Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[C:10]([F:21])[CH:9]=2)[CH:7]=1.[CH2:23]([O:25][C:26](=[O:29])[CH2:27]Br)[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:29])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:15])=[C:10]([F:21])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc(-c2cc(Cl)ccc2O)cc1F)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cl)cc1-c1ccc(C(=O)N2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of step c) (0.11 g) was dissolved in DMF (5 ml), ethylbromoacetate (0.04 ml) and potassium carbonate (0.1 g) were added. The reaction mixture was stirred for 16 h at RT. Water and ethyl acetate were added. The organic layer was removed, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (1:1) to give the sub-title compound. Yield 0.12 g.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.[Cu]>[F:8][C:7]1[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: Sc1ccccc1
Agent: [Cu]
Solvent: ClCCl
Product: Fc1cc(C(F)(F)F)cnc1Sc1ccccc1
Temperature: 160 °C
Reaction time: 2 h

Procedure:
At 148-156° C., 59.6 g (0.326 mol) of 2,3-difluoro-5-trifluoromethylpyridine were added over a period of 2.5 h to 37.7 g (0.338 mol) of 98.7% pure thiophenol and 2.1 mg (0.01 mol %) of copper powder, and the mixture was stirred at 156-164° C. for 2 hours. After cooling, the residue was taken up in methylene chloride, washed with 0.5 N aqueous sodium hydroxide solution and water, dried over magnesium sulfate and concentrated under reduced pressure. 88.9 g (100% of theory) of the title compound of 24 n D
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([N:17]1[N:21]=[CH:20][CH:19]=[N:18]1)[N:6]2[CH3:16]>C(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([N:17]1[N:21]=[CH:20][CH:19]=[N:18]1)[N:6]2[CH3:16]
Reactant: CCCC(O)c1nc(N)c2nc(-n3nccn3)n(C)c2n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCC(=O)c1nc(N)c2nc(-n3nccn3)n(C)c2n1
Reaction time: 8 h
Yield: 40 %

Procedure:
MnO2 (439 mg, 5.04 mmol) was added to a solution of 1-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol (51 mg, 0.2 mmol) in DCM (4 ml) at RT. The resulting heterogeneous solution was stirred overnight. After filtration over a celite pad, the solvent was removed under reduced pressure to afford the desired product as a white powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3CCS2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1 gram (3.3 mmol) of 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylic acid, 1.65 g. (0.0165 mol) of N-methylpiperazine and 20 ml of pyridine was heated to reflux. After twelve hours, 1.65 g. (0.0165 mol) of N-methylpiperazine was added thereto again and the heating to reflux was continued for twelve hours. When the reaction was completed, the mixture was allowed to cool to a room temperature, crystals separated out therefrom were collected by filtration, washed with pyridine and ether and air dried to give the title compound. Yellow powdery crystals. Yield 720 mg (60 percent).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C1(P(C2CCCCC2)[C:19]2C=CC=C[C:20]=2[C:25]2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)cc(C2CC2)c1
Temperature: 100 °C
Yield: 490.8 %

Procedure:
To a solution of 1-bromo-3,5-dimethoxybenzene (2.00 g, 9.21 mmol) in dioxane (30 mL) and water (10 mL) were added potassium cyclopropyl trifluoroborate (2.73 g, 18.4 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (756 mg, 1.84 mmol), palladium(II) acetate (207 mg, 0.92 mmol) and cesium carbonate (18.0 g, 55.3 mmol), and the mixture was heated at 100° C. for 16 hours. After the reaction was completed, water was added to the reaction mixture, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 3/1) to obtain the title compound (1.61 g, 9.03 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C[Si]([N-:42][Si](C)(C)C)(C)C.[K+].[Br-]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([NH2:42])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=CCC1c1ccc(Br)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=CCC1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (400 mg, 1.18 mmol) in toluene (4 mL) is added Pd2(dba)3.CHCl3 (50 mg, 0.05 mmol) and P(tBu)3 (40 mg, 0.20 mmol). The mixture is degassed at −30° C. KHMDS (7.0 mL, 0.5 M solution in toluene, 3.5 mmol)) is added to the flask. The resulting mixture is stirred at room temperature overnight. TLC is used to detect when the starting bromide is consumed, the reaction mixture is diluted with ether and poured into dilute HCl (aq). The ether layer is discarded, the aqueous layer is basified with NH4OH and extracted with CH2Cl2. The CH2Cl2 layer is dried and concentrated. The residue (300 mg) is directly employed in the next step.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([CH:17]=[CH:18][N:19]=3)[CH2:14][CH2:15][CH:16]=2)=[CH:7][CH:6]=1)C(C)=O.[OH-].[K+]>CO.O>[NH2:1][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([CH:17]=[CH:18][N:19]=3)[CH2:14][CH2:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C2=CCCn3ccnc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(C2=CCCn3ccnc32)cc1
Temperature: 25 °C

