Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:25]2[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:59]1[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60]1>CN(C=O)C.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:25]2[CH:24]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32]([N:59]3[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60]3)=[O:34])=[C:25]2[CH:24]=1
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cnn2ccc(N3CCCC3c3cc(F)ccc3F)cc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnn2ccc(N3CCCC3c3cc(F)ccc3F)cc12)N1CC[C@H](O)C1
Reaction time: 0.03 h

Procedure:
5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.29 mmol) was prepared by the method mentioned in Example-3. DIPEA (93.6 mg, 0.72 mmol) was added to a stirred solution of 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.29 mmol) in DMF (1.5 mL) followed by addition of HATU (165 mg, 0.437 mmol) to the reaction mixture. After 2 minutes of stirring, (S)-pyrrolidin-3-ol (81.8 mg, 0.43 mmol) was added and the resulting mixture was stirred at 20-35° C. for 2 h. The reaction mixture was diluted with cold water; extracted with ethyl acetate; dried over sodium sulfate; and concentrated under reduced pressure to get a residue. The residue thus obtained was purified by column chromatography (60-120 silica gel and 3% EtOAc in Hexane as eluent) to afford (5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-3-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (248 mg, 0.97 mmol) [prepared according to the procedure of Example 184], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (321 mg, 0.96 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (557 mg, 1.19 mmol) in chloroform (9.5 mL). DIEA (840 μL, 4.81 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (167 mg, 0.26 mmol, 67%): LC-MS (ES) m/z=521 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[C:8]([S:11]([N:14]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:17][C:16]([CH:25]=O)=[CH:15]3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3]1.CO.[CH3:30][NH2:31].[BH4-].[Na+]>>[O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[C:8]([S:11]([N:14]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:17][C:16]([CH2:25][NH:31][CH3:30])=[CH:15]3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: CN
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc3c(c2)S(=O)(=O)CC3)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc3c(c2)S(=O)(=O)CC3)c1
Yield: 65 %

Procedure:
Using 1-[(1,1-dioxido-2,3-dihydro-1-benzothiophen-6-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (114 mg), 40% methylamine methanol solution (0.3 mL) and sodium borohydride (10.8 mg), a procedure as in Example 126 was performed to give the title compound as a white solid (yield 76.3 mg, 65%).
Reaction SMILES: C1(C(=[N:14][CH:15]([CH2:21]CC2C=C3C(=CC=2)C2=NOC(C4C(C(F)(F)F)=C(C5C=CC=CC=5)ON=4)=C2CC3)[C:16](OCC)=[O:17])C2C=CC=CC=2)C=CC=CC=1.[C:51]1([N:57]2[C:61]([C:62]([F:65])([F:64])[F:63])=[C:60]([C:66]3[O:70][N:69]=[C:68]4[C:71]5[C:76]([CH2:77][CH2:78][C:67]=34)=[CH:75][C:74]([CH:79]=[CH2:80])=[CH:73][CH:72]=5)[CH:59]=[N:58]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[NH2:14][C:15]([CH3:21])([CH2:80][CH2:79][C:74]1[CH:75]=[C:76]2[C:71](=[CH:72][CH:73]=1)[C:68]1=[N:69][O:70][C:66]([C:60]3[CH:59]=[N:58][N:57]([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:61]=3[C:62]([F:63])([F:64])[F:65])=[C:67]1[CH2:78][CH2:77]2)[CH2:16][OH:17]
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Product: CC(N)(CO)CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F

Procedure:
The titled compound was prepared using the experimental protocols described for Preparation 91A, and Example 93 employing 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (89A) as a starting material. The compound had an HPLC retention time=3.03 min. (condition C); LC/MS M+1=483.3; 1H NMR (400 MHz, MeOD) δ ppm 8.14 (1H, s), 7.85 (1H, d, J=7.7 Hz), 7.53-7.65 (5H, m), 7.30 (1H, s), 7.28 (1H, d, J=7.9 Hz), 3.67 (1H, d, J=11.5 Hz), 3.56 (1H, d, J=11.5 Hz), 3.03 (2H, t, J=6.9 Hz), 2.90 (2H, t, J=6.9 Hz), 2.66-2.81 (2H, m), 1.86-2.07 (2H, m), 1.37 (3H, s).
Reaction SMILES: [CH2:1]([SH:16])[CH2:2][CH:3]=[CH:4][CH2:5][CH:6]=[CH:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15].[H-].[Na+].Br[CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[CH2:1]([S:16][CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15]
Reactant: CCC=CCC=CCC=CCC=CCCS
Reactant: CCOC(=O)C(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCSC(CC)C(=O)OCC
Yield: 96.9 %

