Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:59])[CH2:56][NH:55][C@@H:54]([CH2:57][OH:58])[CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:55]2[CH2:56][C:52]([F:59])([F:51])[CH2:53][C@@H:54]2[CH2:57][OH:58])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: OC[C@H]1CC(F)(F)CN1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC(F)(F)C[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-(4,4-difluoropyrrolidin-2-yl)methanol hydrochloride and isolated as white solid. MS (m/e): 437.3 (MH+).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].O[C@:6]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][C@@H:10]([CH:12]=[CH2:13])[C@H:9]([OH:14])[C@H:8]([OH:15])[CH2:7]1.C(N(CC)CC)C>ClCCl>[CH:12]([C@H:10]1[C@@H:9]2[O:14][S:1](=[O:2])[O:15][C@@H:8]2[CH:7]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1)=[CH2:13]
Reactant: O=S(Cl)Cl
Reactant: C=C[C@@H]1C[C@](O)(C(=O)OC)C[C@@H](O)[C@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C[C@@H]1CC(C(=O)OC)=C[C@H]2OS(=O)O[C@@H]12
Reaction time: 0.5 h

Procedure:
Thionyl chloride can be added dropwise to a 0° C. solution of Example 17F and triethylamine in dichloromethane. After stirring for 30 minutes, the reaction mixture can be washed with saturated NaHCO3 solution, and brine, dried (MgSO4) filtered and concentrated to afford the crude desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].CCN(CC)CC.[CH3:39][N:40]=[C:41]=[O:42]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:41](=[O:42])[NH:40][CH3:39])[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: CN=C=O
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
A solution of 3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (145 mg, 0.33 mmol) in CH2Cl2 (3.3 mL) was treated with Et3N (69 mL, 0.49 mmol) and methyl isocyanate (28.2 mg, 0.49 mmol). After stirring at room temperature for 18 h, starting material remained. Methyl isocyanate (28.2 mg, 0.49 mmol) was added to the reaction that was stirred for another 4 h. The solvent was evaporated and the residue was dissolved in EtOAc, washed with HCl (0.1 M) and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using (5% MeOH/CH2Cl2) to provide 3-[(1-Methylcarbamoyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (142 mg, 87% yield). 1H NMR (CDCl3, 400 MHz): 7.65 (m, 2H), 7.45 (m, 3H), 7.00 (s, 1H), 4.78 (m, 1H), 4.35 (q, 1H), 4.05 (dd, 1H), 3.90 (m, 1H), 3.85 (s, 3H), 2.85 (m, 2H), 2.75 (d, 3H), 1.95 (m, 2H), 1.80 (m, 1H), 1.70-1.55 (m, 5H), 1.50-1.25 (m, 3H), 1.10 (m, 1H), 0.78 (d, 3H), 0.75-0.58 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](O)=[O:18].C(O)(=O)C>O1CCCC1.C(O)(=O)C>[CH2:1]([C:8]1[C:9](=[O:16])[NH:10][N:11]([CH:17]=[O:18])[C:12]=1[CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1
Reactant: O=CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.00 g) was dissolved in tetrahydrofuran (10 mL) at room temperature. A mixed anhydride of formic acid and acetic acid (0.489 g) and acetic acid (0.0140 g) were successively added to the solution. After stirring the reaction mixture at room temperature for 5 hours, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate=4:1) to give 4-benzyl-1,2-dihydro-1-formyl-5-isopropyl-3H-pyrazol-3-one (1.07 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH3:17])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:15][CH3:16])=[O:4].[CH3:18][NH:19][CH3:20]>C(O)C>[CH3:18][N:19]([CH3:20])[CH2:2][C:3]([N:5]([CH3:17])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:15][CH3:16])=[O:4]
Reactant: COc1ccc([N+](=O)[O-])cc1N(C)C(=O)CCl
Reactant: CNC
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])cc1N(C)C(=O)CN(C)C
Yield: 81 %

Procedure:
2-Chloro-2'-methoxy-N-methyl-5'-nitroacetanilide (D86) (1.01 g, 3.9 mmol) and dimethylamine (33% in IMS, 2 ml) were stirred in ethanol (10 ml) for 3 days. After evaporation to dryness in vacuo, the crude product was partitioned between 2M HCl and ethyl acetate. The aqueous portion was basified with potassium carbonate solution, and extracted with chloroform. The extract was dried (Na2SO4) and evaporated in vacuo to give the title compound as a dark oil (0.85 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.[CH3:30][Mg]Cl.Cl.O.C([O-])(O)=O.[Na+]>O1CCCC1>[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=[O:9])[CH3:30]
