Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1([O:10]C)[CH:8]=[CH:7][C:6](=[O:9])[CH:5]=[CH:4]1.[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[CH:23]=[C:22]2[C:3]2([OH:10])[CH:4]=[CH:5][C:6](=[O:9])[CH:7]=[CH:8]2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC1(OC)C=CC(=O)C=C1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Product: O=C1C=CC(O)(c2cc3cc(F)ccc3n2S(=O)(=O)c2ccccc2)C=C1
Yield: 21 %

Procedure:
The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienone and 1-benzenesulfonyl-5-fluoro-1H-indole, according to Method C, described above. Yield 21%; mp 166-167° C.; 1H NMR (CDCl3) δ 8.03-8.09 (m, 1H), 7.94 (d, J=8 Hz, 2H), 7.51-7.70 (m, 5H), 7.12-7.20 (m, 2H), 6.86 (s, 1H), 6.42 (d, J=10 Hz, 2H), 5.49 (s, 1H); 13C NMR (CDCl3) δ 185.1, 162.4, 158.5, 147.6, 143.0, 137.7, 134.8, 129.9, 129.8, 129.7, 128.2, 126.9, 116.9, 116.8, 114.8, 114.4, 113.6, 107.8, 107.4, 67.9; MS (AP+) m/z 384.04 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:16]([CH3:19])([CH3:18])[CH3:17])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(N(CC)CC)C.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>[C:16]([C:5]1[CH:4]=[CH:3][C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(Oc2cc(Br)ccc2C(C)(C)C)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2cc(C#C[Si](C)(C)C)ccc2C(C)(C)C)cc1
Temperature: 75 °C

Procedure:
In a sealed tube vessel, a solution of 323 mg (1.0 mmol) of 5-bromo-2-tert-butyl-1-[(4'-methyl)phenoxy]benzene (Compound J) in 6 mL of triethylamine was sparged (with a stream of argon bubbled vigorously into the solution) for several minutes. To this solution was added 48 mg (0.25 mmol) of cuprous iodide and the resultant mixture was sparged with argon for several minutes. To this reaction mixture was then added 175 mg (0.25 mmol) of bis(triphenylphosphine)palladium(II) chloride. After sparging with argon for a couple of minutes, 1.1 mL (1.0 g, 10.1 mmol) of trimethylsilyl acetylene was added to the reaction mixture. The pressure tube was then sealed and heated in an oil bath (75° C.) for 3 days at which time an additional 178 mg (0.25 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.0 mL (0.9 g, 9.4 mmol) of trimethylsilyl acetylene were added. The reaction mixture was heated at 75° C. for 4 days, filtered through celite and washed with ethyl ether (100 mL). The filtrate was extracted with water (3×75 mL-portions) and brine, dried over MgSO4, filtered and concentrated in vacuo to give a dark brown oil residue. Purification by flash chromatography (preabsorbed onto silica with 100% chloroform, eluted with 100% hexane) gave the title compound as a clear, colorless oil which solidified to a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[O:9]1[CH2:12][C:11](=[O:13])[CH2:10]1>C1COCC1>[Br:8][C:6]1[CH:7]=[C:2]([C:11]2([OH:13])[CH2:12][O:9][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: O=C1COC1
Solvent: C1CCOC1
Product: OC1(c2cncc(Br)c2)COC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a cooled (−20° C.) solution of 3,5-dibromopyridine (1.2 g, 5.0 mmol) in THF (2 mL) is added a solution of isopropylmagnesium chloride-lithium chloride complex in THF (1.7 M, 2.9 mL, 4.9 mmol). The resultant mixture is stirred warming to −10° C. for 30 min. The mixture is recooled to −20° C. and 3-oxetanone (432 mg, 6.0 mmol) is added. After stirring for 1 h, the reaction is quenched with saturated aqueous ammonium chloride solution and is extracted with EtOAc. The combined organic extracts are washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. Purification by silica gel column (0-10% MeOH in DCM) provided 3-(5-bromo-pyridin-3-yl)-oxetan-3-ol (320 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][CH3:10])[C:3]=1[C:13]#[N:14].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18].C(OC(=O)C)(=O)C>O1CCOCC1>[C:13]([C:3]1[C:4]([C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][CH3:10])=[N:5][S:6][C:2]=1[N:1]=[CH:15][O:16][CH2:17][CH3:18])#[N:14]
Reactant: CCCC(C)(C)c1nsc(N)c1C#N
Reactant: CCOC(OCC)OCC
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: CCCC(C)(C)c1nsc(N=COCC)c1C#N
Yield: 100.3 %

