) as the eluent. After washing with an ether/isopropyl ether mixture, the brown solid obtained is used directly in the deacetylation reaction described in Example 160.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH3:12]>>[CH2:11]([C:13]1[O:14][C:15]([CH:4]=[O:5])=[CH:16][CH:17]=1)[CH3:12]
Reactant: CCc1ccco1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc(C=O)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A sample of DMF (9.3 mL, 120 mmol) was cooled to 0° C. and POCl3 (3.37 g, 22 mmol) was added, the mixture was stirred for 1 hour at 0° C., then 2-ethyl furan (1.92 g, 20 mmol) was added. The reaction was quenched by pouring onto ice, and the mixture was stirred for 18 hours. The mixture was extracted with hexane, which was dried over MgSO4 and concentrated to give 1.71 g of the title compound (used without further purification).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[CH:6][CH:5]=1.[Li]CCCC.[Cl:22]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:22][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:15])[F:16])=[CH:5][CH:6]=2)=[CH:11][N:12]=1
Reactant: FC(F)(F)Oc1ccc(-c2cnco2)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(-c2cnc(Cl)o2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
To a round bottom flask was added 5-(4-(trifluoromethoxy)phenyl)oxazole (3.49 g, 15.23 mmol) and THF (15 mL). The reaction was cooled to −78° C. Then 2.5 M nBuLi (6.70 mL, 16.75 mmol) was added to the reaction at −78° C. The reaction turned to deep red color. After 15 min, hexachloroethane (2.59 mL, 22.84 mmol) was added at −78° C. The reaction was slowly warmed to rt over 2 hrs. The reaction was then poured onto ice and extracted with EtOAc (2×30 ml). The combined EtOAc layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 2-chloro-5-(4-(trifluoromethoxy)phenyl)oxazole, (2 g, 7.59 mmol, 49.8% yield) as a light orange liquid. Anal. Calcd. for C10H5F3NO2 m/z 263.1, found: 264.1 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.64 (s, 2 H), 7.30 (s, 4 H); 13C NMR (126 MHz, CDCl3) δ ppm 152.51, 149.41, 146.62, 125.57, 123.83, 121.41, 119.36.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.Cl[CH2:12][CH:13]=O.C(=O)(O)[O-].[Na+].C>C(OCC)C>[CH3:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]2[CH:12]=[CH:13][N:1]=[C:2]2[CH:7]=1
Reactant: CSc1nc(C)cc(N)n1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CSc1nc(C)cc2nccn12
Temperature: 80 °C

Procedure:
A mixture of 5 g (32 mmole) of 4-amino-6-methyl-2-methylthiopyrimidine and 10 g (64 mmole) of a 50% aqueous solution of chloroacetaldehyde was heated at 80° C. for one hour. The mixture was cooled with an ice bath and immediately neutralized with sodium bicarbonate. The mixture was extracted with chloroform and the extracts were dried over magnesium sulfate and evaporated to provide an oil. The oil was extracted with hot ethyl acetate, and the extracts were filtered and then evaporated. The residue was dissolved in hot benzene, treated with decolorizing charcoal, and filtered, and the filtrate was evaporated. The residue thereby obtained was dissolved in hot diethyl ether, treated with decolorizing charcoal, and filtered, the filtrate then being evaporated. The residue obtained was recrystallized first from a benzene/hexane mixture and then from cyclohexane, each time accompanied by treatment with decolorizing charcoal. The solid was purified on a preparative scale high pressure liquid chromatograph using ethyl acetate as the eluent. The solid obtained was recrystallized from hexanes to give white crystals of 7-methyl-5-methylthioimidazo[1,2-c]pyrimidine, m.p. 67°-69° C. Analysis: Calculated for C8H9N3S: %C, 53.6; %H, 5.1; %N, 23.4; Found: %C, 53.2; %H, 5.0; %N, 23.8.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cncc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cncc(/C=C/C(=O)O)c2)cc1
Reaction time: 120 h
Yield: 90.3 %