Reactant: CON(C)C(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Mg]Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Into a microwave vial was placed a solution of tert-butyl 4-(8-chloro-6-{[methoxy(methyl)amino]carbonyl}imidazo[1,5-a]pyridin-5-yl)piperazine-1-carboxylate (31 mg, 0.073 mmol) in anhydrous tetrahydrofuran (0.5 mL) under N2 at 0° C. A solution of 3.0 M methylmagnesium chloride in tetrahydrofuran (85 μL, 0.26 mmol) was added dropwise. The solution was stirred at 0° C. for 30 minutes. It was stirred for 2 hours at room temperature. The reaction solution was quenched at 0° C. with 1.0 M hydrogen chloride in water (0.5 mL, 0.5 mmol), poured into 25 mL of saturated NaHCO3 solution and was extracted into ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to give the crude which was purified on silica gel with ethyl acetate (0-60%) to give desired product (22 mg, 78%). LCMS calculated for C18H24ClN4O3 (M+H)+: m/z=379.2. found: 378.9.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1.CO>ClCCl>[NH:12]1[C:16]2=[N+:17]([O-:9])[CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CO
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(Antonini, Ippolito; Claudi, Francesco; Cristalli, Gloria; Franchetti, Palmarisa; Grifantini, Mario; Martelli, Sante; J. Med. Chem. 1982, 25(10), 1258-1261) 540 g (2.35 mol) of 3-chloroperbenzoic acid are dissolved in 6.11 l of dichloromethane, and the water that separates off is removed. The organic phase is dried over sodium sulfate and cooled to 0° C. A solution of 163 g (1.38 mol) of 1H-pyrrolo[2,3-b]pyridine (Hands, D.; Bishop, B.; Cameron, M.; Edwards, T. S.; Cottrell, I. F.; Wright, S. H. B.; Synthesis 1996 (7), 877-882) in 1.00 l of dichloromethane is then added, and the temperature is allowed to rise to room temperature. After 2 hours, such an amount of methanol is added that the precipitate formed redissolves. The mixture is filtered through silica gel (mobile phase: dichloromethane/methanol 95:5). After concentration, the product fractions are dried under high vacuum.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:11]1([NH:14][C:15]2[N:20]3[N:21]=[CH:22][C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/4)=[C:19]3[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH2:13][CH2:12]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:13][CH2:12]2)[N:20]2[N:21]=[CH:22][C:23](/[CH:24]=[C:25]3/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/3)=[C:19]2[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: OCc1ccccc1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(OCc4ccccc4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (14.2 μL, 0.138 mmol) was dissolved in NMP (0.2 ml). Sodium Hydride (60%, 5.5 mg, 0.138 mmol) was added and the reaction stirred at room temperature for one hour. A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]-triazin-8-yl)methylene)imidazolidine-2,4-dione (10 mg, 0.027 mmol) was added and the mixture was stirred at room temperature for one hour. Water was added and the material was extracted with ethyl acetate. After concentration at the rotary evaporator, addition of methanol formed a precipitate that was filtered and dried. (Z)-5-((2-(benzyloxy)-4-(cyclopropylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione was isolated as a solid (5.6 mg). LCMS (ES):>95% pure, m/z 392 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:22]([OH:24])=[O:23].CCOC(C)=O>CC(N(C)C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[C:4]1[NH:18][C:19]2[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:25]=[CH:26][C:27]=2[N:28]=1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To mixture of 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (22.35 g, 0.0975 mol) and 3,4-diamino-benzoic acid (17.2 g, 0.113 mol) was added DMA (120 mL) via a syringe and the resulting solution was stirred at 0° C. for 2 h, and at the room temperature for 3 h. The robber stopper was removed and the reaction mixture was heated at 110° C. for 14 h open to the air. The DMA was removed under reduced pressure and the residue was mixed with 200 mL EtOAc, and sonicated for 15 min. The mixture was filtered to get the solid precipitate, which was mixture with 150 mL EtOAc, and sonicated for 5 min. The resulting mixture was filtered to get the solid crude that was dried at 40° C. for 6 h under reduced pressure to afford a mixture of the title compound and DMA (ratio 1:1) (16.15 g, 38%). 1H NMR (DMSO-d6) δ 3.92 (s, 3H), 7.14 (m, 1H), 7.15 (s, 1H), 7.64 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 7.84 (d, J=6 Hz, 1H), 7.91 (d, J=6 Hz, 1H), 8.19 (d, J=6 Hz, 1H), 8.21 (d, J=6 Hz, 1H), 8.29 (s, 1H). DMA also shows as 61.96 (s, 3H), 2.79 (s, 3H) and 2.94 (s, 3H). ESI-MS m/z 362.