Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O.N>>[O:20]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:18]1[C:16]1[CH:15]=[CH:14][C:6]2[N:7]([CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[C:3]([CH3:2])=[N:4][C:5]=2[CH:17]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Nc1ccccc1O
Agent: Cl
Agent: N
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 160 °C
Reaction time: 17 h
Yield: 0.2 %

Procedure:
An eggplant flask (100 mL) was charged with 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.64 g, 2.46 mmol), 2-aminophenol (0.32 g, 2.95 mmol) and polyphosphoric acid (approx. 18 g), and this was heated to 160° C. and stirred for 17 hours. After being allowed to cool, ice was added and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. This was extracted with chloroform (approx. 50 mL, 3 times) and dried over anhydrous magnesium sulfate. The crude product (0.08 g) obtained after the solvent was distilled off was purified by PTLC (CHCl3) with double development to yield the title compound (0.002 g, 0.2% yield) as a yellowish-brown semisolid.
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].[CH3:13][C:14]1[CH:15]=[C:16]([C:31]2[CH:32]=[CH:33][C:34]([CH:37]=O)=[N:35][CH:36]=2)[CH:17]=[C:18]([NH:20][C:21]2[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=2)[CH:19]=1.[C:39](=[O:42])([O-])[O-:40].[K+].[K+]>CO.O>[C:37]([C:34]1[N:35]=[CH:36][C:31]([C:16]2[CH:17]=[C:18]([NH:20][C:21]3[N:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][N:22]=3)[CH:19]=[C:14]([CH3:13])[CH:15]=2)=[CH:32][CH:33]=1)#[CH:3].[C:39]([OH:40])([C:27]([F:30])([F:29])[F:28])=[O:42]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C=O)nc2)c1
Reactant: O=C([O-])[O-]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethyl (1-diazo-2-oxopropyl)phosphonate (0.200 mL, 1.15 mmol) was added to a solution of 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carbaldehyde (201 mg, 0.560 mmol) and potassium carbonate (155 mg, 1.12 mmol) in dry methanol (8.00 mL). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was directly purified by reverse phase HPLC to yield N-[3-(6-ethynylpyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine as a TFA salt. MS APCI C19H14F3N4 [M+H]+ 355. found 355.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1>>[N+:21]([C:19]1[CH:20]=[C:15]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:16]=[N:17][CH:18]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: O=[N+]([O-])c1cncc(O)c1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([N+](=O)[O-])c1
Yield: 72.4 %

Procedure:
1-BOC-2-(S)-azetidinylmethanol (868 mg, 4.64 mmol) and 3-hydroxy-5-nitropyridine from Example 132d (500 mg, 3.57 mmol) were coupled according the procedure of Example 17a. Solvent was removed, and the residue was chromatographed (silica gel, hexane/ethyl acetate, 5:1) to afford the title compound (800 mg, 73%). 1H NMR (CHCl3, 300 MHz) δ1.45 (s, 9H), 2.56 (m, 2H), 4.52 (m, 4H), 4.82 (m, 1H), 8.25 (t, J=3 Hz, 1 H), 8.65 (d, J=3 Hz, 1H), 9.05 (d, J=3 Hz, 1H). MS (DCI/NH3) m/z 310 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[N:25]=[C:21]([NH:20][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[C:4]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[N:3]=3)[S:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2nc(-c3cccnc3)nc(Nc3nc(-c4ccc(Cl)cc4)cs3)c2c1
Temperature: 80 °C
Reaction time: 9.5 h
Yield: 36.2 %

Procedure:
(The method G13 is representative of method G12 also. This method can be implemented in a similar way except for substitution of the appropriate base, solvent and temperature) To a suspension of 4-chloro-6-methoxy-2-(pyridine-3-yl)quinazoline (645.2 mg, 2.375 mmol) and 2-amino-4-(4-chlorophenyl)thiazole (1050 mg, 4.98 mmol) in DMA (40 mL) was added Cs2CO3 (2430 mg, 7.46 mmol) at room temperature. The mixture was stirred at 80° C. for 9.5 h. Water was added and a precipitate formed which was collected by filtration and washed with H2O. Recrystallization from acetone/DMF/methanol gave 383.6 mg of the product in a 36% yield as yellow solid, >98% purity by 1H NMR). 1H NMR (400 MHz DMSO-d6) δ 12.52 (s, 1H), 9.78 (d, J=1.56 Hz, 1H), 8.91-8.88 (m, 1H), 8.74 (dd, J=4.74, 1.60 Hz, 1H), 8.33 (brs, 1H), 8.06 (d, J=8.56 Hz, 2H), 7.93 (d, J=9.08 hz, 1H), 7.89 (s, 1H), 7.66-7.59 (m, 2H), 7.55 (d, J=8.56 Hz, 2H), 4.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[C:15]([Cl:17])[CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=O.Cl.O([NH2:22])C.N1C=CC=CC=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[C:15]([Cl:17])[CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH2:22]
Reactant: CON
Reactant: O=C1CC2(CCCCC2)Oc2c(Cl)cc(Cl)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: NC1CC2(CCCCC2)Oc2c(Cl)cc(Cl)cc21
Temperature: 25 °C