Procedure:
A solution of 3Z,6Z,9Z,12Z)-pentadeca-3,6,9,12-tetraene-1-thiol (9.80 g, 41.5 mmol) in dry dimethylformamide (DMF) (70 mL) at 0° C. under inert atmosphere was added NaH (60% in mineral oil, 1.82 g, 45.6 mmol) and stirred at this temperature for ten minutes. Ethyl bromobutyrate (6.39 mL, 43.5 mmol) was added and the mixture was stirred at ambient temperature for 30 minutes. The mixture was partitioned between saturated NH4Cl (150 mL) and heptane (150 mL). The aqueous layer was extracted twice with heptane (100 mL each) and the combined organic extract were washed with water (100 mL) and brine (100 mL). The organic layer was dried (Na2SO4), filtrated and concentrated. The residue was purification by flash chromatography on silica gel (heptane:EtOAc 99:1 then 95:5). Concentration of the appropriate fractions afforded 14.1 g (97% yield) of the title compound as oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=2)[CH2:3]1.C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:21])=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=2)[CH2:3]1
Reactant: CSc1ncc(C(=O)O)c(N[C@@H]2CCC[C@H](O)C2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.5 %

Procedure:
4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (4.5 g, 15.88 mmol) and HATU (9.06 g, 23.82 mmol) were dissolved in DMF (75 ml) and allowed to stir for 5 min at room temperature before adding ammonium chloride (4.25 g, 79 mmol) and DIEA (13.87 ml, 79 mmol). The reaction turned yellow upon addition of the base. The reaction was allowed to stir at room temperature for 1 h then partitioned between water and ethyl acetate. The organic layer was washed once with brine before drying over sodium sulfate, filtering, and concentrating to afford 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxamide (4.19 g, 14.84 mmol, 93% yield) as an off-white solid. MS (ESI) m/z 283.2 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CCO.[OH-].[Na+:36].CC(O)C>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:36]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 63.3 %

Procedure:
Into a 100 ml flask were placed fluvastatin methyl ester (3.0 g), EtOH (7.5 ml) and a solution of NaOH (0.28 g) in water (0.75 ml). The mixture was heated to reflux for two h, propan-2-ol was added (58 ml) and the mixture was cooled to room temperature and stirred over night. The product was isolated by filtration under nitrogen, washed with propan-2-ol (50 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.92 g (62.8%) of fluvastatin sodium crystal Form IX.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.CC1C=CC(C)=CC=1C.[K+].[Br-:37]>O>[Br:37][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Agent: Cc1ccc(C)c(C)c1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Br)nc2-c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 70.5 %

Procedure:
A mixture of 1,2-dihydro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 2, Step 3) (0.66 g, 1.81 mMol), 12 ml of 1,2,4-trimethylbenzene, 1.0 g of KBr, and 5 g of PBr5 was heated to 80° C. for 2 hours and then to 180° C. overnight. The reaction mixture was cooled to room temperature and stirred with 75 ml of water for 1 hour. The organic portion was extracted into dichloromethane. The dichloromethane extract was washed once with brine, dried over MgSO4, and evaporated to dryness. The residual oil was purified by HPLC to give 0.55 g (72% yield) of solid: m.p. 229.5-231.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CC(N(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>[Cl-].[Na+].O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[C:11](=[CH:12][C:13]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:15]=4)[CH2:10][CH2:9]3)[N:5]=[CH:6][N:7]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 80 °C