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>C(N(CC)CC)C.C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:30]#[C:29][C:27]([OH:31])([C:22]4[N:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[CH3:28])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Reactant: C#CC(C)(O)c1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2c(C(=O)O)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a pressure tube containing 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid (550 mg, 1.44 mmol), copper(I) iodide (27.48 mg, 0.14 mmol), bis(triphenylphosphine)palladium(II) chloride (101.29 mg, 0.14 mmol) in triethylamine (4 mL) and THF (4 mL), was added 2-(pyrimidin-2-yl)but-3-yn-2-ol (427.62 mg, 2.89 mmol). The reaction was sealed and stirred at 55° C. for 1 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (Biotage, 5-10% methanol in DCM followed by 10-20% [7M NH3 in methanol] in DCM) to give the title intermediate as an orange/brown oil: 1H NMR (250 MHz, DMSO) delta 1.92 (3H, s), 6.27 (1H, s), 6.98 (3H, s), 7.09 (1H, d, J=5.5 Hz), 7.26 (1H, d, J=9.5 Hz), 7.50 (1H, t, J=4.9 Hz), 8.20-8.41 (3H, m), 8.73-9.02 (2H, m); LC-MS: m/z=+402.00 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C[Li].[C:11](C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(OCC)C.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:11])[C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1cnc(Cl)nc1
Agent: [Li]C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cnc(Cl)nc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2-chloro-5-methylpyrimidine (EXAMPLE 144, STEP 1) (0.50 g, 0.00389 mol) in diethyl ether (12 mL) at −30° C. and under nitrogen was added dropwise 1.4M methyllithium (2.90 mL, 0.00405 mol) and the reaction allowed to stir at −30° C. for 30 min and at 0° C. for 30 min. The reaction was quenched with a solution of acetic acid (0.242 mL), water (0.039 mL, and THF (0.8 mL) and then a solution of DDQ (0.92 g, 0.00405 mol) in THF was added. The reaction was stirred 5 min at rt, recooled to 0° C. and 3N sodium hydroxide added. The reaction was allowed to stir at 0° C. for 30 min after which a thick oily precipitate formed. The organic supernatant was decanted and the residue washed with diethyl ether (2×20 mL). The organic layers were dried over sodium sulfate, filtered through a pad of silica and the silica pad washed with diethyl ether. The filtrate was concentrated in vacuo to give the title compound as an oil. M.S.(M+1): 143.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][C:21]2=[O:26])=[CH:4]1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[O:35][CH2:36][CH2:37][F:38]>C(Cl)Cl>[CH3:2][N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][N:23]([C:34]([O:35][CH2:36][CH2:37][F:38])=[O:39])[CH2:22][C:21]2=[O:26])=[CH:4]1
Reactant: Cn1cc(N2CCNCC2=O)c2ccc(OCc3ccccn3)nc21
Reactant: O=C(Cl)OCCF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(N2CCN(C(=O)OCCF)CC2=O)c2ccc(OCc3ccccn3)nc21
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of 1-[1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperazin-2-one, hydrochloride (0.15 g, 0.40 mmol) and triethylamine (0.121 g, 1.20 mmol) in DCM (15 mL) is added dropwise 2-fluoroethyl carbonochloridate (0.076 g, 0.602 mmol) at room temperature, and the reaction mixture is stirred for 3 h. The reaction is quenched with a saturated solution of sodium bicarbonate (20 mL) at 0° C. and extracted with DCM (3×50 mL). The combined organic layers are dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified on neutral alumina, eluting with 1% MeOH in DCM to give a product, which on triturating in Et2O, affords the title compound (0.07 g, 0.164 mmol) as an off-white solid. MS (m/z): 428 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ 3.68 (s, 3H), 3.77 (m, 4H), 4.17 (bs, 2H), 4.28 (t, 1H), 4.35 (t, 1H), 4.58 (t, 1H), 4.71 (t, 1H), 5.49 (s, 2H), 6.66 (d, 1H), 7.30-7.34 (m, 2H), 7.50 (d, 1H), 7.77-7.83 (m, 2H), 8.56 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:14])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].NC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C.C(=O)(O)[O-].[Na+].