Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[C-:2].[Li+].[Li+].[C:5]1([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.O>C1COCC1>[CH:5]1([C:11]([OH:12])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:1]#[CH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: [C-]#[C-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)(c1ccccc1)C1CCCCC1
Temperature: 0 °C

Procedure:
Lithium acetylide (47.84 g, 0.52 mole) was added to 70 ml of THF. The solution was cooled to 0° C. and a solution of cyclohexyl phenyl ketone in 100 ml of THF was added over a period of 15 minutes with stirring. The solution was allowed to warm to room temperature and stirred for 16 hours. The solution was then cooled to 0° C. and 50 ml of a 5N HCl was added. The solution was then warmed to room temperature and 200 ml of water was added. The solution was transferred to a separatory funnel and washed with ether. The ether washes were combined and dried. Upon removal of the ether under vacuum and vacuum distillation of the crude product a pale yellow oil was isolated (60.33 g, 82.9%): bp 111°-4° C. (0.8 mm), NMR (CDCl3) δ7.7-7.2(m, 5H), 2.6(s, 1H), 2.3(s, 1H), 2.1-0.9(m, 11H). IR (neat) 3433, 3304, 2111, 1448, 1016 cm-1.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[C:19]1[S:20][C:21]2[C:26]([N:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29]1)[N:22]=2)[C:14]#N.C(C(C(C([O-])=O)O)O)([O-])=[O:38]>C(Cl)Cl>[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[C:19]1[S:20][C:21]2[C:26]([N:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29]1)[N:22]=2)[CH:14]=[O:38]
Reactant: Cc1cc(C#N)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
DIBAL-H (11.0M in hexanes; 315 μl, 315 μmol) was added to a solution of 3-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile (105.2 mg, 286 μmol) in CH2Cl2 (4.5 mL) at 25° C., and the resulting solution was stirred at 25° C. for 45 min. Additional DIBAL-H (1.0M in hexanes; 86 μL, 86 μmol) was then added, and the resulting solution was stirred at 25° C. for 30 min. Saturated aqueous Na/K tartrate solution (4.0 mL) was added, and the resulting mixture was vigorously stirred for 15 min, then partitioned between CH2Cl2 (40 mL) and saturated. Aqueous Na/K tartrate solution (10 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-40% EtOAc/hexanes) provided 3-methyl-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde as a light-yellow foam. MS (ESI) m/z: Calculated: 370.1; Observed: 371.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.B.O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(Cl)c1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1cccc(Cl)c1
Reaction time: 15 h
Yield: 75.3 %

Procedure:
3-(3-Chlorophenyl)propionic acid (5.00 g) was dissolved in tetrahydrofuran (100 ml), a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 34.5 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 15 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (3.48 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[O:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:37])[C:5]=2[N:14]=1
Reactant: [NH4+]
Reactant: Cc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Product: Cc1nc2c(N)nc3ccccc3c2n1CCC(=O)N1CCOCC1
Reaction time: 2 h

Procedure:
2-Methyl-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline (4.8 g, 15 mmol) was treated with mCPBA (5.95 g, 25.9 mmol) followed by ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (5.49 g, 28.8 mmol) according to a modification of the method described in Part D of Example 8. The reaction was not washed with 10% aqueous sodium hydroxide prior to the addition of ammonium hydroxide. After the amination reaction was stirred for two hours, water was added. Following the work-up procedure, the chromatographic purification was carried out eluting with 90:10 dichloromethane:methanol. The resulting product was triturated with ethyl acetate and isolated by filtration to provide 2-methyl-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-4-amine as brown needles, mp 166-169° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C=O.[C:23]([BH3-])#N.[Na+]>C(O)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][N:19]([CH3:23])[CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: CNC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 1-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N-methylmethanamine (0.148 mmol, 50 mg) and a 37% aqueous formaldehyde solution (0.445 mmol, 33.4 μL) was added sodium cyanoborohydride (0.163 mmol, 10.25 mg). After stirring for 30 minutes, acetic acid was added to adjust the pH of the reaction mixture to neutral. Stirring was continued for an additional hour during which time the pH was maintained neutral by addition of acetic acid. The reaction mixture was concentrated in vacuo. To the residue dichloromethane and 2N sodium hydroxide (aq) solution were added and the organic layer was separated. The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give 1-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N,N-dimethylmethanamine (57 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[C:13]([NH2:15])=O.C(O)C>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[CH2:13][NH2:15]
Reactant: NC(=O)c1cc(Cl)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1cc(Cl)ccc1O
Yield: 88 %

