Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([N+:34]([O-:36])=[O:35])[CH:30]=[CH:31][C:32]=1F>CN(C)C=O.C(OCC)(=O)C>[F:26][C:27]1[CH:28]=[C:29]([N+:34]([O-:36])=[O:35])[CH:30]=[CH:31][C:32]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.3 %

Procedure:
To a stirred solution of 3-(1-Methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 28, 600 mg, 2.39 mmol) in N,N-dimethylformamide (6 mL) at 0° C. was added potassium carbonate (332 mg, 2.39 mmol). The mixture was stirred for 30 minutes at 0° C. 3,4-Difluoronitrobenzene (318 mg, 1.99 mmol) was added drop wise to the reaction mixture and allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was washed sequentially with water (3×10 mL) and brine (1×10 ml), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound (870 mg, quantitative). This material was used without purification in the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO.[F:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:36])[N:30]2[CH2:33][CH:34]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:36])[N:30]2[CH2:33][CH2:34][N:5]2[CH2:6][CH2:7][C@@H:2]([OH:1])[C@@H:3]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:4]2)=[CH:25][CH:24]=1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Reactant: O=C(NC[C@H]1CNCC[C@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)CC[C@H]1O)OCc1ccccc1
Reaction time: 18 h
Yield: 25 %

Procedure:
To a mixture of phenylmethyl {[(3R,4R)-4-hydroxy-3-piperidinyl]methyl}carbamate (for a preparation see Example 135(f); 0.72 g; 2.72 mmol) in anhydrous DCM (10 mL) and anhydrous MeOH (2 mL) was added (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (for a preparation see Example 88(a)) (0.559 g; 2.72 mmol) and activated 4A sieves. The reaction was stirred under N2 for 18 h. The crude intermediate was treated with sodium triacetoxyborohydride (2.72 mmol; 577 mg) and stirred for 2 h. The product was obtained as a pale yellow oil after column:chromatography (90:10:DCM:MeOH) to yield 306 mg (25%) of the product as its free base.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])=[CH:4][CH:3]=1.[Cl:12]Cl>Cl>[Cl:12][C:7]1[CH:6]=[C:5]([C:8]([Cl:9])([Cl:10])[Cl:11])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: ClCl
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cl
Product: Clc1ccc(C(Cl)(Cl)Cl)cc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
In this apparatus, a mixture of 1,725 g (7.5 moles) of 4-chlorobenzotrichloride and 12 g (0.075 mole) of FeCl3 was heated to 70° C. and circulated. The introduction of 585 g (8.25 moles) of chlorine gas was then started. (chlorine gas was fed in at a rate such that no chlorine was detectable in the exit gas.) The reaction was complete after 5 hours. 2 liters of dilute hydrochloric acid were added to the reaction mixture and the organic phase was separated off, washed twice with 2 liters of water and dried over CaCl2. Subsequent fractional distillation gave 1,824 g of 3,4-dichlorobenzotrichloride (92% of theory) (98% purity according to a gas chromatogram), of boiling point 138°-140° C. at 12 mbar.
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH:13](Cl)[C:14]([OH:16])=[O:15])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10].[NH3:18]>>[CH2:1]([O:11][CH2:12][CH:13]([NH2:18])[C:14]([OH:16])=[O:15])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: COCCOCCOCCOCC(Cl)C(=O)O
Reactant: N
Product: COCCOCCOCCOCC(N)C(=O)O
Yield: 70 %

Procedure:
This product is obtained with a melting point of 184°-185° and a yield of 70% by treatment of 3-(3,6,9-trioxadecyloxy)-2-chloropropionic acid (Ex. 11A) with 25% ammonia (1 mol/3.5 mol) at 115° C. for two hours and removal of the salts by passage through an ion exchange resin column.