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41]>ClCCl.O>[OH:14][C@@H:3]([CH2:2][NH:1][S:40]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=1)(=[O:42])=[O:41])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Agent: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a solution of 3.06 g (15.0 mmol) of tert-butyl (1S,2S)-3-amino-2-hydroxy-1-methylpropylcarbamate & tert-butyl (1S,2R)-3-amino-2-hydroxy-1-methylpropylcarbamate in 100 mL of dichloromethane was added 3.78 g (45.0 mmol) of sodium bicarbonate and 50 mL of water. The reaction mixture was cooled to 0° C. and 16.5 mL (16.5 mmol) of a 1.0 M solution of 2-pyridinesulfonyl chloride in dichloromethane was added gradually over 20 min. The reaction mixture was stirred at room temperature for 16 h. The layers were then separated and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under vacuum to afford the crude product. This product was purified via silica gel chromatography eluting with ethyl acetate:hexane (8:2) to afford 2.0 g (34%) of tert-butyl (1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & tert-butyl (1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate as a pale yellow oil. 1H-NMR (300 MHz, CDCl3): δ 8.72 (m, 1H), 8.07–7.92 (m, 2H), 7.51 (m, 1H), 6.25, 6.08 (2br s, 1H), 4.83-4.64 (m, 2H), 3.74–3.47 (m, 3H), 3.27–3.19 (m, 1H), 1.23, 1.22 (2s, 9H), 1.12 (m, 3H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=C[CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].ClC1N=C(Cl)C(C)=C[N:14]=1.Cl>CN(C=O)C.O>[N:11]1[CH:10]=[CH:9][C:4]([CH2:5][C:6]#[N:14])=[N:3][CH:8]=1
Reactant: N#CCc1ccccn1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (1.3 g, of NaH in a 60% dispersion oil, 32.5 mmol, 4 eq) in anhydrous DMF (10 mL), was added dropwise at room temperature a solution of 2-pyridylacetonitrile (960 mg, 8.12 mmol, 1 eq) in anhydrous DMF (10 mL). The reaction mixture was stirred at room temperature for 1 hour. A solution of 2,4-dichloro-5-methyl-pyrimidine (1.32 g, 8.12 mmo, 1 eq), dissolved in anhydrous DMF (5 ml), was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 14 hours. The mixture is hydrolysed with water (1 mL) and acidified with 1.6 mL of 10M HCl. The solvents were evaporated under vacuum. The residue was extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography with 50:50 (EtOAc:cHex). The fractions evaporated to give a yellow solid which was dried under vacuum at 40 degrees. The yellow crystalline product 4-pyrimidineacetonitrile, 2-chloro-5-methyl-alpha-2(1H)-pyridinylidene was isolated. (1.7 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15](Br)[CH:16]=[C:11]2[N:10]=[N:9]1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)CCC>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)[CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: Cn1ncnc1COc1nc2c(cc1Br)nnn2-c1ccccc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1-c1ccco1)nnn2-c1ccccc1F
Temperature: 100 °C
Yield: 36.6 %

Procedure:
A mixture of 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.12 g, 0.29 7 mmol) (Example 3, step c), 2-tributylstannylfuran (0.19 ml, 0.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 5 mol %) in DMF (3 ml) was heated in a sealed tube at 100° C. for 7 h. The solution was cooled, diluted with water (40 ml) and extracted with 10% methanol-dichloromethane (2×20 ml). The extracts were dried (Na2SO4), filtered and concentrated. The residue was dissolved in ethyl acetate-dichloromethane and decolourised with charcoal (50 mg). The filtrate was concentrated to give 3-(2-fluorophenyl)-6-(2-furyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine (0.086 g, 74%) as an off-white solid, m.p. 170-173° C. Found: C, 57.28; H, 3.67. C19H14FN7O2.0.5(H2O) requires C, 57.00; H, 3.78. δH (400 MHz; CDCl3) 3.84 (3H, s), 5.66 (2H, s), 6.51 (1H, dd, J=3 and 2), 6.93 (1H, d, J=3), 7.37-7.43 (2H, m), 7.56-7.60 (2H, m), 7.71 (1H, dd, J=8 and 8), 7.90 (1H, s) and 8.80 (1H, s); m/z (ES+) 392 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH3:18].C(O)C(CC)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][C@@H:16]([CH2:17][CH3:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CCC(C)CCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)CO
Solvent: CN(C)C=O
Product: CC[C@H](C)CCCCCOc1ccc(C#N)cc1

Procedure:
Add 5.75 g of 4-cyanophenol 10 g of 1 brom-6-methyl octane synthesized of available active amyl alcohol, 6.67 g of anhydrous potassium carbonate, 30 ml of N,N-dimethyl formamide into 100 ml four-mouth flask under nitrogen atmosphere, allow to react for 8 hours at 110° C. After the reaction, filter the insoluble matter, then extract ether. The organic layer is then washed with 5% NaOH, water and saturated salt water, then dried and evaporated to remove the ether. Then when the obtained oily matter is refined, 11.4 g of optical (s)-4-(6-methyloctyloxy)benzonitrile is obtained.