Procedure:
A mixture of Example 6A (1.001 g, 3.51 mmol), methoxylamine hydrochloride (293 mg, 3.51 mmol), and pyridine (1.4 mL, 17.3 mmol) in methanol (25 mL) was stirred overnight at room temperature. After this time, the solvent was evaporated in vacuo, and the residue was dissolved in ether and washed with water and brine. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo, and the residue further dried azeotropically (CH3CN). A solution of the residue in tetrahydrofuran (4 mL) was cooled to 0° and was then treated slowly with 1M BH3-tetrahydrofuran (5 mL, 5 mmol). After the addition was complete, the reaction was refluxed for 2.5 h. The mixture was cooled to room temperature and was treated carefully with H2O (3 mL) and 20% aq. KOH (3 mL), then was refluxed for 1 h. The mixture was cooled and extracted with ethyl acetate. The organic extracts were washed with 1N HCl. The aqueous layer was basified with 2M NaOH, followed by extraction with ethyl acetate, afforded the title compound as a yellow oil, 64 mg (6%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.55 (dd; J=14.9, 2.7 Hz; 1H), 7.36 (m, 1H), 3.82 (m, 1H), 2.11 (m, 2H), 1.20-1.82 (m, 10H). MS (DCI+) m/z 286 (M+H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([NH:11][O:12][CH3:13])=[NH:10])=[CH:7][CH:6]=1)=[N+]=[N-]>C(O)C.O=[Pt]=O>[NH2:1][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([NH:11][O:12][CH3:13])=[NH:10])=[CH:7][CH:6]=1
Reactant: CONC(=N)c1ccc(CN=[N+]=[N-])cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CONC(=N)c1ccc(CN)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-azidomethyl-N-methoxy-benzamidine (11.3 g, 0.055 mol; see step (i) above) in 200 mL of ethanol was added 200 mg of PtO2. The mixture was hydrogenated with constant bubbling ofhydrogen for 4 h and subsequently filtered through Celite® and evaporated. Yield: 7.34 g (74%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)[F:33])(=O)=O.F[N+]1C=CC=CC=1.[NH4+].[Cl-].CCOCC>ClC(Cl)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)[C:10]([F:33])=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: Cc1c(F)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 11.4 %

Procedure:
To a solution of 21 mg (0.054 mmol) of 2-(1-benzyl-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 80) in 1 mL of dichloroethane were added 16 mg (0.065 mmol) of 1-fluoropyridinium triflate. After stirring at RT for 72 hrs, the mixture was poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 yielded 2.5 mg (11%) of 2-(1-benzyl-3-fluoro-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light brown waxy solid. MS: 404 (M−H)−.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](=O)[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>C(O)C>[CH2:26]([O:33][N:34]=[C:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)Oc1ccc(Oc2ccc(CCC(=O)C(C)C)cc2)cn1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(Oc2ccc(CCC(=NOCc3ccccc3)C(C)C)cc2)cn1

Procedure:
1-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-4-methylpentan-3-one (310 mg, 0.947 mmol) was stirred with O-benzylhydroxylamine hydrochloride (181 mg, 1.14 mmol) and pyridine (0.92 ml, 1.14 mmol) in 5 ml of ethanol at room temperature for 18 h. The reaction mixture was concentrated and further reacted without purification. Yield: 310 mg, M+H+: 433.26.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:10][N:11]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:13]/[C:12]/2=[N:20]\[C:21]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=S)[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:39]#[C:40][NH2:41]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([O:4][C:5]1([CH2:10][N:11]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:13]/[C:12]/2=[N:20]\[C:21]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[N:41][C:40]#[N:39])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: N#CN
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCCC1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cl)cc1C(=NC#N)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCCC1
Yield: 75 %