Procedure:
5 g of the crude product from Example 8 is dissolved in 10 ml of methanol and added to a solution of 14 g of potassium hydroxide in 15 ml of methanol and 10 ml water. Heat to reflux for 2 hr. Cool to room temperature, and pour into 300 ml of water with good mixing. The resulting precipitate is recrystallized from ether to provide the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1C[C@@H]1C1CCN(c2ccc(C=O)cn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1C[C@@H]1C1CCN(c2ccc(CO)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-{4-[(1R,2S)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyridine-3-carbaldehyde (1.75 g, 4.50 mmol) was placed in a 250 ml flask and dissolved in MeOH (11.26 ml). Sodium borohydride (0.170 g, 4.50 mmol) was added and the mixture stirred at RT for 1 hour. The mixture was concentrated, dissolved in EtOAc (200 ml) and washed with 1:1 brine:saturated sodium bicarbonate (200 ml). The layers were separated, the aqueous phase extracted with EtOAc (2×70 ml), the organic fractions combined, washed with brine, dried over sodium sulfate filtered, and concentrated under reduced pressure to afford the title compound. LC/MS (m/z): 391 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]3[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=3[N:12]=2)[CH3:10])[N:5]=[C:4]([NH2:27])[N:3]=1.[NH3:28]>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:9]([NH:8][C:6]3[N:5]=[C:4]([NH2:27])[N:3]=[C:2]([NH2:28])[N:7]=3)[CH3:10])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]=2[CH:22]=1
Reactant: N
Reactant: C[C@H](Nc1nc(N)nc(Cl)n1)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)nc(N)n1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 100 °C
Yield: 77 %

Procedure:
To a solution of 6-chloro-N—[(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[1,3,5]triazine-2,4-diamine (100 mg, 0.26 mmol) in dioxane (1 mL) was added 880 NH3 (4 mL). The reaction mixture was heated at 100° C. for 1 h using microwave irradiation. After cooling to RT, the reaction mixture was evaporated and purified by column chromatography (Si—PCC, gradient 2-12% 2M NH3/MeOH in DCM) affording 286 as a pink foam (72.9 mg, 77%). LCMS (Method K): RT 2.89 min [M+H]+ 365.0. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.67-7.60 (3H, m), 7.57-7.51 (3H, m), 7.05 (1H, ddd, J=10.1, 8.8, 2.6 Hz), 6.78 (1H, dd, J=9.0, 2.5 Hz), 6.31 (1H, bd, J=7.5 Hz), 5.61 (4H, bs), 5.22 (1H, quintet, J=7.1 Hz), 1.40 (3H, d, J=6.9 Hz)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1.Br[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Reactant: COc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(-c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)cc1
Temperature: 120 °C
Yield: 48.8 %

Procedure:
To a mixture of 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (250 mg, 0.61 mmol) in Dioxane (3 mL) was added 4-bromoanisole (115 mg, 0.61 mmol), 2N K2CO3 (1 mL, 2 mmol) and PdCl2(dppf)2 (20 mg, 0.025 mmol). The reaction mixture was heated at 120° C. under microwave heating conditions for 30 minutes before concentrated to remove the solvent. The residue was dissolved in ethyl acetate, washed with water with the separated organic layer dried and concentrated to yield a crude product which was purified by prep-HPLC separation to give title compound (116 mg, 49%). 1H NMR (400 MHz, MeOD): δ 7.55-7.51 (m, 2H), 7.35-7.27 (m, 4H), 7.24-7.15 (m, 3H), 7.01-6.97 (m, 2H), 6.92-6.89 (m, 1H), 4.66 (brs, 1H), 4.56-4.51 (m, 2H), 4.16-4.07 (m, 2H), 3.92 (brs, 1H), 3.83 (s, 3H), 3.58-3.48 (m, 3H), 3.32-3.22 (m, 2H), ppm; ESI-MS (m/z): 390.2 [M+1]+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([S:12][CH3:13])[N:5]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][OH:16].CN(C)C=O>O>[CH3:11][O:10][C:8]1[N:7]=[C:6]([S:12][CH3:13])[N:5]=[C:4]([O:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[CH:9]=1
Reactant: COC(=O)CO
Reactant: COc1cc(Cl)nc(SC)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OC)nc(SC)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.9 %