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]>>[O:3]=[C:4]1[O:1][C@H:7]([C@H:5]([CH2:4][OH:3])[OH:6])[C:7]([OH:8])=[C:5]1[OH:6]
Reactant: OCC(O)CO
Reactant: [OH-]
Agent: [Na+]
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 10.5 h

Procedure:
The fourth and final fermentation step is performed in a 15000-liter vessel with the inoculation from step no 3. The fermentation is performed at 37° C. for 9 to 12 hours with stirring and pH control. At the start of the fermentation the pH is 6.5. The pH control starts when the pH drops below 5.4 using a 20% sodium hydroxide solution. The pH control is set to pH 5.5. 100 mM glycerol is added in the final phase of the fermentation, just before the culture reaches the stationary phase. The fermentation is complete when the culture reaches the stationary phase, which can be seen by the reduction of the addition of the sodium hydroxide solution. Roughly 930 liters of the sodium hydroxide solution is added to the 10200 liters of media and 600 liters of inoculum during the fermentation.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1OC)[C:6]([OH:8])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.[F:49][C:50]1[CH:67]=[CH:66][C:53]2[N:54]([CH2:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:55]([SH:57])=[N:56][C:52]=2[CH:51]=1>C1COCC1>[C:62]([O:61][C:59](=[O:60])[CH2:58][N:54]1[C:53]2[CH:66]=[CH:67][C:50]([F:49])=[CH:51][C:52]=2[N:56]=[C:55]1[S:57][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=1)([CH3:65])([CH3:63])[CH3:64]
Reactant: COc1ccc(C(=O)O)cc1CO
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2cc(F)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(SCc2cccc(C(=O)O)c2)nc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 181.4 %

Procedure:
To a solution of 3-hydroxymethyl-4-methoxy-benzoic acid (Starting material H-00e, 910 mg, 5 mmol) in dry THF (50 ml) cooled to 0° C. under inert atmosphere are added successively triphenylphosphine (1782 mg, 6 mmol, 1.2 eq.) and di-tert-butyl-azodicarboxylate (1381 mg, 6 mmol, 1.2 eq). The initially deep yellow colour disappears after 10 min. Then tert-butyl (5-fluoro-2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-III, 1270 mg, 0.9 mmol, 0.9 eq.) is added. The reaction mixture is allowed to warm up to rt and stirred at this temperature for 1 h. Evaporation of the solvent in vacuo and purification by flash-chromatography on silica gel (AcOEt/heptane/AcOH, 10:90:1), provides the title compound (680 mg) in 30% as beige solid:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc(OC(F)(F)F)cc1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethoxyaniline gave 2-chloro-5-fluoro-N4-(4-trifluoromethoxyphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.11 (d, 1H, J=2.1 Hz), 7.68 (dd, 2H, J=2.4 and 7.6 Hz), 7.26 (dd, 2H, J=3 and 8.7 Hz), 7.0 (bs, 1H); 19F NMR (CD3OD): δ −16517 and −44523; LCMS: purity: 94%; MS (m/e): 308 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].P(Br)(Br)[Br:22].C([O-])(O)=O.[Na+]>C(OCC)C>[Br:22][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[C:3]([C:17]([F:20])([F:19])[F:18])[CH:4]=2)=[CH:8][CH:9]=1
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: FC(F)(F)c1cc(Oc2ccc(CBr)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
To the solution of (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol (4.5 g, 14.87 mmol) in Diethyl ether (100 mL) was added PBr3 (1.402 mL, 14.87 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 5 h. The mixture was poured into ice water and neutralized with sat. NaHCO3 solution to pH-7, then extracted with Et2O. The organic was dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (3.2 g, 7.88 mmol, 53.0% yield) as a light yellow solid. LCMS: rt=2.01 min, [M+H+]=365, 367.