Procedure:
A solution of 25 g of 5-amino-4-cyano-3-(1,1-dimethylbutyl)isothiazole and 35.6 g of triethyl orthoformate in 200 ml of dioxane was heated under reflux for two hours. To the solution was added 24.5 g of acetic anhydride and the mixture was heated under reflux an additional 20 hours. The mixture wss concentrated under reduced pressure and the residue was distilled in a short path still at 120° under 0.1 mm Hg to give 31.8 g of 4-cyano-3-(1,1-dimethylbutyl)-5-[N-(ethoxymethylene)amino] isothiazole which was dissolved in 125 ml of ethanol, without further purification. The ethanolic solution was placed in a flask equipped with a gas inlet tube and one outlet of which was closed by a small rubber balloon. Dimethylamine gas was passed into the solution until the balloon remained inflated; during the introduction of dimethylamine, the temperature of the mixture increased to 60°. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of diethyl ether (90 parts) and pentane (10 parts) at low temperature to give 26.5 g of N'-[4-cyano-3-(1,1-dimethylbutyl)-5-isothiazolyl]-N,N-dimethylformamidine, m.p. 65°-67°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[Cl:13].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[Cl:13][C:6]1[C:7]([OH:12])=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([C:14]#[N:15])=[CH:3][C:2]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([F:16])[CH:18]=1)=[CH:11]2
Reactant: COc1ccc(B(O)O)cc1F
Reactant: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12
Product: COc1ccc(-c2cc(C#N)c3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-7-hydroxy-1-naphthonitrile (0.20 g, 0.71 mmol) with 3-fluoro-4-methoxyphenylboronic acid (0.17 g, 1.0 mmol) according to Method A to yield 0.14 (60%) of a yellow solid: mp 198–200° C.;1H NMR (DMSO-d6): δ 3.91 (3H, s), 7.27–7.33 (1H, m), 7.45 (1H, d, J=8.93 Hz), 7.71–7.74 (1H, m), 7.85 (1H, dd, J=2.23 Hz, J=13.09 Hz), 8.00 (1H, d, J×9.08 Hz), 8.48 (1H, d, J=1.97 Hz), 8.57 (1H, d, J=1.95 Hz), 11.18 (1H, s); MS (ESI) m/z 326/328 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[C@H:11]2[C@H:9]([O:10]2)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6]1.CC[O:18]C(C)=O>C1COCC1.O.OS(O)(=O)=O>[OH:18][CH:9]1[C@H:11]([OH:10])[C@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6][C:7]([C:12]([O:14][CH3:15])=[O:13])=[CH:8]1
Reactant: COCO[C@@H]1CC(C(=O)OC)=C[C@H]2O[C@H]21
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: COCO[C@@H]1CC(C(=O)OC)=CC(O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a well stirred solution of compound 14 (107 mg, 0.5 mmol) in THF/H2O (3:1), concentrated H2SO4 (5 drops) was added. The reaction was stirred for 2 h at 25° C. After the completion of reaction (monitored by TLC), the reaction mixture was diluted with excess of EtOAc 20 mL The organic layer is further washed with H2O, brine, dried over anhydrous Na2SO4. Removal of solvent under reduced pressure gave crude product which on chromatographic purification with petroleum ether/ethyl acetate (2:8 v/v) gave title compound 19 as gum.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][NH:6][C:5]1=[O:15])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[CH2:1]([N:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][N:6]([CH2:19][CH2:20][CH2:21][CH2:22][Cl:23])[C:5]1=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2cccnc2)n[nH]c1=O
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2cccnc2)nn(CCCCCl)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-allyl-5-(3-pyridyl)-1,2,4-triazol-3(2H,4H)-one (5 g) in dimethylformamide (50 ml) was added dropwise at ambient temperature under nitrogen to a stirred mixture of sodium hydride [0.92 g; 60% dispersion in mineral oil--pre-washed with petroleum ether (b.p. 40-60° C.)] and dimethylformamide (50 ml). The mixture was then stirred at ambient temperature for 1 hour, 1-bromo-4-chlorobutane (2.65 ml) was added, and stirring at ambient temperature was continued for 16 hours. The solvent was removed in vacuo, the residue was diluted with water (60 ml), and the product was extracted into ethyl acetate (2×200 ml). The extracts were dried (MgSO4), and the solvent was removed in vacuo to leave 4-allyl-2-(4-chlorobutyl)-5-(3-pyridyl)-1,2,4-triazol-3(2H,4H)-one as a yellow oil (6.93 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:23]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.CCOCC>[CH2:17]([NH:16][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:7][CH:6]=3)[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:23]=3)=[C:11]2[CH:12]=[CH:13][CH:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNc1nccc(-c2c(-c3ccc(N)cc3)nn3c(NCCCC)cccc23)n1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCNc1nccc(-c2c(-c3ccc(NC4CCCCC4)cc3)nn3c(NCCCC)cccc23)n1
Yield: 70.4 %