Procedure:
To a solution of methyl (E)-3-[5—(4-methylphenyl)-pyridin-3-yl]acrylate (2.25 g) in tetrahydrofuran (20 ml) was added 1N sodium hydroxide (11 ml) at room temperature, and the mixture was stirred for 5 days. To the reaction mixture was added 1N hydrochloric acid (12 ml), and the mixture was concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with water and diethylether to give (E)-3-[5—(4-methylphenyl)pyridin-3-yl]acrylic acid (1.92 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Mg].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([OH:14])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A solution of 5.00 g of N-t-butoxycarbonyl-3-oxopiperidine in 10 ml of tetrahydrofuran was added dropwise under ice-cooling to a Grignard reagent solution prepared from 4.73 g of bromobenzene and 0.79 g of magnesium in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 1 hour, followed by cooling with ice, and 100 ml of a saturated aqueous solution of ammonium chloride was added thereto dropwise. The reaction mixture was extracted with ethyl acetate, and the extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give 4.21 g of N-t-butoxycarbonyl-3-hydroxy-3-phenylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(C(C)C)CC)(C)C.O>O1CCCC1>[CH3:32][S:33]([O:31][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:9][S:10](=[O:12])(=[O:13])[C:11]=2[C:2]=1[NH2:1])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(O)c3N)N2)c(O)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(OS(C)(=O)=O)c3N)N2)c(O)c2ccccc21
Yield: 247.5 %

Procedure:
A solution of the product of Example 354 (44 mg, 0.099 mmol) and methane sulfonyl chloride (0.010 mL, 0.011 mmol) in tetrahydrofuran (4 mL) was treated with diisopropylethylamine (0.075 mL, 0.040 mmol) at roo, temperature for 2 hours. The solution was poured into water. The resulting the precipitate was filtered, dried, and purified by flash column, eluting with 1% methanol in dichloromethane to yield the title compound (14.2 mg, 28%). The sodium salt was made by the procedure of Example 1D. MS (ESI−) m/z 520 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.03 (d, J=6.62 Hz, 6 H) 1.88 (m, 1 H) 2.71 (m, 2 H) 3.46 (s, 3 H) 5.94 (m, 1 H) 6.53 (m, 1 H) 7.16 (m, 1 H) 7.35 (m, 1 H) 7.64 (m, 2 H) 8.09 (d, J=7.35 Hz, 1 H) 16.23 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)c1ccc(O)cc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1cc([N+](=O)[O-])c(O)cc1F
Temperature: -5 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a mixture of 1-(2-fluoro-4-hydroxy-phenyl)-ethanone (5 g, 32.5 mmol) in concentrated sulfuric acid (50 mL) at −5° C. was added KNO3 (3.29 g, 32.6 mmol) in portions and the mixture was stirred for 3 h at −5° C. The mixture was poured into ice water (120 mL) and the aqueous solution was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 2-10% EtOAc in petroleum ether) to give 1-(2-fluoro-4-hydroxy-5-nitro-phenyl)-ethanone as a yellow solid (4.59 g, 71%). 1H-NMR (CDCl3, 400 MHz): δ 10.95 (s 1H), 8.79 (d, J=7.2 Hz, 1H), 6.92 (d, J=11.2 Hz, 1H), 2.63 (d, J=5.2 Hz, 3H).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N:27]=[C:28]=[S:29]>C1C=CC=CC=1.CCCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[NH:27][C:28]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:29]
Reactant: CCCCCCC(=N)N
Reactant: FC(F)(F)c1ccc(Cl)c(N=C=S)c1
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCCCCCC(=N)NC(=S)Nc1cc(C(F)(F)F)ccc1Cl