Procedure:
0.4 g of sodium hydride was added to a mixture of 1.59 g of 4-chloro-6-methoxy-2-methylthiopyrimidine, 0.98 g of methyl glycolate and 10 ml of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 5 hours, then, the reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.22 g of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylthiopyrimidine.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([Mg]Br)[CH:2]=1.C([O:12][CH2:13][C:14]([O:16][CH3:17])=O)C>O1CCCC1.C(O)=O>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([C:13]([C:3]2[CH:2]=[C:1]([CH3:9])[CH:6]=[CH:5][CH:4]=2)([OH:12])[CH2:14][O:16][CH3:17])[CH:2]=1
Reactant: CCOCC(=O)OC
Reactant: Cc1cccc([Mg]Br)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: COCC(O)(c1cccc(C)c1)c1cccc(C)c1

Procedure:
A solution of 1,1-bis(3-tolyl)-2-methoxyethanol (24.66 g) (obtained by the reaction of 3-tolylmagnesium bromide with methyl 2-ethoxyacetate in tetrahydrofuran) in formic acid (30 cc) is heated to reflux for 12 hours, cooled and poured into a mixture of saturated sodium carbonate solution (400 cc) and ethyl acetate (400 cc). The organic phase is washed with water (3×300 cc) and with saturated sodium chloride solution (300 cc) then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis(3-tolyl)acetaldehyde (20.45 g) in the form of a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:12]=2[C:13]#[N:14])[CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+].O>C(O)C.C(Cl)Cl>[N+:1]([CH:4]1[CH2:9][N:8]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:20]=3)[C:12]([C:13]#[N:14])=[C:7]2[NH:6][CH2:5]1)([O-:3])=[O:2]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc([N+](=O)[O-])cnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC([N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of 6-nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (90 mg, 0.25 mmol) in 2 mL of ethanol and 2 mL of DCM was added NaBH4 (19 mg, 0.5 mmol) at RT. After stirring at RT for 30 min, 5 mL of water was added. The mixture was concentrated. The residue was partitioned between 50 mL of DCM and 50 mL of brine. The combined organic layers were washed with brine (50 mL×2), dried over Na2SO4 and concentrated to afford 50 mg of 6-nitro-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (55%) as a yellow solid. MS (ESI) m/e [M+1]+ 362.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:37][C:38]1[CH:42]=[C:41]([CH3:43])[O:40][N:39]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:37][C:38]2[CH:42]=[C:41]([CH3:43])[O:40][N:39]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(CBr)no1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)C)cn4COCC[Si](C)(C)C)c3ccc(Cl)cc32)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 165 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (10.6 mg, 264 μmol) was added and the mixture was allowed to stir for 30 min. 3-(Bromomethyl)-5-methylisoxazole (31.9 mg, 181 μmol) was added and the mixture was warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20%-50% ethyl acetate in hexanes 15 min) to give 2-(6-chloro-1-((5-methylisoxazol-3-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 153 μmol, 93.0%) as a yellow powder. MS (M+Na)+=602; 1H NMR (CDCl3) δ: 9.23-9.32 (m, 1H), 8.48 (s, 2H), 8.18-8.30 (m, 1H), 7.54-7.61 (m, 1H), 7.27 (m, 2H), 5.70-5.76 (m, 2H), 5.65-5.69 (m, 2H), 4.38-4.56 (m, 1H), 3.52-3.65 (m, 2H), 2.31-2.41 (m, 3H), 1.35-1.47 (m, 6H), 0.89-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH:6]([C:11](O)=[O:12])[CH2:5][C:4]=2[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH:6]([CH2:11][OH:12])[CH2:5][C:4]=2[N:3]=1
Reactant: O=C(O)C1Cc2ccc(Cl)nc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1Cc2ccc(Cl)nc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of 1.83 g (9.26 mmol) of (+/−)2-chloro-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid (prepared by analogy to the method described in WO 99/02517) in 50 ml of anhydrous tetrahydrofuran under argon was added 0.52 g (13.89 mmol) of lithium aluminium hydride. The resulting mixture was stirred at room temperature for 2 h. Excess of lithium aluminium hydride was hydrolysed with 2.13 ml of water and 0.53 ml of sodium hydroxide (15%). The precipitate was filtered off and washed with diethyl ether, the filtrate was evaporated to give 1.61 g (95%) of product as an oil.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)([CH3:4])[CH3:3].[ClH:16].O1CCOCC1>C(Cl)Cl>[ClH:16].