Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:18]C3C=C(C)N=C(C)N=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6].ClC1C=C(C=C(Cl)C=1N1C=C2C(Cl)=NC=CC2=N1)C#N.[F:49][CH2:50][C:51]1[CH:56]=[CH:55][N:54]=[C:53](N)[N:52]=1>>[Cl:28][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:18][C:53]3[N:52]=[C:51]([CH2:50][F:49])[CH:56]=[CH:55][N:54]=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6]
Reactant: Nc1nccc(CF)n1
Reactant: Cc1cc(Nc2nccc3nn(-c4c(Cl)cc(C#N)cc4Cl)cc23)nc(C)n1
Agent: N#Cc1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Product: N#Cc1cc(Cl)c(-n2cc3c(Nc4nccc(CF)n4)nccc3n2)c(Cl)c1
Yield: 5 %

Procedure:
Following the procedure described for 3,5-dichloro-4-[4-(2,6-dimethylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzonitrile, 3,5-dichloro-4-(4-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile and 4-fluoromethylpyrimidin-2-ylamine were reacted to afford the title compound as a yellow solid (6 mg, 5% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.74-9.73 (m, 1H), 8.98 (d, J=5.2 Hz, 1H), 8.53 (s, 2H), 8.07 (s, 1H), 8.05 (s, 1H), 7.62 (dd, J=7.3, 0.9 Hz, 1H), 7.55-7.52 (m, 1H), 5.78-5.75 (m, 1H), 5.66-5.63 (m, 1H). LCMS (Method B): RT=3.04 min, m/z: 414 [M+H+].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[CH3:15][O:16][CH2:17][CH:18]1[O:20][CH2:19]1>>[CH3:15][O:16][CH2:17][CH:18]([OH:20])[CH2:19][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: COCC1CO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COCC(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 98 °C
Yield: 108.4 %

Procedure:
A mixture of 4-pyrazoleboronic acid pinacol ester (4.24 g, 21.9 mmol) and glycidyl methyl ether (7.94 g, 76.6 mmol) was heated to 98° C. for 4 h. It was cooled to r.t. and concentrated in vacuo to give the title compound (6.7 g, quantitative) as a yellow oil. δH (CDCl3) 1.32 (12H, s), 3.37 (3H, s), 3.12-3.54 (3H, m), 4.08-4.37 (3H, m), 7.73 (1H, s), 7.80 (1H, s).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N+:7]2[O-:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2c(F)c(F)ccc2n1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(F)c(F)ccc2[n+]1[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
1.0 g of 5,6-difluoro-2-methylquinoline was dissolved in 30 ml of chloroform and then a mixture of 20 ml of chloroform and 1.0 g of 3-chloroperbenzoic acid was added dropwise thereto under cooling in an ice bath. The resulting mixture was stirred for 2 hours at 0° C. and for additional one hour at room temperature. The reaction mixture was washed twice with a saturated aqueous solution of sodium bicarbonate and washed with a saturated aqueous solution of sodium chloride. After drying, the solvent was distilled off in vacuo and the residue was purified by silica gel column chromatography to give 830 mg of 5,6-difluoro-2-methylquinoline-1-oxide. The product was recrystallized from a mixture of benzene and hexane to give a white powder with mp 125°-127° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[N:13]([CH2:25][C:26]#[C:27][CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([C:17](OC)=[O:18])[N:16]=1.Cl.O>O1CCCC1>[Br:11][C:12]1[N:13]([CH2:25][C:26]#[C:27][CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH:17]=[O:18])[N:16]=1
Reactant: CC#CCn1c(Br)nc(C(=O)OC)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCn1c(Br)nc(C=O)c1C(=O)OC
Temperature: -70 °C
Reaction time: 4 h

