Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][Cl:19])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCC2CCNCC2)cc1
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: ClCCCN1CCC(COc2ccccc2)CC1
Yield: 83.6 %

Procedure:
A mixture of 28.6 g (0.15 mole) of 4-phenoxymethylpiperidine, 23.5 g (0.15 mole) of 1-bromo-3-chloropropane, 40.4 g (0.4 mole) of triethylamine and 150 ml of tetrahydrofuran is heated under reflux for 5 hours. After cooling, the reaction mixture is filtered, the filtrate is evaporated in a vacuum, the residue is extracted with diethyl ether and the extract is evaporated. There are obtained 33.6 g (84% of theory) of crude 3-(4-phenoxymethylpiperidino)-propyl chloride in the form of an oil which can be further used in this form. The pure compound is obtained by distillation and boils at 180° - 183° C/0.4 mm Hg.
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:9]1[C:10]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@@H]1CCc2ncnc(O)c21
Product: C[C@@H]1CCc2ncnc(Cl)c21
Yield: 44 %

Procedure:
The solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (2.08 g, 13.9 mmol) in POCl3 (10 ml) was refluxed for 2 hours. After cooling, the excess POCl3 was evaporated and the residue was dissolved in CH2Cl2 (50 ml) and was neutralized with saturated NaHCO3. The aqueous phase was extracted with CH2Cl2. The organic phase was dried and concentrated. The residue purified on silica gel (20% EtOAc in hexanes) to afford the title compound (1.0 g, 44% yield).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Cl:18][C:19]1[S:23][N:22]=[C:21]([C:24]2[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=2)[N:20]=1>ClCCl.N1C=CC=CC=1>[Cl:18][C:19]1[S:23][N:22]=[C:21]([C:24]2[S:28][C:27]([S:29]([NH:14][C:13]3[CH:15]=[C:9]([N:4]4[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]4)[CH:10]=[CH:11][C:12]=3[O:16][CH3:17])(=[O:31])=[O:30])=[CH:26][CH:25]=2)[N:20]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(-c2nsc(Cl)n2)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2nsc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (33 mg, 0.14 mmol) in dichloromethane (2 ml) and pyridine (0.5 ml) was treated with 5-(5-chloro-1,2,4-thiadiazol-3-yl)-2-thiophenesulfonyl chloride (50 mg, 0.17 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then concentrated in vacuo, co-evaporated with toluene and the crude product purified by mass directed autoprep HPLC to afford the desired product which was characterized as the hydrochloride salt. MS (ES+) m/e 500/502 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][CH:8]1[CH2:12][S:11][C:10]([NH:13]C(=O)OC(C)(C)C)=[N:9]1.CO>O1CCOCC1>[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][CH:8]1[CH2:12][S:11][C:10]([NH2:13])=[N:9]1
Reactant: CC(C)(C)OC(=O)NC1=NC(Cc2ncc[nH]2)CS1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1=NC(Cc2ncc[nH]2)CS1
Temperature: 20 °C
Reaction time: 48 h
Yield: 36.8 %

Procedure:
5 cm3 of 4N hydrochloric acid in dioxane are added to a solution of 1.39 g of tert-butyl N-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl]carbamate in 5 cm3 of dioxane, followed by addition of methanol to dissolve the reaction medium. After stirring at a temperature in the region of 20° C. for 48 hours, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and washed with isopropyl ether, with ethyl acetate and then with methanol. The suspension obtained is filtered and the filtrate is evaporated as above and then chromatographed on a column of silica gel, eluting with a mixture of dichloromethane/methanol/28% aqueous ammonia (50/5/1 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions to give 0.33 g of (4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl-amine in the form of a viscous yellow oil [1H NMR spectrum (300 MHz, CD3)2SO-d6, δ in ppm): 2.93 (mt: 1H); 3.26 (mt: 1H); 4.03 (d, J=6 Hz: 2H); 4.39 (mt: 1H); 6.49 (unresolved complex: 2H); 6.87 (mt: 1H); 7.20 (mt: 1H); 7.63 (broad s: 1H)].
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].FC(F)(F)[C:15]1[CH:20]=[CH:19][C:18](Cl)=[C:17](Cl)[CH:16]=1.CS(C)=[O:27]>[Cu]>[O:27]([CH2:10][O:9][C:5]1[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(OC)c1
Reactant: CS(C)=O
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Product: c1ccc(OCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To m-methoxyanisole (100 g) in DMSO (350 ml) was added 39 g sodium hydride (50%) in portions. The solution was stirred at room temperature under nitrogen overnight. 4-Trifluoromethyl-1,2-dichlorobenzene (173.2 g) was added to the solution in one portion, followed by copper powder (2 spatulas) and 18-crown ether (i,4,7,10,13,16-hexaoxacyclooctadecane, 2 g). The slurry was kept 152°-170° under nitrogen for 24 hours, then added to ice (1.5 l). The mixture was allowed to stand until the ice melted, then filtered. The solid which was collected was dissolved in methylene chloride (1.5 l) and filtered. The aqueous filtrate was extracted with methylene chloride (500 ml) and the methylene chloride phase was washed with water, dried (MgSO4), filtered and stripped to yield a dark oil. The other methylene chloride solution (1.5 l) was washed with water, dried (MgSO4), filtered and stripped to yield an oil. Both oil fractions were treated with petroleum ether and filtered. The filtrates were combined and stripped to yield the phenoxy methoxybenzene product, 244 g.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)(=O)[CH3:2].[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([OH:23])C>>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:20][NH+:19]([O-:23])[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:2])=[CH:5][CH:6]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1cc[n+]([O-])cc1
Reactant: CCO
Product: CC(=N[NH+]([O-])C(=O)c1ccccc1)c1ccncc1
Yield: 77 %