Reaction SMILES: [CH3:1]N(C)CCN(C)C.Cl[Si](C)(C)C.Cl[C:15]12[C:22](=[O:23])[CH2:21][CH:20]1[CH:19]=[CH:18][CH2:17][CH2:16]2>O1CCCC1.[Cu].[Zn]>[CH3:1][C:15]12[C:22](=[O:23])[CH2:21][CH:20]1[CH:19]=[CH:18][CH2:17][CH2:16]2
Reactant: CN(C)CCN(C)C
Reactant: O=C1CC2C=CCCC12Cl
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC12CCC=CC1CC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2.7 ml of tetramethylethylenediamine and 2.0 g of zinc-copper couple in 30 ml of tetrahydrofuran was stirred at room temperature, and a solution of 11.3 ml of chlorotrimethylsilane and 950 mg of 6-chlorobicyclo[4.2.0]oct-2-en-7 one, prepared as shown in Preparation 7, in 30 ml of tetrahydrofuran added dropwise. The mixture was stirred overnight at room temperature, then the precipitate filtered off, washed with ether and the combined filtrates evaporated under reduced pressure. The residue was treated with a mixture of diethylether and hexane, the precipitate filtered off and solvent removed from the filtrate under reduced pressure. The residue was dissolved in 10 ml of tetrahydrofuran, cooled to -78° C., 4 ml of 1.5M methyllithium added, stirred at -78° C. for 10 minutes, then at -30° C. for 10 minutes, recooled to -78° C. and a mixture of 5.1 g of methyl iodide and 2.1 ml of hexamethylphosphoramide added. The temperature was allowed to rise to room temperature while stirring. The mixture was poured into water, extracted with ether and the solvent removed from the extract carefully under moderately reduced pressure. The residue was chromatographed on silica gel, eluting with 10% ether in pentane, giving 400 mg of 6-methylbicyclo[4.2.0]oct-2-en-7-one, the compound of formula (8) where Y is hydrogen.
Reaction SMILES: [N:1]([CH:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:7][CH2:6][CH:5]1[OH:19])=[N+:2]=[N-:3].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]([CH:4]1[CH:5]([O:19][Si:24]([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25])[CH2:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:9]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [N-]=[N+]=NC1C=C(c2ccncc2[N+](=O)[O-])CCC1O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccncc2[N+](=O)[O-])=CC1N=[N+]=[N-]
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of (+/−)-2-azido-4-(3-nitropyridin-4-yl)cyclohex-3-enol (1.0 equiv.) in DCM (0.15 M) was added TBSCl (2.0 equiv.), imidazole (2.0 equiv.) and DMAP (0.1 equiv.) at room temperature. After 18 h, water was added, the organics were dried with brine, then Na2SO4, and concentrated. The crude material was loaded to silica gel and purified via column chromatography (ISCO) eluting with ethyl acetate and hexanes (20%). Obtained (+/−)-4-(3-azido-4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl)-3-nitropyridine as a yellow oil in 60% yield. LCMS (m/z): 376.3 (MH+), LC Rt=5.848 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[BH3-][C:32]#[N:33].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:3][C:2]2[NH:1][CH:5]=[CH:32][N:33]=2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: [BH3-]C#N
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2ncc[nH]2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19.4 %

Procedure:
Using General Procedure A: To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (200 mg, 0.49 mmol) and the amine (41 mg, 0.49 mmol) from above in MeOH (5 mL) was added NaBH3CN (94.3 mg, 1.5 mmol) and the mixture was stirred at room temperature for 5 days. Purification of the crude yellow foam by column chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded AMD9741 (26 mg, 15%) as a brown solid (22mg, 10%). 