Procedure:
43 ml of a 1 M solution of diisobutyl-aluminium hydride in tetrahydrofuran are added dropwise within 20 minutes to a solution of 13.5 g of dimethyl 2-bromo-1-(2-butyn-1-yl)-1H-imidazole-4,5-dicarboxylate in 220 ml of tetrahydrofuran under an argon atmosphere at −70° C. The mixture is stirred for a further four hours at −70° C., then 20 ml of a mixture of 1M hydrochloric acid and tetrahydrofuran are added dropwise. After heating to ambient temperature approx. 200 ml of water are added and the mixture is extracted three times with 70 ml of ethyl acetate. The combined extracts are dried and evaporated down. The crude product thus obtained is purified by column chromatography over silica gel with petroleum ether/ethyl acetate (80:20 to 50:50) as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH:6]=1.O.NN.[OH-].[K+].C(OCC)C>COCCOC>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH:6]=1
Reactant: O=C(O)C(=O)c1ccc(-n2cc(Cl)cn2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: O=C(O)Cc1ccc(-n2cc(Cl)cn2)cc1
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
To 2.51 g (10 mmoles) of 4-(4-chloropyrazol-1-yl) phenylglyoxylic acid in 20 ml of 1,2-dimethoxyethane there are added 1.5 g (30 mmoles) of hydrazine hydrate and, after 15 minutes, 1.34 g of potassium hydroxide. Heating to 150° C. is effected for one hour, followed by pouring on to ice water, extraction with diethyl ether, acidification of the aqueous phase, extraction again with ether, concentration of the ethereal phase; 4-(4-chloropyrazol-1-yl) phenylacetic acid is obtained as oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16]O.S(Cl)([Cl:20])=O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16][Cl:20]
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Product: Oc1c(CCl)cnc2cc(C(F)(F)F)ccc12
Yield: 82.6 %

Procedure:
4-Hydroxy-7-trifluoromethyl-3-(hydroxymethyl)-quinoline (3.6 grams) was added to an excess (5.9 grams) of thionyl chloride and the mixture was refluxed for 1 hour. Excess thionyl chloride was then evaporated and the remaining residue was crystallized from hexane to give 4-hydroxy-7-trifluoromethyl-3-(chloromethyl)-quinoline (3.2 grams).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:17]3[O:21][CH:20]=[CH:19][CH:18]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: O=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1cc(Cl)cc(Nc2n[nH]c(NCc3ccco3)n2)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and furfural (85.1 mg, 886 μmol) in MeOH (3 ml) was stirred at room temperature for 3 days. The resulting suspension was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (65.1 mg, 1.72 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in DCM and washed with water (2×4 ml), dried over MgSO4 and concentrated to give a solid. Trituration with DCM/Hexanes afforded a white solid as desired product (50.5 mg, 54% yield). MS +m/z: 324 (M+H)+
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].CO>N.[Ni]>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:11]
Reactant: N#CCc1ccccc1C(F)(F)F
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCc1ccccc1C(F)(F)F
Yield: 44.9 %

Procedure:
Using analogous reaction conditions as described in Example 16, step 1, (2-trifluoromethyl-phenyl)-acetonitrile (I-22a: 2.4 g) in methanolic ammonia (10 mL) was reacted with Raney nickel (5 g) and methanol (30 mL) to afford 1.1 g of the product (44% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15](Cl)=[O:16].S1C=CC=C1C(Cl)=O>>[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:16]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cc(F)ccc1F
Agent: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(F)ccc1F

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 2,5-difluorobenzoyl chloride according to the procedure of Example 256a substituting 2,5-difluorobenzoyl chloride for thiophene-2-carbonyl chloride to provide 2,5-Difluoro-N-(4-fluoro-3-nitro-phenyl)-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>C(Cl)Cl.C(Cl)Cl.O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 4-(4-trifluoromethyl-phenoxy)-phenylamine (15.18 g, 60 mmol) and pyridine (7.2 mL, 90 mmol) in dried CH2Cl2 (100 mL) under N2 at 0° C. was added methanesulfonyl chloride (5.22 mL, 66 mmol) dropwise. The mixture was stirred at 0° C. for 1 h and was then poured into CH2Cl2/H2O (100 mL/100 mL). 2N HCl(aq) (30 mL) was added into additional funnel. The organic layer was then washed with H2O (100 mL), brine (100 mL), dried (Na2SO4), and filtered. After removal of solvent, the crude product can be resolidified from Et2O/hexane to give 18.2 g of the titled product (92%) as a pale brown solid. 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=9.0 Hz, 2H), 7.30 (d, J=9.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 4H), 6.93 (s, 1H, NH), 3.04 (s, 3H); MS (EI) 331 (M+), 330 (M+−1, 100).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:24])[NH2:25]
Reactant: NC(=O)[C@@H](N)c1ccccc1
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: NC(=O)[C@@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 15, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and (S)-2-amino-2-phenyl-acetamide (CAN 6485-52-5, 52.6 mg, 0.53 mmol) as starting materials, and isolated (25 mg, 17.07%) as light brown solid; LC-MS (UV peak area, ESI) 98.31%, 418.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1.O>CN(C=O)C.C(OCC)(=O)C>[CH:11]([N:8]1[C:6]2[N:7]=[C:2]([O:1][CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[CH:10]=[N:9]1)([CH3:13])[CH3:12]
Reactant: CN1CCC(Br)CC1
Reactant: CCOC(=O)c1cc(O)nc2c1cnn2C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC2CCN(C)CC2)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 6-hydroxy-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in DMF and K2CO3 (1.5 equiv.) and 4-bromo-1-methylpiperidine (1.5 equiv.) was added to it. The reaction mixture was stirred at room temperature for overnight. On completion of reaction, water was added to it and extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1>CO>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([OH:9])[CH2:4]1
Reactant: COc1cccc(O)c1
Solvent: CO
Product: CO[C@H]1CCC[C@H](O)C1