Procedure:
A mixture of 6a (0.4 g, 1.29 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.5 eq), DMA (5 mL) and potassium carbonate (0.4 g, 2.2 eq) was heated at 80° C. for 42 h. After allowing the reaction mixture to cool down to room temperature, 100 mL of brine was added and the mixture was extracted with ethyl acetate twice (100 mL and 30 mL). The combined extracts were washed with brine (2×50 mL), dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give a solution of 6b in DMA.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]([O:17]CC)=[CH2:16])[N:12]=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[N:29][CH:28]=4)=[C:23]([O:34][CH3:35])[CH:22]=3)[N:10]=2)[CH2:3]1.O.Cl>O1CCOCC1>[F:36][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[N:10]=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[N:29][CH:28]=4)=[C:23]([O:34][CH3:35])[CH:22]=3)[N:12]=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=2)[CH2:3]1
Reactant: C=C(OCC)c1cc(COCC2CC(F)(F)C2)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)=O)n2)ccc1-c1cnnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
To a solution of 4-(((3,3-difluorocyclobutyl)methoxy)methyl)-6-(1-ethoxyvinyl)-N-(3-methoxy-4-(6-methylpyridazin-4-yl)phenyl)pyrimidin-2-amine (104 mg, 0.21 mmol) in dioxane (15 mL) were added water (1 mL) and HCl (conc. 0.052 mL, 0.63 mmol). The mixture was stirred at 50° C. for 20 minutes. The solvent was evaporate and 50% saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with DCM. The organic phase was separated on phase separator and evaporated to give the title compound (94 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)=[CH:4][N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)C>COCCOC>[CH2:23]([O:22][C:20]([C:19]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([B:8]([OH:9])[OH:12])=[CH:4][N:3]2[CH:18]=1)=[O:21])[CH3:24]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1cn2cc(B(O)O)ccc2n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2.5 g of 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in 50 mL of 1,2-dimethoxyethane are added 2.14 mL of ethyl 3-bromo-2-oxopropionate. The reaction mixture is stirred for 3.5 hours at 25° C., 50 mL of ethanol are then added and the resulting mixture is refluxed for 16 hours. The reaction mixture is cooled and concentrated to dryness. The residue is suspended in 100 mL of water at 0° C. and treated, while stirring vigorously, with solid sodium carbonate until a pH of 8-9 is obtained. The precipitate is filtered off by suction and washed with 100 mL of water at 0° C. and then dissolved in 150 mL of methanol. The solution is dried over magnesium sulfate, filtered, concentrated and dried under vacuum to give 2.36 g of 2-ethoxycarbonylimidazo[1,2-a]pyridine-6-boronic acid in the form of a cream-coloured solid.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6]([OH:14])([CH2:7]3)[CH2:5]1)[CH2:11]2.I[CH3:16]>O1CCCC1.C(Cl)Cl>[CH3:16][O:14][C:6]12[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][C:4]([NH2:3])([CH2:11]3)[CH2:5]1)[CH2:7]2
Reactant: CI
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC12CC3CC(CC(N)(C3)C1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred, ice-water chilled suspension of potassium hydride (0.680 gm; 5.95 mmol) in 15.0 ml of tetrahydrofuran is added a mixture of 1-aminoadamantane-3-ol (1.00 g; 5.95 mmol) and 15.0 ml of tetrahydrofuran dropwise over 30 minutes. The resulting mixture is then stirred for an addition 30 minutes and iodomethane (0.370 ml; 5.95 mmol) is then added dropwise over one minute. The resulting opaque white reaction is then stirred at room temperature for 18 hours. The mixture is then diluted with 50 ml of methylene chloride and filtered to remove the inorganic impurities. The filtrate is then concentrated and purified on silica gel employing a SIMS/Biotage apparatus and 19% methanol and 1% ammonium hydroxide in methylene chloride as eluent to yield 3-methoxy-1-adamantylamine as an opaque oil.
Reaction SMILES: [S:1]1[C:5]2=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.C(O[CH2:20][CH3:21])(=O)C>>[CH2:5]([N:4]1[CH2:12][CH2:11][CH:20]([CH2:21][O:14][C:13]([C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]3[CH2:3][CH2:2][S:1][C:5]=23)=[O:15])[CH2:2][CH2:3]1)[CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1c2n(c3ccccc13)CCS2
Reactant: CCOC(C)=O
Product: CCCCN1CCC(COC(=O)c2c3n(c4ccccc24)CCS3)CC1
Yield: 31 %