Procedure:
A mixture of 5.48 gm (0.04 mole) of 4-acetylpyridine 1-oxide, 5.45 gm (0.04) of benzhydrazide and 100 ml of absolute ethanol is refluxed for a total of 4 hr and cooled. The reaction mixture is evaporated in vacuo to yield a solid which is crystallized from ethanol to yield 7.82 gm (77%) of the title compound having a melting point of 248.9° C. (decomp).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.ClC(Cl)(O[C:16](=[O:22])OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>C1COCC1>[CH2:33]([NH:37][C:16](=[O:22])[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1)[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(N)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)NCC(C)C)n(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 168.5 %

Procedure:
To a solution of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate (compound 351.4, 0.088 g, 0.57 mmol) in THF (5 ml) was added triphosgene (0.084 g, 0.28 mmol) followed by DIEA (0.2 ml, 1.14 mmol). After the mixture was stirred at room temperature for 2 hours, isobutyl amine (0.225 ml, 2.28 mmol) was added. The resulting mixture was stirred at room temperature over night. The mixture was partitioned between water and EtOAc. The EtOAc layer was washed with 1 M aqueous NaH2PO4 solution followed by brine, dried with Na2SO4, and concentrated to give 120 mg (83%) of a light yellow solid. m/z (ES+) 255 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=2[C:16]#[N:17])[CH2:8][CH2:7]1.C(=O)(O)O.[NH2:30][C:31]([NH2:33])=[NH:32].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:15]=2[C:16]([NH2:17])=[N:32][C:31]([NH2:33])=[N:30]3)[CH2:8][CH2:7]1
Reactant: N=C(N)N
Reactant: N#Cc1c(F)cccc1OCC1CCC(Cc2cccc(Cl)c2)CC1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(N)c2c(OCC3CCC(Cc4cccc(Cl)c4)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
2-[4-(3-Chlorobenzyl)cyclohexylmethoxy]-6-fluorobenzonitrile (150 mg; 0.42 mmol) was heated to 135° C. in the presence of guanidine carbonate (76 mg; 0.42 mmol) in 1.5 mLs of dimethylacetamide. After 6 hours, mixture was cooled to room temperature and 2 mLs of water added. After 30 minutes solids were collected by filtration. Solids were purified by trituration using a 3:1 mixture of ethyl alcohol and water. Solids collected by filtration to give title compound as a white solid. (128 mgs; 76% yield).
Reaction SMILES: Br[C:2]1[C:3](=[O:36])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:63][O:64][C:65]1[N:70]=[CH:69][C:68](B(O)O)=[CH:67][CH:66]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:27][CH2:28]4)=[CH:7][CH:8]=3)[C:3](=[O:36])[C:2]=2[C:68]2[CH:69]=[N:70][C:65]([O:64][CH3:63])=[CH:66][CH:67]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc3C2=O)cn1