Procedure:
The product of Example 24D (1.6 g, 3.2 mmol), triethylamine (1.8 mL, 13 mmol), cyanamide (0.40 g, 9.7 mmol) and Hg(OAc)2 (2.0 g, 6.5 mmol) in acetonitrile (20 mL) were processed as described in Example 16E to provide the title compound (1.2 g, 2.4 mmol, 74% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.34-1.40 (m, 9H), 1.65-1.84 (m, 4H), 1.86-2.09 (m, 4H), 2.00-2.02 (m, 3H), 3.91 (s, 3H), 4.72 (s, 2H), 6.70 (s, 1H), 6.94 (d, J=9.1 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.35 (dd, J=8.7, 2.8 Hz, 1H); MS (DCI/NH3) m/z 489 (M+H)+. Anal. calculated for C24H29ClN4O3S: C, 58.94; H, 5.98; N, 11.46. Found: C, 58.88; H, 5.86; N, 11.32.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=12.CN(C)[CH:34]=[O:35]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:21]([CH:34]=[O:35])=[CH:22][C:15]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
n-Butyllithium (2.5M in hexanes, 3.56 mmol) was added dropwise to a solution of diisopropylamine (3.56 mmol) in anhydrous tetrahydrofuran (5 mL) at −78° C. under nitrogen. The reaction was stirred for 30 minutes at −78° C. and then a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.97 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise via syringe. The resulting reaction was stirred at −78° C. for 2 h and then a solution of N,N-dimethylformamide (11.88 mmol) in tetrahydrofuran (1 mL) was added dropwise by syringe. The reaction was stirred at −78° C. for 2 h and then quenched with saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 70-100% CH2Cl2/hexanes) afforded the title compound as a white solid (66%). ESMS [M+H]+: 365.0
Reaction SMILES: N.C(O)C.[Br:5][C:6]1[C:14]2[O:15][CH2:16][CH2:17][C:13]=2[C:12]2/[C:11](=[CH:18]/[C:19]#[N:20])/[CH2:10][CH2:9][C:8]=2[CH:7]=1.[H][H]>[Ni].C(O)C>[BrH:5].[CH2:17]1[CH2:16][O:15][C:14]2[CH:6]=[CH:7][C:8]3[CH2:9][CH2:10][CH:11]([CH2:18][CH2:19][NH2:20])[C:12]=3[C:13]1=2
Reactant: N#C/C=C1\CCc2cc(Br)c3c(c21)CCO3
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: Br
Product: NCCC1CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
Raney nickel (0.4 g, W2) and 4 M ammonia/ethanol solution (10 ml) were added to an ethanol (30 ml) suspension of (E)-(4-bromo-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile (0.44 g, 1.59 mmols) and stirred in a hydrogen atmosphere (at from 4 to 5 atmospheres) at room temperature for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (50 ml), and 5% palladium-carbon (1 g, containing 50% water) was added thereto and stirred in a hydrogen atmosphere (at ordinary pressure) at room temperature for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 0.42 g (yield: 93%) of the target compound. This was amorphous.
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([C:14]1[O:18][C:17]([C:19]2[C:20]([NH2:37])=[N:21][CH:22]=[C:23]([C:25]3[N:29]([CH3:30])[N:28]=[C:27]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:26]=3)[N:24]=2)=[N:16][N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[NH2:37][C:20]1[N:21]=[CH:22][C:23]([C:25]2[N:29]([CH3:30])[N:28]=[C:27]([CH:31]3[CH2:36][CH2:35][N:34]([C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:33][CH2:32]3)[N:26]=2)=[N:24][C:19]=1[C:17]1[O:18][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[N:15][N:16]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(C)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
Ethyl 3-chloro-3-oxopropanoate (0.037 mL, 0.29 mmol) was added dropwise to a stirred solution of 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (100 mg, 0.26 mmol) and triethylamine (0.047 mL, 0.34 mmol) dissolved in CH2Cl2 (1.5 mL) over a period of 2 minutes at 0° C. under nitrogen. The mixture was stirred at 0° C. for 10 minutes then allowed to warm to room temperature and stirred for 1 hour. The mixture was evaporated, dissolved in DMF; a white solid was filtered off and the filtrate was purified by preparative HPLC using a Waters X-Terra reverse-phase column eluting with a mixture of water (containing 0.2% ammonium carbonate) and acetonitrile to afford ethyl 3-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-oxopropanoate (80 mg, 61.7%) as a yellow solid. This material was suspended in THF (2 mL). 2N Sodium hydroxide (0.235 mL, 0.47 mmol) and water (0.5 ml) were added. The mixture was stirred at room temperature overnight. 2N Hydrochloric acid (230 μL) was added to the mixture. The solvents were evaporated. The residue was diluted with CH2Cl2 (30 mL) and water (5 mL). The organic phase was washed with brine and dried over MgSO4. The solvents were evaporated. The resulting foam was triturated in ether. The resulting yellow solid was filtered, dried, triturated in acetonitrile (3 mL). The yellow solid was collected by filtration, dried at 40° C. to afford the title compound (50 mg, 68%) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:21])[CH2:18][CH2:19][CH3:20].Cl>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: CCCC(=O)N(C)OC
Reactant: Brc1cccc2sccc12
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Approximately 5 ml of a solution of 4-bromobenzo[b]thiophene (1.85 g; prepared in a manner similar to that described in Bull. Soc. Chim. Fr., 1966, 111, 3667) in tetrahydrofuran (20 ml) was added under nitrogen to magnesium turnings (0.22 g) in tetrahydrofuran (2 ml). Two crystals of iodine were added, and the mixture was heated to initiate the reaction. The remainder of the 4-bromo-benzo[b]thiophene solution was added at reflux temperature over 15 minutes, then the mixture was heated under reflux 20 minutes and allowed to cool to ambient temperature. A solution of N-methoxy-N-methylbutyramide (1.13 g) in tetrahydrofuran (10 ml) was added, the mixture was heated under reflux for 50 minutes, then it was allowed to cool to ambient temperature and 2M hydrochloric acid (25 ml) was added. The mixture was stirred at ambient temperature for 1 hour, then the product was extracted into ethyl acetate (100 ml). The extract was washed with water (50 ml) and saturated aqueous sodium chloride solution (2×50 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 96:4 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)butan-1-one (0.41 g) as a colourless oil which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH:28]=3)=[CH:19][CH:18]=2)[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:32][S:29]([N:26]1[CH2:25][CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH3:15])=[CH:18][CH:19]=2)[CH2:28][CH2:27]1)(=[O:30])=[O:31]
Reactant: CC(Oc1ccc(C2=CCN(S(C)(=O)=O)CC2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1ccc(C2=CCN(S(C)(=O)=O)CC2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of 4-{1-[4-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (1.16 g, 2.50 mmol) in dichloromethane (25 mL) is added trifluoroacetic acid (1.32 mL, 17.48 mmol). The reaction is stirred at room temperature for 18 h. The mixture is concentrated in vacuo and diluted with 3 mL of ethyl acetate. 2 M aqueous sodium hydroxide is added to produce a white solid. The solid is filtered and dried to afford 0.86 g of the title compound. MS (m/z) 365 (M+1). The title compound (0.320 g, 0.88 mmol) is separated into its enantiomers using an eluent of 0.2% dimethylethylamine in 2:3 acetonitrile:methanol on a 4.6×150 mm Chiralcel AD-H column at 1 mL/min to afford 0.115 g of isomer 1 (100% ee, RT=5.27 min) MS (m/z) 365 (M+1) and 0.112 g of isomer 2 (100% ee, RT=8.59 min). MS (m/z) 365 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:26])[CH2:25][CH2:24]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 4-bromomethyl-benzoic acid methyl ester (3.0 g; 15 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (3.77 g; 16.5 mmol) and potassium carbonate (4.35 g, 31.5 mmol) in 100 ml acetonitrile is stirred for 5 h at 80° C. Precipitates were removed by filtration and the solution is evaporated. The residue is purified by silica gel column chromatography (gradient: DCM/Methanol 98:2 to 95:5 to yield 4-(4-tert-Butoxycarbonylamino-piperidin-1-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [O:1]=O.[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:17]1([C:15]2[C:7]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[C:5](=[O:1])[C:4](=[O:3])[CH:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=O
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: C1CCNCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: O=C1C=C(N2CCCCC2)c2oc3ccccc3c2C1=O