[NH:7]1[CH2:8][CH:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(C(C)(C)O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(O)C1CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of tert-butyl 3-(2-hydroxypropan-2-yl)azetidine-1-carboxylate (0.87 g, 4.04 mmol) in DCM (15 mL) at 0° C. was added 4 M HCl in dioxane (8.08 mL, 16.16 mmol) dropwise. The reaction was stirred overnight at RT. The reaction mixture was concentrated and dried in vacuo to generate 2-(azetidin-3-yl)propan-2-ol hydrochloride as a brown solid (0.44 g, 71.8% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cncc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cncc3ccccc23)CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
A mixture of 2.0 gm (6.1 mMol) 1-tert-butoxycarbon-yl-4-(isoquinolin-4-yl)-4-hydroxypiperidine, and 4 mL trifluoroacetic acid in 20 mL dichloromethane was stirred at room temperature for 18 hours. The reaction mixture was diluted with 2N sodium hydroxide and the phases were separated. The aqueous phase was extracted well with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 10% to 40% methanol and a trace of ammonium hydroxide Fractions containing product were combined and concentrated under reduced pressure to provide 0.793 gm (57%) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=O)=[N:4][N:3]=1.[CH2:12]([NH2:14])[CH3:13]>CO>[NH2:1][C:2]1[S:6][C:5]([C:7]([NH:14][CH2:12][CH3:13])=[O:9])=[N:4][N:3]=1
Reactant: CCOC(=O)c1nnc(N)s1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1nnc(N)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a suspension of ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (200 mg, 1.155 mmol) in methanol (1.5 mL) was added a 70% aqueous solution of ethylamine (0.5 mL, 6.29 mmol). The mixture was stirred at room temperature overnight, concentrated, mixed with water and lyophilized to give 5-amino-N-ethyl-1,3,4-thiadiazole-2-carboxamide as a yellowish solid (200 mg). MS (ES+) m/z: 173 (M+H); LC retention time: 0.70 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[NH:5][C:6]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[NH2:47][C@@H:48]([CH3:64])[CH2:49][N:50]1[CH:54]=[CH:53][C:52]([C:55]2[CH:62]=[CH:61][C:58]([C:59]#[N:60])=[C:57]([Cl:63])[CH:56]=2)=[N:51]1>CN(C=O)C.O>[Cl:63][C:57]1[CH:56]=[C:55]([C:52]2[CH:53]=[CH:54][N:50]([CH2:49][C@@H:48]([NH:47][C:7]([C:6]3[NH:5][C:4]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[N:3][C:2]=3[CH3:1])=[O:9])[CH3:64])[N:51]=2)[CH:62]=[CH:61][C:58]=1[C:59]#[N:60]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nc(-c2cccnc2)[nH]c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(-c2cccnc2)[nH]c1C(=O)N[C@@H](C)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid (78 mg; 0.384 mmol) and DIPEA (0.20 ml, 1.151 mmol) were dissolved in 5 ml of dry DMF. HOBt hydrate (88 mg; 0.575 mmol) and EDCI (110 mg; 0.575 mmol) were added at RT. Solid (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg; 0.384 mmol) was added in one portion and the reaction was stirred for 2 h at 60° C. temperature and stirred at RT overnight. Water (40 ml) was added and the mixture was allowed to stir 1 h at RT. The precipitated product was filtered, dried in vacuum at 40° C. for 12 h, to give the title compound 136 mg. 1H-NMR (400 MHz; d6-DMSO): δ 1.12 (d, 3H), 2.49 (s, 3H), 4.40 (m, 3H), 6.97 (d, 1H), 7.48 (m, 1H), 7.88 (m, 2H), 8.02 (m, 2H), 8.07 (d, 1H), 8.21 (m, 1H), 8.58 (m, 1H), 9.13 (d, 1H), 12.85 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:15]([O:17][CH2:18][C@H:19]2[CH2:21][O:20]2)[CH3:16])=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1>C(O)C.[Rh]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:15]([O:17][CH2:18][C@H:19]2[CH2:21][O:20]2)[CH3:16])=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(Cl)ccc1[C@@H](C)OC[C@H]1CO1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)CCc1cc(Cl)ccc1[C@@H](C)OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
Ethyl (2E)-3-(5-chloro-2-{(1R)-1-[(2R)-oxiran-2-yl methoxy]ethyl}phenyl)acrylate (822 mg, 2.65 mmol), which had been obtained in Example 3 (3c)-15, was dissolved in ethanol (25 mL), added with rhodium/alumina (246 mg), and stirred for 5 hours at room temperature under hydrogen atmosphere. The reaction solution was filtered using Celite. The solvent was distilled off under reduced pressure to give the title compound as a colorless oily substance (816 mg, yield 99%).