Procedure:
The title compound was prepared from 2,3-dihydrothiazolo[3,2-a]indole-9carboxylic acid (D15) using the method of Example 10. The crude product was purified by chromatography on silica gel eluting with 5% methanol/chloroform to give a yellow oil. This was passed through a plug of basic alumina eluting with ethyl acetate to afford the title compound as a pale yellow oil (31%) which was converted to its oxalate salt and was crystallised from acetone as an off-white solid mp 212°-215° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([Si:7]([CH3:58])([CH3:57])[O:8][C@H:9]([C@@H:27]([CH3:56])[CH2:28]/[C:29](/[CH3:55])=[CH:30]\[C@H:31]([CH3:54])[C@@H:32]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[C@@H:33]([CH3:45])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[C@H:10]([CH3:26])[C@@H:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C@@H:12]([CH3:15])[CH2:13][OH:14])([CH3:6])[CH3:5].[CH2:59](Br)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C.[I-].[K+]>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][O:16][C@@H:11]([C@@H:12]([CH3:15])[CH2:13][O:14][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@H:10]([CH:9]([O:8][Si:7]([CH3:57])([CH3:58])[C:4]([CH3:6])([CH3:5])[CH3:3])[CH:27]([CH3:56])[CH2:28][C:29]([CH3:55])=[CH:30][CH:31]([CH3:54])[CH:32]([C@@H:33]([CH3:45])[CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[O:46][Si:47]([CH3:48])([CH3:49])[C:50]([CH3:53])([CH3:52])[CH3:51])[CH3:26])=[CH:19][CH:20]=1
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C(/C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](OCc2ccc(OC)cc2)[C@@H](C)CO)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC[C@H](C)C(O[Si](C)(C)C(C)(C)C)C(C)C=C(C)CC(C)C(O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](OCc2ccc(OC)cc2)[C@@H](C)COCc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
NaH (12 mg, 0.49 mmol, 2 eq) is added to a solution of (2S,3S,4R,5R,6S,8Z,10S,11R,12S)-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,13-bis[(4-methoxyphenyl)methoxy]-2,4,6,8,10,12-hexamethyl-8-tridecen-1-ol (200 mg, 0.245 mmol, 1 eq) in DMF (3 mL) at −78° C. The reaction is slowly warm to 23° C. and is stirred for 1 h. Benzyl bromide (84 mg, 0.49 mmol, 2 eq) and potassium iodide (cat. 1 mg) are added and stirred for 18 h. The solvent is removed. The crude product is chromatographed (from hexane to 10% EtOAc in hexane) to give 204 mg (80%) of the desired compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:29][C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)=[CH:8][CH:7]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:23][CH:24]=1
Reactant: Nc1cccnc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNc4cccnc4)cc2)CC3)cc1
Temperature: 25 °C
Yield: 8.1 %

Procedure:
In THF (7 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 3-aminopyridine (109 mg). The mixture was refluxed for 45 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=3/1) and recrystallized from ethyl acetate-hexane to give 7—(4-methylphenyl)-N-[4-[N-(3-pyridyl)aminomethyl]phenyl]-3,4-dihydronaphthalene-2-carboxamide (Compound 47) (14 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2[N:7]=[CH:8][N:9]=[C:10](O)[C:5]=2[C:4]=1[CH3:13])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[C:5]2[C:4]([CH3:13])=[C:3]([CH2:1][CH3:2])[NH:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CCc1[nH]c2ncnc(O)c2c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1[nH]c2ncnc(Cl)c2c1C
Yield: 66 %

Procedure:
A mixture comprising 1.18 g (6.64 mmol) 6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (prepared according to intermediate example 1b) and 37.1 mL phosphorus oxychloride was heated at 100° C. for 1 hour. The reagent was removed and the residue purified by chromatography. The product was further purified by digestion with diethyl ether to give 855 mg (66%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.[O:11]1CCCC1>Cl>[F:1][C:2]1[C:3]([C:9]([NH2:10])=[O:11])=[N:4][C:5]([F:8])=[CH:6][N:7]=1
Reactant: N#Cc1nc(F)cnc1F
Reactant: C1CCOC1
Agent: Cl
Product: NC(=O)c1nc(F)cnc1F
Temperature: 32.5 °C
Reaction time: 6.5 h

Procedure:
In a mixture of 570 mL of 12 mol/L hydrochloric acid and 57 mL of tetrahydrofuran was suspended 57.3 g of 3,6-difluoro-2-pyrazinecarbonitrile. The suspension was stirred at 30-35° C. for 6.5 hours. The reaction mixture was concentrated to dryness under reduced pressure, 100 mL of ethanol was added, and then the solvent and hydrochloric acid were removed under reduced pressure. The residue thus obtained was washed with ethanol and diisopropyl ether to obtain 53.7 g of 3,6-difluoro-2-pyrazinecarboxamide as a colorless solid product.