Procedure:
Oxygen was bubbled, at a fast rate, for 3 hours, through a vigourously stirred solution of 2-hydroxydibenzofuran (73.8 g; 0.40 mol), copper (II) acetate (4.60 g; 0.025 mol) and piperidine (79.9 g; 0.94 mol) in methanol (600 ml) at room temperature. The resulting dark reaction mixture was filtered and the collected solid dried in air to give 4-piperidinodibenzofuran-1,2-dione as a very dark blue solid (66.3 g; 59%), m.pt. 151°-6° C. ##STR11##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][N:16](Cl)[CH2:15][N:14]2[CH:20]=1.[H][H].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]2[CH:20]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2cn3c(n2)C=CN(Cl)C3)c(OC)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cn3cnccc3n2)c(OC)c1

Procedure:
A solution of 3 g. of 2-(2,4-dimethoxyphenyl)-6-chloro-imidazo[1,2-c]pyrimidine (free base) in ethyl acetate was treated with 1 g. of 5% palladium-on-carbon and subjected to hydrogenation until hydrogen uptake ceased. Two grams of triethylamine were added and hydrogenation was continued. When hydrogen uptake ceased, the catalyst was removed by filtration, and the ethyl acetate solution was washed with 300 ml. of a saturated sodium chloride solution. The organic solution was evaporated in vacuo, and the resulting residue was crystallized from ethyl acetate/ether to give 1.2 g. of the title product, M+ =255.