Procedure:
To a suspension of LiAlH4 (437 mg, 11.5 mmol) in dry tetrahydrofuran (30 mL) under nitrogen atmosphere, a solution of 5-chloro-2-hydroxybenzamide 74 (1.5 g, 5.7 mmol) in THF (10 mL) was added and the mixture was refluxed for 3 h. After cooling, the excess of LiAlH4 was destroyed with a saturated solution of sodium sulfate. The mixture was filtered on MgSO4 and the filtrate concentrated in vacuo. The residue was partitioned between water (30 mL) and CH2Cl2 (30 mL). The aqueous phase was separated and extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated. The obtained solid was recrystallized from ethanol obtaining 787 mg of pure product (yield 88%). 1H NMR (CDCl3, 300 MHz) δ 7.10 (dd, J=6.6, 2.7 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.76 (d, J=8.7 Hz, 1H), 4.10 (br s, 2H), 1.61 (br s, 2H). MS (m/e) (API-ES) 158 (M+H)+, m.p. 160-162° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1C=O>>[C:1]1([S:7](/[CH:10]=[CH:11]/[C:20]2[CH:19]=[CH:16][C:15]([Cl:14])=[CH:22][C:21]=2[Cl:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1Cl)c1ccccc1
Yield: 60 %

Procedure:
A solution of phenyl sulfonylacetic acid (0.01 mol) and 2,4-dichlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 60-65% yield.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[N:17]=[C:16]([S:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:15]=[C:14]([C:33]([F:36])([F:35])[F:34])[C:13]=2[C:12](=[O:37])[CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO>[NH:3]([C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[N:17]=[C:16]([S:26][CH2:27][C:28]([OH:30])=[O:29])[CH:15]=[C:14]([C:33]([F:36])([F:35])[F:34])[C:13]=2[C:12](=[O:37])[CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CSc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CSc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
NaOH (160 mg, 4.0 mmol) was added to a stirred solution of ethyl {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetate (30.0 mg, 0.060 mmol) in aqueous EtOH (10 mL EtOH in 4 mL H2O). The mixture was allowed to stir for 4 h and was then concentrated in vacuo. The reaction was acidified with 1N HCl and extracted with CH2Cl2. The organic layer was dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetic acid (19.0 mg, 66%): LCMS RT: 2.50 min, MH+: 472.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[O:14][CH:20]1[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]1
Reactant: Oc1ccc(CN2CCCC2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CCCC3)c(F)c2)C1
Yield: 79.4 %

Procedure:
Using a similar protocol as described in Example 29C employing 31A (6.6 g, 33.8 mmol) and tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (10.2 g, 40.6 mmol) as starting materials afforded 9.4 g (80%) of 31B as a solid. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 1.77 (m, 4H), 2.52 (m, 4H), 3.61 (s, 2H), 3.99 (m, 2H), 4.27 (m, 2H), 4.84 (m, 1H), 6.43 (dd, 1H), 6.49 (dd, 1H), 7.27 (t, 1H), MS (APCI+) m/z 351 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]#[N:21]>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5])[O:10][CH2:19][C:20]#[N:21]
Reactant: N#CCBr
Reactant: O=Cc1c(F)cc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cc(F)c(C=O)c(F)c1
Yield: 82.5 %

Procedure:
In a manner described previously, a mixture of 2,6-difluoro-4-hydroxybenzaldehyde (538 mg, 3.40 mmol), K2CO3 (705 mg, 5.10 mmol) and bromoacetonitrile (303 μL, 4.40 mmol) in DMF (9 mL) was reacted, processed and purified by flash chromatography (0 to 100% EtOAc/Hex) to provide 2-(3,5-difluoro-4-formylphenoxy)acetonitrile (553 mg, 83%). 1HNMR (400 MHz, CDCl3) δ10.24 (s, 1H), 6.75-6.52 (m, 2H), 4.85 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(#N)C.[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[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(I)cnc(N)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: Cc1c(C#C[Si](C)(C)C)cnc(N)c1C#N