Procedure:
A mixture of cis- and trans-4-methoxy-cyclohexanol (7:3) was prepared by hydrogenation of 3-methoxy-phenol in methanol at room temperature in the presence of Nishimuras catalyst.
Reaction SMILES: [NH+:1]1([O-])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CS([Cl:15])(=O)=O.[OH-].[Na+]>CN(C=O)C>[Cl:15][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: [O-][NH+]1C=Cc2cccnc21
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]ccc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution of 2a (1.926 kg) in DMF (9.705 kg) was heated to about 50° C. Methanesulfonyl chloride (4.399 kg) was added to the heated solution at such a rate as to maintain the reaction temperature at 65 to 75° C. The resulting mixture was heated at about 68 to 77° C. until the reaction was judged complete by reversed phase HPLC analysis. The reaction mixture was cooled to about 30° C., and then quenched with water (31.024 kg). Upon cooling the quenched reaction mixture to 5° C., sufficient 10 N NaOH solution was added to raise the pH of the solution to about 7. The resulting slurry was warmed to 25° C., agitated for approximately 1 h, and then filtered to collect the product. The product was washed with additional water, and dried under high vacuum at 45 to 50° C. to afford 1.904 kg of 3a.
Reaction SMILES: Cl.[CH3:2][C:3]([OH:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:12]=[CH:13][C:14]([S:17]([O:6][CH2:5][CH2:4][C:3]([OH:8])([CH3:7])[CH3:2])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(O)CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(O)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of 3-methyl-1,3-methanebutane diol (2.00 g, 19.2 mmol), (4-trifluoromethyl)benzene sulfonyl chloride (7.046 g, 28.8 mmol) in dry pyridine (20 mL) was stirred at 0° C. for 2 hours, poured into the cold HCl (50 mL, 2 N), and extracted with ethyl acetate. The organic phase was washed with HCl (4×50 mL, 2 N), brine (1×25 mL), dried over MgSO4, and evaporated to dryness. (3.72 g, 97%). 1H NMR (400 MHz, CDCl3): δ 1.21 (s, 6H), 1.87 (t, J=6.9, 2H), 2.03 (d, J=14.0, 2H), 4.26 (t, J=6.9, 2H), 7.81 (d, J=8.6, 2H), 8.03 (d, J=8.1, 2H). Repeat synthesis: To a solution of 3-methyl-1,3-butane diol (1.9 g, 18.2 mmol) in pyridine (15 mL) was added p-(trifluoromethyl)benzenesulfonyl chloride (3.67 g, 15 mmol). The solution was stirred at 0° C. for 2 h. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with 1 M HCl (3×50 mL), saturated aqueous NaHCO3 (1×50 mL) and saturated aqueous NaCl (1×50 mL). The organics were dried over Na2SO4 and concentrated to give a white low melting point solid (3.33 g, 71%). 1H NMR (400 MHz CDCl3) δ 8.04 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 4.72 (t, 2H, J=7.0 Hz), 1.87 (t, 2H, J=7.0 Hz), 1.21 (s, 6H). Anal. Calcd. For C12H15F3O4S: C, 46.15; H, 4.84. Found: C, 46.14; H, 4.90.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: NCc1ccccc1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5ccccc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and benzylamine (51.7 mg, 0.482 mmol) was heated at 140° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 10 g, 200˜300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford the crude product which was purified by prep-HPLC and concentrated to afford benzyl-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine (Yield 25 mg, 15.5%). 1H NMR (300 MHz, CDCl3): δ 8.71 (brs, 1H), 8.31 (d, 1H, J=4.8 Hz), 8.04 (s, 1H), 7.42-7.28 (m, 5H), 6.94 (d, 1H, J=5.4 Hz), 5.68 (brs, 1H), 4.71 (d, 2H, J=5.7 Hz), 4.24 (brs, 4H), 2.60-2.57 (m, 4 H), 2.36 (s, 3H). LC-MS: [M+H]+ 401.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[N:4]=1)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:5]1[NH:6][C:7](=[O:9])[CH:8]=[C:3]([C:1]2[NH:22][N:21]=[N:20][N:2]=2)[N:4]=1)[CH2:18][CH3:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOc1ccccc1-c1nc(O)cc(C#N)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccccc1-c1nc(-c2nnn[nH]2)cc(=O)[nH]1