1H NMR (CDCl3) δ 1.61-1.76 (m, 1H), 1.92-2.09 (m, 2H), 2.17-2.27 (m, 1H), 2.68-2.76 (m, 1H), 2.80-2.90 (m, 1H), 3.64 (s, 2H), 3.89 (d, 1H, J=16.5 Hz), 4.05-4.14 (m, 2H), 4.22 (s, 2H), 4.39 (br s, 1H), 6.54 (s, 2H), 7.06 (d, 2H, J=7.8 Hz), 7.15-7.20 (m, 3H), 7.25 (d, 2H, J=6.9 Hz), 7.43 (d, 1H, J=7.8 Hz), 7.54 (br s, 2H), 8.67 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 19.22, 21.83, 27.12, 45.73, 46.41, 51.49, 58.49, 111.83, 112.90, 115.59, 119.64, 120.29, 125.33, 126.71, 132.76, 135.33, 135.86, 136.22, 144.75, 148.75, 154.19, 155.23. ES-MS m/z 464.3 (M+H). Anal. Calcd. for C28H29N7.1.4CH2Cl2: C, 60.62; H, 5.50; N, 16.83. Found: C, 60.53; H, 5.48; N, 16.94.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=C=O)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>ClCCl>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:22](=[O:23])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) (880 mg, 3.6 mmol), benzyl chloroformate (575 uL, 4.0 mmol) and Hunig's base (935 uL, 5.4 mmol) in dichloromethane (9.0 mL) was stirred at rt for 16 h. Saturated ammonium chloride was added and the separated aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were dried (anh. Magnesium sulfate), filtered and evaporated to yield a residue which was purified by reverse phase preparative HPLC. LC-MS m/z 377.1 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)O1.Br[C:25]1[N:29]2[N:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[N:33][C:28]2=[N:27][CH:26]=1>>[OH:37][C:34]([C:32]1[CH:31]=[N:30][N:29]2[C:25]([C:9]3[CH:10]=[C:11]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:13][CH:14]=3)=[CH:26][N:27]=[C:28]2[N:33]=1)([CH3:36])[CH3:35]
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1cnn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1
Yield: 29 %

Procedure:
3′-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (see Example 1, step c) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 29% yield using a similar procedure to that described in Example 3, step f, to give a yellow solid: mp 166° C.; 1H NMR (360 MHz, CDCl3) δ 1.71 (6H, s), 3.50 (1H, br s), 7.49-7.71 (5H, m), 7.83 (1H, m), 8.10 (1H, m), 8.27 (1H, s), 8.31 (1H, m), 8.79 (1H, s); MS (ES+) m/z 356 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[H-].[Na+].I[CH3:25]>C1COCC1>[CH3:25][O:1][CH2:2][CH2:3][CH:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(NC(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
To a solution of tert-butyl [3-hydroxy-1-(3-nitrophenyl)propyl]carbamate (2 g; 6.75 mmol; 1.00 eq.) in anhydrous THF (10 mL) was added NaH (567 mg; 14.17 mmol; 2.10 eq.) at 0° C. The mixture was stirred for 20 minutes and iodomethane (1.53 g; 7.42 mmol; 1.10 eq.) was added. The mixture was stirred for 2 hours at 0° C. After work up, the crude product was purified by flash chromatography on silica gel (EtOAc:Hex=1:4) to provide 1.5 g of tert-butyl [3-methoxy-1-(3-nitrophenyl)propyl]carbamate.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=1.CC(C)([O-])C.[K+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CS(C)=O.O>[CH3:1][S:2][C:3]1[N:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[N:6]=[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CSc1cc(-c2cccnc2)n[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(-c2cccnc2)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
A solution of the above pyrazole(1.94 g, 10.15 mmol) and potassium t-butoxide (1.2 g, 10.6 mmol) in anhydrous DMSO (15 mL) was stirred at room temperature for 5 min and then 4-flouronitrobenzene (1.08 mL, 10.15 mmol) was added. The reaction mixture was heated to 100° C. in an oil bath for 5 h under argon. The reaction mixture was cooled, diluted with water, the yellow solid obtained was filtered, washed with water and dried. The residue obtained was recrystallized from ethyl acetate to give 5-methylthio-1-(4-nitrophenyl)-3-(3-pyridinyl)pyrazole (2.4 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][C:16](C)(C)C)=[O:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:24]O>>[NH2:1][C@H:2]([C:3]([O:5][CH3:24])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C[C@H](N)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of (S)-2-amino-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid (500.0 mg, 1.88 mmol) in MeOH (20 