Procedure:
In another variation in the method to the 2,4-diamino-5,6-disubstituted-5-deazapteridines described above, 2-amino-3-cyano-5-iodo-4-methylpyridine is reacted with trimethylsilylacetylene in the presence of copper(I) iodide and bis(triphenylphosphine)palladium(II) chloride under basic conditions in acetonitrile, affording 2-amino-3-cyano-4-methyl-5-(trimethylsilylethynyl)pyridine. The 5-(trimethylsilylethynyl)pyridine is in turn treated with potassium carbonate in methanol, yielding the corresponding 2-amino-3-cyano-4-methyl-5-ethynylpyridine. The 5-ethynylpyridine is then reacted with an appropriately substituted halide, for example, 4-trifluoromethylphenyl iodide, again in the presence of copper(I)iodide and bis(triphenylphosphine)palladium(II) chloride under basic conditions in acetonitrile, yielding a 2-amino-3-cyano-4-methyl-5-(substituted-ethynyl)pyridine, for example, 2-amino-3-cyano-4-methyl-5-[(4-trifluoromethylphenyl)ethynyl]pyridine. The so-prepared pyridine is then cyclized and hydrohalogenated with chloroformamidine hydrochloride in diglyme, affording the corresponding 2,4-diamino-5-methyl-6-[1-chloro-2-substituted-ethenyl]-5-deazapteridine, for example, 2,4-diamino-5-methyl-6-[1-chloro-2-(4-trifluoromethylphenyl)ethenyl]-5-deazapteridine. Cyclizations with an appropriately substituted 2-amino-3-cyanopyridine and chloroformamidine hydrochloride in diglyme are taught by N. V. Harris et al (J. Med. Chem. 1990, 33, 434-444). Example 10 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=1)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Cl.CCOCC.Cl>CCOCC.CCO>[CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=1)[CH2:13]2)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A mixture of 22 g (0.048 mole) of ethyl 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoate, 86 mL of 3N NaOH and 200 mL of EtOH was refluxed for 1 h. After cooling the mixture was made acidic with conc. HCl. The solvent was decanted away from the gum which formed. The gum was titurated with Et2O and Et2O/HCl and was placed into a drying oven overnight at 45° C. to yield 19.2 g of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoic acid; mp. 285-290° C. MS m/z (MH+) 425. 1H NMR δ 7.9 (d, 2H); 7.4-7.2 (ar, 12H); 3.7 (bs, 2H); 3.0 (bs, 4H); 2.8 (bd, 2H); 2.2 (t, 2H); 2.0 (m, 2H); 1.65 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[S:28][C:27]3[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:25][C:24](Cl)=[N:23][C:22]=3[CH:21]=2)[CH2:15][CH2:14]1)[CH2:9][CH2:10][O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:45]=2[CH:46]=[CH:47][NH:48]3)O1>>[CH2:1]([N:8]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[S:28][C:27]3[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:25][C:24]([C:44]4[CH:52]=[CH:51][CH:50]=[C:49]5[C:45]=4[CH:46]=[CH:47][NH:48]5)=[N:23][C:22]=3[CH:21]=2)[CH2:15][CH2:14]1)[CH2:9][CH2:10][O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN(Cc1ccccc1)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Product: COCCN(Cc1ccccc1)C1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Benzyl-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-ylmethyl)-piperidin-4-yl]-(2-methoxy-ethyl)-amine (150 mg), was used in a Suzuki coupling with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (141 mg), to give after flash silica purification the title compound (105 mg) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:34][C:20]3=[N:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH:24]=[C:19]3[C:18]=2[C:35](=[O:38])[NH:36][CH3:37])=[CH:13][CH:12]=1.[CH3:39][C:40]([NH2:43])([CH3:42])[CH3:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:40]([NH:43][C:28]([C:27]1[CH:26]=[C:25]([C:23]2[CH:24]=[C:19]3[C:18]([C:35]([NH:36][CH3:37])=[O:38])=[C:17]([C:14]4[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=4)[O:34][C:20]3=[N:21][CH:22]=2)[CH:33]=[CH:32][CH:31]=1)=[O:30])([CH3:42])([CH3:41])[CH3:39]
Reactant: CC(C)(C)N
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC(C)(C)C)c3)cc12
Reaction time: 2 h
Yield: 28.8 %