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using t-butyl 4-(3-(2-bromo-3-(3,5-difluorophenyl)-1-oxo-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate obtained in Step 1 of Example 104 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(O[C:22](=[O:24])[CH3:23])(=O)C>N1C=CC=CC=1>[C:2]([O:3][C@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:22](=[O:24])[CH3:23])[O:7][C@H:1]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
500 mg (2.05 mmol) of the above product 3 is taken as the starting material, and dissolved in 35 mL of pyridine. Then 11 ml of acetic anhydride is added with continuously stirring. The solution is concentrated under reduced pressure by removing the residual part of the solution after the completion of the reaction, and then purified by rapid column chromatography (acetone/n-hexane=4:5). A white product (1-(2′,3′,5′-Tri-O-acetyl-β-D-arabinofuranosyl)-pyrimidin-2,4-(3H)-dione) 4 is obtained. Its weight and yield are 675 mg and 89% respectively.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])=[CH:8][S:7][CH:6]=1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:12]([CH3:13])[C:11]([NH:10][C:9]3[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=3)=[O:15])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1cscc1NC(=O)C(C)Cl
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Product: CC(Oc1ccc(-c2ccc(F)cc2)cc1)C(=O)Nc1cscc1C(=O)O

Procedure:
In analogy to Example 2, the title compound was prepared using rac-4-(2-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester and 4′-fluoro-biphenyl-4-ol. MS (m/e): 384.1 (M−H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:13]=[N:12][C:11]1=2>C(#N)C>[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21]([NH:1][CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:22])[CH:13]=[N:12][C:11]1=2
Reactant: NCCN1CCCC1
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCN1CCCC1
Reaction time: 1 h
Yield: 85.2 %

Procedure:
0.500 g. (4.38 mmol) of 1-(2-aminoethyl)-pyrrolidine was heated 100°-110° C. with 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) in a 10 ml round bottom flask with stirring for one hour. Then, 10 ml of acetonitrile was added and the solution was stirred for 15 minutes. The resulting precipitate was collected by vacuum filtration. The solid was washed with acetonitrile and then with ether to yield 275 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(1-pyrrolidinyl)ethyl]propanamide (AIT-0068) as a white solid. Yield: 85%.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.O1CCCC1.[CH:22]1([Na])[CH:26]=[CH:25][CH:24]=[CH:23]1.Cl>O.C(OCC)C>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=2)=[C:25]2[CH:24]=[CH:23][CH:22]=[CH:26]2)=[CH:9][CH:10]=1
Reactant: [Na]C1C=CC=C1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=C2C=CC=C2)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 74.5 %

Procedure:
A 200 ml two-necked flask equipped with a dropping funnel, a magnetic stirrer and a three-way cock, was purged thoroughly with nitrogen. Into the flask, 4,4′-dimethylbenzophenone 6.72 g (31.9 mmol) was introduced, and dehydrated tetrahydrofuran 30 ml was further added. With cooling in an ice bath, 2 mol/L tetrahydrofuran solution of cyclopentadienyl sodium, 19.0 ml (38.0 mmol), was dropwise added to the flask. The contents were stirred at room temperature in a nitrogen atmosphere for 6 days to obtain a solution. With the flask cooled in an ice bath, 1 N hydrochloric acid aqueous solution 100 ml and diethyl ether 100 ml were gradually added in this order. The resulting two-phase solution was poured into a 300 ml separation funnel, and the funnel was shaken several times so that the water phase was removed. The obtained organic phase was washed twice with water 100 ml and once with a saturated salt solution 100 ml, and dried over anhydrous magnesium sulfate. The solution was filtered to remove solids, and the solvent of the filtrate was distilled away to obtain a red oily matter 9.40 g. The oily matter was subjected to silica gel chromatography to obtain 6.15 g of 6,6-di-p-tolyl fulvene as a red solid (23.8 mmol, 74.5% yield). Identification of the 6,6-di-p-tolyl fulvene was made by 1H NMR, the results being given below:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30](OCC(C2C=CC(F)=CC=2)=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([O-])(=O)[CH3:44].[NH4+:47]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]2[NH:47][CH:10]=[C:9]([C:43]3[CH:44]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:8]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)[O-]
Reactant: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2CC(=O)OCC(=O)c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Reactant: [NH4+]
Product: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2Cc2nc(-c3ccc(F)cc3)c[nH]2)c(-c2ccc(F)cc2)s1