Procedure:
Following a procedure similar to that described in Example 42 but using 1.86 g. sodium in 250 ml. dry acetone, 13.4 g. heptanamidine hydrochloride, and 19.2 g. 2-chloro-5-(trifluoromethyl)phenyl isothiocyanate [prepared from 2-chloro-5-(trifluoromethyl)aniline] in 70 ml. acetone there was obtained 1-[2-chloro-5-(trifluoromethyl)phenyl]-3-(heptanimidoyl)-2-thiourea, m.p. 88°-90°C. (from benzene-n-hexane); hydrochloride (10.3 g.), m.p. 160°-161°C. (from acetonitrile).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24]([O:28]C)=[N:23][CH:22]=[CH:21]3)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1.O>[N:11]1([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[NH:23][CH:22]=[CH:21]3)(=[O:17])=[O:16])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COc1nccc2cc(S(=O)(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]ccc2cc(S(=O)(=O)N3CCCNCC3)ccc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
110 mg of 6-(4-tert-butoxycarbonyl-1,4-diazepan-1-ylsulfonyl)-1-methoxyisoquinoline was dissolved in 2 mL of 1,4-dioxane and 1.5 mL of water. 4 mL of a 4 M hydrochloric acid-dioxane solution was added dropwise thereto, and the mixture was then stirred at 90° C. for 16 hours. After the completion of reaction, the reaction solvent was distilled off. The obtained residue was dissolved in 5 mL of methanol, and 5 mL of ethyl acetate was then added with vigorous stirring. The deposited white crystal was collected by filtration and dried under reduced pressure to obtain 64 mg of the compound of interest as a white crystal (72%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:14]=1.C(O)(=O)C>COC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: COc1ccc(O)cc1
Agent: COC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
NaH (155 mg) was added to a solution of 4-methoxy-phenol (500 mg) in dimethyl ether (DME) (2 ml) and stirred for 1 hour. (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added to the mixture, and the mixture was heated at 150° C. for 30 minutes under microwave irradiation. The reaction mixture was acidified to pH=7 with acetic acid and purified by preparative LC-MS to give [1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (30 mg). LC-MS: m/e 347(MH+). 1H NMR(CDCl3): δ 2.18(s, 3H), δ 3.85(s, 3H), δ 5.64(s, 1H), δ 6.78(s, 1H), δ 6.87(s, 1H), δ 7.02(m, 2H), δ 7.21(m, 3H), δ 7.31(m, 1H), δ 7.54(d, 2H), δ 8.27(d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:6](=[N:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][C:3]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[OH:17][C:16]1[C:15]([OH:19])=[N:1][C:2]2[C:10]3=[N:9][N:8]([CH3:11])[N:7]=[C:6]3[CH:5]=[CH:4][C:3]=2[N:12]=1
Reactant: Cn1nc2ccc(N)c(N)c2n1
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cn1nc2ccc3nc(O)c(O)nc3c2n1
Yield: 30.1 %

Procedure:
A solution of 4,5-diamino-2-methylbenzotriazole (2.5 g, 15.3 mmol) and oxalic acid dihydrate (2.5 g, 19.8 mmol) in 80 ml of 4M hydrochloric acid was refluxed on an oil bath for 1 h. The cooled mixture was filtered, and the precipitate was washed with water and ethanol. Recrystallization from ethanol with decolourising charcoal afforded 1.0 g (30%) of the title compound; m.p. >300° C.; IR (KBr): 3500-200, 1690 cm-1 ; lH-NMR (DMSO-d6): 4.48 (s, 3H, CH3), 7.25 (d, J =9 Hz, lH, ArH), 7.60 (d, J =9 Hz, lH, ArH), 2.03 (broad s, lH, OH), 12.47 (broad s, lH, OH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].C(#N)C.[OH:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:15][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
tert-Butyl(2-bromoethyl)carbamate (5.00 g, 23.5 mmol) was stirred under an argon atmosphere at room temperature with acetonitrile (74 mL). Then, N-hydroxyphthalimide (Pht-OH, 3.83 g) and triethylamine (5.64 g) were added, followed by stirring the reaction mixture at 70° C. for 24 hours. After completion of the reaction, the reaction solution was concentrated, followed by diluting with ethyl acetate and washing with 0.5M hydrochloric acid and saturated sodium bicarbonate aqueous solution, and the organic layer was dried over magnesium sulfate, to the residue resulting from distilling off the solvent under reduced pressure was added ethyl acetate (10 ml), followed by adding hexane, thereby 4.72 g of the title compound was afforded (yield 65.7%). The instrumental data were consistent with those of the compound of Reference Example 7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH:5]2[CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8]1.Cl[C:21]1[N:26]=[C:25]([NH:27][CH2:28][C:29]2[C:30]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[N:31][CH:32]=[CH:33][CH:34]=2)[C:24]([C:41]([F:44])([F:43])[F:42])=[CH:23][N:22]=1.COC1C(CCN)=CC(OC)=C([125I])C=1>O1CCOCC1>[CH3:40][N:35]([C:30]1[C:29]([CH2:28][NH:27][C:25]2[C:24]([C:41]([F:44])([F:42])[F:43])=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:12]=[CH:11][C:10]4[CH:9]5[CH2:13][CH:5]([CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:8]5)[C:4]=4[CH:3]=3)[N:26]=2)=[CH:34][CH:33]=[CH:32][N:31]=1)[S:36]([CH3:39])(=[O:37])=[O:38]
Reactant: Nc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Reactant: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Agent: COc1cc(CCN)c(OC)cc1[125I]
Solvent: C1COCCO1
Product: CN(c1ncccc1CNc1nc(Nc2ccc3c(c2)C2CC3CN(C(=O)C(F)(F)F)C2)ncc1C(F)(F)F)S(C)(=O)=O
Yield: 19.9 %