Procedure:
DIEA (31 μL, 0.18 mmol) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid (23 mg, 0.059 mmol), 2-methylpropan-2-amine (20 μL, 0.059 mmol), and HATU (27 mg, 0.071 mmol) in DMF (0.6 mL) at room temperature. It was allowed to stir for 2 hours. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (8 mg, 0.017 mmol, 29% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.74 (1H, d, J=2.14 Hz), 8.55-8.61 (1H, m), 8.39 (1H, d, J=2.44 Hz), 8.16 (1H, s), 8.07 (2H, dd, J=8.85, 5.19 Hz), 7.94 (1H, s), 7.92 (1H, d, J=7.63 Hz), 7.86 (1H, d, J=7.93 Hz), 7.59 (1H, t, J=7.63 Hz), 7.43 (2 H, t, J=8.85 Hz), 2.87 (3H, d, J=4.58 Hz), 1.42 (9H, s). LC-MS retention time: 1.68 min; m/z (MH+): 446. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column. Phenomenex Gemini C1 C-18, 4.6×150 mm, 3 mm, Rt=13.66 min, purity=98%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=13.69 min, purity=98%.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9].C[Si](Cl)(C)C.Cl[C:24]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>N1C=CC=CC=1>[CH:27]1([O:26][C:24]([NH:17][C:3]2[C:2]([F:1])=[CH:15][N:6]([C@@H:7]3[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:5](=[O:16])[N:4]=2)=[O:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)OC1CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](n2cc(F)c(NC(=O)OC3CCCCC3)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
5'-Deoxy-5-fluorocytidine (2.5 g) was dissolved in dry pyridine (20 ml). To the mixture, trimethylsilyl chloride (3.4 ml) was added dropwise at 0° C., and stirred for 30 min at room temperature. To the reaction mixture, cyclohexyl chloroformate (2.0 ml) was added in one portion at 0° C. After stirring of the mixture for 1 hour at room temperature, pyridine was evaporated under reduced pressure. The residue was then partitioned between saturated aqueous NaHCO3 and ether. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. To the residue were added citric acid (2.0 g) and methanol (50 ml). The mixture was stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue was dissolved in CH2Cl2 /MeOH (95:5) and neutralized by aqueous NaOH. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using CH2Cl2 /MeOH (20:1) as an eluent, followed by recrystallization from ethyl acetate to give N4 -(cyclohexyloxycarbonyl)-5'-deoxy-5-fluorocytidine (3.47 g:92% yield):mp. 134°-136° C., FAB-MS m/z 372 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:12][NH:13][CH3:14]>>[CH2:1]([N:5]1[CH2:10][CH2:9][C:8]([N:13]([CH3:14])[CH3:12])=[CH:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(=O)CC1
Reactant: CNC
Product: CCCCN1CC=C(N(C)C)CC1
Yield: 77.9 %

Procedure:
1-Butyl-4-piperidone is reacted with dimethylamine gas as described in Example 1, affording 1-butyl-4-dimethylamino-1,2,5,6-tetrahydropyridine with a yield of 77.9%, bp.: 103°-106° C./1.5 kPa. The tetrahydropyridine derivative so obtained is freshly distilled and reacted with acrolein as described in Example 1, to give a light yellow oil with a yield of 44.2%, consisting of 75% of 6α-, and 25% of 6β-dimethylamino-3-butyl-3-azabicyclo[3.3.1]nonan-9-one, bp.: 110°-116° C./7 Pa; nD20 =1.4933.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].CCO.CCN(C(C)C)C(C)C.Cl[C:44]1[S:45][C:46]([C:49]#[N:50])=[CH:47][N:48]=1>C(Cl)Cl>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:44]2[S:45][C:46]([C:49]#[N:50])=[CH:47][N:48]=2)[CH2:4]1)[CH3:2]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C[C@H](Nc2ncc(C#N)s2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 150 °C
Yield: 83.9 %

Procedure:
A mixture of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.20 g, 0.47 mmol), EtOH (1.3 mL), DIEA (0.33 mL, 1.88 mmol), and 2-chlorothiazole-5-carbonitrile (0.082 g, 0.56 mmol, Ark Pharm) was heated in a CEM microwave at about 150° C. for about 30 min (250 psi maximum pressure, 5 min maximum ramp, 300 maximum watts). The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The crude oil was dissolved in DCM (10 mL) and washed with water (2×10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude mixture was purified by silica gel chromatography eluting with a gradient of 0-70% EtOAc in DCM to give 2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile (0.21 g, 84%): LC/MS (Table 1, Method c) Rt=1.53 min; MS m/z: 533 (M+H)+.