Procedure:
A stirred solution of 4-cyano-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (325 mg), sodium azide (91 mg) and ammonium chloride (75 mg) in dimethylformamide (15 ml) was heated at 125° C. for 5 hours. Most of the dimethylformamide was removed under reduced pressure and water added to the oily residue which solidified. The mixture was cooled and the solid was collected, washed with water and recrystallised from glacial acetic acid to yield the title compound, 174 mg, m.p. 219°-221° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[C:34]([O:37][CH2:38][CH2:39][NH2:40])(=[O:36])[CH3:35].C(N(CC)CC)C>CC#N.C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:40][CH2:39][CH2:38][O:37][C:34](=[O:36])[CH3:35])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCN
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (500 mg, 1.3 mmol) in CH3CN (10 mL) was added 2-aminoethyl acetate trifluoroacetate (600 mg, 3 mmol) and triethylamine (0.5 mL, 3.5 mmol). The mixture was stirred at room temperature for 1 h. The solution was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (20 mL), and the organic extract was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(2-acetoxyethyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (580 mg, 92% yield). 1H NMR (600 MHz, DMSO-d6) δ 2.06 (s, 3H), 2.08 (s, 3H), 2.11 (s, 3H), 2.12 (s, 3H), 2.15 (s, 3H), 3.66-3.80 (m, 2H), 3.85 (ddd, 1H, J=2.5, 4.5, 9.0 Hz), 4.14 (dd, 1H, J=2.0, 12.5 Hz), 4.22 (dd, 1H, J=5.0, 5.0 Hz), 4.29 (dd, 1H, J=4.5, 12.5 Hz), 4.65-4.75 (m, 1H), 5.13-5.22 (m, 2H), 5.73 (d, 1H, J=8.5 Hz).13C NMR (125 MHz, DMSO-d6) δ 20.82, 20.86, 20.98, 21.04, 21.19, 40.51, 57.21, 61.85, 62.75, 68.25, 71.84, 73.12, 92.65, 169.34, 169.73, 170.13, 170.49, 170.77, 184.26.
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:16])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].O.CO>C1COCC1>[CH3:1][CH:2]([C:8](=[O:16])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C(=O)O)C(=O)Nc1ccccc1

Procedure:
Prepared according to Procedure B using ethyl 2-methyl-3-oxo-3-(phenylamino)-propanoate (8.60 g, 39 mmol) and sodium hydroxide (2.00 g, 50 mmol) in THF (40.00 mL), water (10.00 mL, 555 mmol) and MeOH (10.00 mL) to afford product as a colorless solid, which was used without further purification. Mass Spectrum (ESI) m/e=192.1 [M−1].
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.O[CH:8]=[C:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12]>C(Cl)(Cl)Cl>[Cl:4][CH:8]=[C:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CC(=CO)C(=O)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)CC(=CCl)C(=O)C(C)C
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 174.2 %

Procedure:
Over a period of 20 min, a solution of oxalylchloride (6.5 mL, 9.6 g, 75.6 mmol) in chloroform (10 mL) is added slowly to a solution of 1-hydroxy-2-isobutyl-4-methyl-pent-1-en-3-one (7.35 g, 43.2 mmol) in chloroform (100 mL) cooled to −10° C. The mixture is stirred for further 30 min, quenched with ice (100 g) and 1 N aq. NaOH (100 mL). When the quite violent gas evolution ceases the phases are separated. The organic phase is washed with 1 N aq. NaOH (3×75 mL) and 1 N aq. NaH2PO4 (75 mL), dried (MgSO4), filtered and evaporated to give crude 1-chloro-2-isobutyl-4-methyl-pent-1-en-3-one (14.2 g) as a brown oil.