mL) at 0° C. was slowly added thionyl chloride (447.64 mg, 3.77 mmol). The reaction was stirred for 1 h at 0° C. then warmed to RT and stirred for 1 h. The solvent was removed under reduced pressure. The reaction mixture was washed with saturated aqueous NaHCO3 (20 ml) and extracted with DCM (3×10 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 425 mg (95%) of (S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate as the HCl salt. LCMS-ESI (m/z) calculated for C12H15NO4: 237.1. found 238.0 [M+H]+, tR=1.01 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 3H), 7.94 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 4.37 (t, J=6.8 Hz, 1H), 3.86 (s, 3H), 3.68 (s, 3H), 3.20 (dd, J=11.8, 6.8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:5]=2[N:6]=1.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(Br)sc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-bromo-6-methoxybenzothiazole (0.67 g) in dry dichloromethane (30 ml) at ambient temperature under an atmosphere of nitrogen was added dropwise a solution of boron tribromide in dichloromethane (5.5 ml, 1M). The mixture was stirred for 2 hours at ambient temperature, stored for 2 days then poured into water. The organic phase was separated, washed with water, dried over magnesium sulphate then evaporated under reduced pressure to give 2-bromo-6-hydroxybenzothiazole as a pale pink solid, 0.60 g, m.p. 203-204° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:14]2C2CCCCO2)=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@H:30]2[CH3:35])[N:9]=1.Cl.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C1COCC1>[CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:14]2)=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@H:30]2[CH3:35])[N:9]=1
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(-c3ccccn3)n(C3CCCCO3)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(-c3ccccn3)[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
2,6-Bis-((R)-3-methyl-morpholin-4-yl)-8-pyridin-2-yl-9-(tetrahydro-pyran-2-yl)-9H-purine (33 mg, 69 μmol) was dissolved in 3 mL of THF. 2N aqueous HCl (344 μl, 688 μmol) was added, and the reaction was stirred for 2 hours at room temperature. 100 mg of Na2CO3 and 10 mL of CH2Cl2 were added, and the reaction mixture was stirred for 20 minutes. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (12 g SiO2, heptane/EtOAc in a gradient from 100/0 to 3/2) to give the product as a solid (24 mg, 88%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=O.[ClH:7].Cl.[O:9]([CH2:11][CH:12]([F:16])[CH2:13][NH:14][CH3:15])[NH2:10]>C(O)C>[ClH:7].[C:4](=[N:10][O:9][CH2:11][CH:12]([F:16])[CH2:13][NH:14][CH3:15])([CH3:6])[CH3:3]
Reactant: CNCC(F)CON
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCC(F)CON=C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 ml of 1N sodium hydroxide solution and 0.36 ml (5 mmol) of acetone are added to a solution of 488 mg (2.5 mmol) of N-(3-aminoxy-2-fluropropyl)-methylamine dihydrochloride in 10 ml of ethanol and the mixture is stirred for 24 hours at room temperature. The reaction mixture is then concentrated to dryness by evaporation. The residue is taken up in ethanol, filtered and crystallised by the addition of ether.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[N:5]1.[F:11][C:12]([F:21])([F:20])[CH2:13][CH2:14][CH:15]([C:18]#[N:19])[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:9]([C:6]1[CH:7]=[CH:8][N:4]([CH2:3][C:15]([CH2:14][CH2:13][C:12]([F:11])([F:20])[F:21])([C:16]#[N:17])[C:18]#[N:19])[N:5]=1)=[O:10]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: O=Cc1ccn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(C=O)n1
Yield: 2.1 %

Procedure:
1.57 g of 1-chloromethyl-3-formylpyrazole hydrochloride and 1.52 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 30 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of [(3-formyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (8), hereinafter) shown by below formula.