Procedure:
(RS)-4-{1-[5-(4-Fluorophenyl)-2-methylthiazol-4-yl]-methanoyl}-3-[2-(4-fluoro-phenyl)-2-oxo-ethoxycarbonylmethyl]-piperazine-1-carboxylic acid tert-butyl ester from description 111 (0.360 g) and anhydrous ammonium acetate were heated to 140° C. under argon for 1.5 hours with stirring. After cooling, the reaction mixture was partitioned between dichloromethane and saturated potassium carbonate solution. The organic solution was washed with brine, dried (MgSO4) and evaporated. The residue was chromatographed over silica gel, eluting with 0 to 10% ethanol in ethyl acetate. The title compound was obtained as a white foam (0.125 g), mass spectrum (API+) 580 [MH+], C30H31F2N5O3S requires 579.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH3:43])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:19](=[O:36])[C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH3:43])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:19](=[O:36])[C:20]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[NH:3][C:4](=[O:7])[O:5][N:35]=2)=[CH:26][CH:27]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: CCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.61 g), sodium hydrogen carbonate (0.87 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(4-ethyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.42 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.30 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[C:21]([Cu])#[N:22]>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:21]#[N:22])=[CH:14][C:6]1=2
Reactant: N#C[Cu]
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Product: N#Cc1cnc2c(c1)N(Cc1cc(F)ccc1F)CCN2
Yield: 86 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (394 mg) was reacted with CuCN as in General Procedure 6 to give the title compound as a brown solid (86% yield). M.p. 204-206° C., LCMS: m/z=287.07 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.23-3.37 (m, 2H), 3.44-3.50 (m, 2H), 4.49 (s, 2H), 6.82 (s, 1H), 7.09-7.22 (m, 2H), 7.25-7.33 (m, 1H), 7.62 (bs, 1H), 7.73 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:8][N:9]=1)[CH2:3][CH3:4].[CH2:17]([C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CN=2)CCCC1>C(Cl)Cl>[CH3:1][CH:2]([C:5]1[S:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28]([C@H:25]3[CH2:26][CH2:27][C@H:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24]3)=[O:29])=[CH:14][CH:15]=2)=[N:8][N:9]=1)[CH2:3][CH3:4]
Reactant: CCC(C)c1nnc(-c2ccc(O)cc2)s1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ncn1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(-c3nnc(C(C)CC)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a mixture of 0.3 g (1.28×10-3 mol) of 1-methylpropyl-5-[4-hydroxyphenyl]-1,3,4-thiadiazole, 0.26 g (1.31×10-3 mol) of trans-4-n-pentylcyclohexanecarboxylic acid, 0.27 g (1.31×10-3 mol) of dicyclohexylcarbodiimide and 0.03 g of 4-(1-pyrrolidinyl)pyrimidine, 15 ml of methylene chloride was added, followed by 20 hours of stirring at room temperature. After the reaction, the reaction was filtered and the solid was washed with methylene chloride. The filtrate and the washing liquid were dehydrated, and the solvent was distilled off therefrom to obtain a crude product, which was then recrystallized twice to obtain 0.24 g of 2-(1-methylpropyl)-5-[4-(trans-4-n-pentylcyclohexylcarbonyloxy)-phenyl]-1,3,4-thiadiazole. (Yield: 45.2%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)N1CCCCC1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCCCC1
Temperature: 160 °C
Yield: 17.5 %

Procedure:
To a microwave vial was added 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (139.3 mg, 0.30 mmol), piperidine (0.04 mL, 0.35 mmol), 2-methyl-2-(1-piperidyl)propanal (68.8 mg, 0.4400 mmol) and toluene (3 mL). The vial was heated under microwave conditions at 160° C. for 3 hrs. The reaction was cooled and concentrated, then dissolved in ethyl acetate (30 mL) and washed with 2M HCl. The aqueous layer was basified to pH˜7.5 with sat. NaHCO3 and washed with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated and the crude material was purified by Isolera (1%-10% MeOH/ethyl acetate) to obtain 32 mg (18%) of the title compound. MS (pos. ion) m/z: 609 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:14](=[C:16]([C:20]([O:22]C)=O)[CH:17]=[CH:18][CH:19]=3)[N:15]=2)=[CH:7][CH:6]=1)[CH3:3].O.[NH3:25]>>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:14](=[C:16]([C:20]([NH2:25])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:15]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: N
Reactant: COC(=O)c1cccc2oc(-c3ccc(CN(C)C)cc3)nc12
Solvent: O
Product: CN(C)Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
Methyl 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-4-carboxylate (40 mg, 0.13 mmol) and ammonia water (17.2 mg, 0.52 mmol) were added and the mixture was stirred at 30° C. for 1 h. The resulting mixture was evaporated under reduced pressure and purified by pre-HPLC. 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-4-carboxamide (16 mg) was obtained, yield 41%. LC-MS (ESI) m/z: 296 (M+1)+. 1H-NMR (400 MHz, DMSO-d6): δ 2.94 (s, 6H), 4.46 (s, 2H), 7.57-7.58 (m, 1H), 7.75-7.77 (m, 2H), 7.93 (brs, 1H), 8.09 (brs, 1H), 8.43-8.44 (m, 2H).