Procedure:
A mixture of 1-(4-Amino-10-aza-tricyclo[6.3.1.02.7]dodeca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (158 g, 0.624 mmol) (see International Publication Nos. WO01/076576A2, WO01/062736A1, WO99/35131 and European Patent No. EP 1078637), 1,4-dioxane (1.00 mL), N-{3-[(2-Chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (247 mg, 0.624 mmol) and DIAE (255 mL, 1.47 mmol) was heated to 110° C. under a gentle flow of nitrogen. After sixteen hours, the mixture was concentrated, and the resulting residue was purified over silica (95:5:0.5 CHCl3:CH3OH:NH4OH) to provide (+/−) N-Methyl-N-(3-{[2-(10-trifluoroacetyl-10-aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-trien-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide (3) as a white foam (78 mg, 0.124 mmol, 20%). C26H25F6N7O3S LC/MS (Method F) 630.3 (MH+); 19F NMR (D6-DMSO) δ −60.38, −67.99 (1:1 ratio) ppm.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:3]=1N.[CH:12](O)=[O:13]>>[CH:12]([NH:9][C:6]1[CH:7]=[CH:8][CH:2]=[CH:3][CH:5]=1)=[O:13]
Reactant: O=CO
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Product: O=CNc1ccccc1

Procedure:
2-Chloro-5-nitroaniline (43.1 g, 250 mmol), formic acid (250 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated in vacuo. The solid residue was taken up in water (350 mL), filtered, washed with water (×2). The solid residue was dried at 50° C. under vacuum to give a crude formanilide as a light brown amorphous. The crude formanilide, thionyl chloride (164 mL) and sulfuryl chloride (58 mL) was combined, and heated at 55° C. for 48 hr. The mixture was concentrated in vacuo. The residue was dissolved in petroleum ether, decanted from a precipitate and the clear solution was evaporated in vacuo to give the title compound (42.2 g, 166 mmol, 67%) as a light brown amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[CH:18]=3)=[CH:15][C:14]([CH:43]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]>C(O)(C(F)(F)F)=O.OS(C(F)(F)F)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[CH:18]=3)=[CH:15][C:14]([CH:43]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(C(C)N4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)nc(C)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)N3CCOCC3)cc2-c2cc(N)nc(C)n2)cc1F
Temperature: 80 °C
Yield: 68.3 %

Procedure:
A solution of 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-(1-(4-morpholinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.272 g, 0.400 mmol) in TFA (3 mL) was treated with a few drops of triflic acid and heated at 80° C. for 3 h. After cooling to RT, the reaction mixture was concentrated. A few ice cubes were added and saturated NaHCO3 (aq.) was added until pH of about 7. The aqueous layer was extracted with CH2Cl2/n-BuOH (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 30% MeOH in CH2Cl2 to give 120 mg of 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-(1-(4-morpholinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamine as a mixture of enantiomers as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.21 (s, 1H); 8.33 (dd, J=13.01, 2.25 Hz, 1H); 8.12-8.21 (m, 2H); 7.96 (d, J=2.15 Hz, 1H); 7.04 (s, 2H); 6.79 (s, 1H); 3.92 (s, 3H); 3.57 (t, J=4.79 Hz, 4H); 3.43 (q, J=6.65 Hz, 1H); 2.51 (s, 3H); 2.38-2.47 (m, 2H); 2.27-2.36 (m, 2H); 1.34 (d, J=6.65 Hz, 3H). m/z (ESI, +ve) 440.1 (M+H)+.