Procedure:
A solution of N-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine (62 mg, 0.15 mmol) in 1,2-dichloroethane (2 mL) was treated with cyclohexanone (0.02 mL, 0.22 mmol), acetic acid (0.04 mL, 0.72 mmol), and sodium triacetoxyborohydride (61 mg, 0.29 mmol). The resultant solution was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was added dropwise followed by ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) provided N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(cyclohexylamino)phenyl]pyrazolo[1,5-a]pyridin-7-amine (54 mg, 73%) as an orange oil. 1H NMR (CDCl3): δ 7.94 (d, 1 H), 7.73 (d, 1 H), 7.39 (d, 2 H), 7.23 (m, 1 H), 6.59 (d, 2 H), 6.41 (d, 1 H), 6.03 (m, 1 H), 5.91 (d, 1 H), 5.11 (broad, 1 H), 3.66 (broad, 1 H), 3.44 (m, 2 H), 3.30 (m, 3 H), 2.05 (m, 2 H), 1.75–1.12 (m, 16 H), 0.95–0.92 (m, 6 H); MS m/z 512 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochloride salt.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[N:18]1([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)[CH:29]=O)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[N:18]1([C:24]2[CH:31]=[C:28](/[CH:29]=[CH:3]/[C:1]#[N:2])[CH:27]=[N:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=Cc1cncc(N2CCOCC2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#C/C=C/c1cncc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) cooled at 0° C. was added 1.0 M potassium tert-butoxide in THF (0.50 mL) dropwise. The cold bath was removed and the reaction was warmed to room temperature over 30 minutes. The reaction was cooled to 0° C. and a solution of 5-morpholin-4-ylnicotinaldehyde (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was stirred at room temperature for 4 h, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (2E)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (75 mg, 100%) as a mixture of isomers; LC/MS: 216 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[CH3:23][C:24]([CH3:26])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:23][CH:24]([N:18]1[CH2:19][CH2:20][C:21]2=[CH:22][N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:5]4[O:4][N:3]=[C:2]([CH3:1])[N:6]=4)=[CH:8][CH:9]=3)[N:14]=[C:15]2[CH2:16][CH2:17]1)[CH3:26]
Reactant: CC(C)=O
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C(C)C)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 35) (31 mg, 0.10 mmol) in dichloromethane (4 ml) was added acetone (24 mg, 0.42 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and stirring continued overnight. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. Crude product was purified further by column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol/dichloromethane (0-1%). Resulting crude product was purified further by column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol/dichloromethane (0-1%) to afford the title compound (E15). MS (ES+) m/e 338 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[Cl:12].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>C1(C)C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[Cl:12])[CH:14]=[CH2:13]
Reactant: O=C1OCc2c1ccc(Br)c2Cl
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1Cl)COC2=O

Procedure:
To a flask charged with 5-bromo-4-chloro-2-benzofuran-1(3H)-one (190 mg, 0.77 mmol) and a stir bar was added allyl tri-n-butyltin (0.36 mL, 1.2 mmol), PdCl2(dppf)-DCM complex, lithium chloride (0.098 mg, 2.3 mmol), and toluene (5 mL). The flask was fitted with a condensor, purged three times with nitrogen, and heated to reflux for 6 hours. LC showed complete reaction, and crude material was purified by MPLC to deliver 5-allyl-4-chloro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 209 [M+1]+;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1.C([O-])(O)=O.[Na+].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[N:11]=[N:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2ccccn2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc(-c2ccccn2)nn1
Temperature: 0 °C
Yield: 95 %

Procedure:
4 g of pyridinylpyridazinone 7 dissolved in an excess (40 ml) of phosphorus oxychloride are refluxed for 8 hours. After cooling, the reaction mixture is poured into 250 ml of ice-cold water and then neutralized, dropwise, with a saturated aqueous solution of NaHCO3. After extraction with dichloromethane (5×100 ml), the organic phase is dried over MgSO4 and then concentrated under reduced pressure, to give the chlorinated pyridazine 8a with a yield of 95%.
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[N:27]=[C:20]3[C:21]([CH3:26])=[N:22][CH:23]=[C:24]([CH3:25])[N:19]3[N:18]=2)=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:80]1[CH2:84][CH2:83][CH2:82][CH2:81]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][C:24]1[N:19]2[N:18]=[C:17]([C:3]3[C:2]([N:80]4[CH2:84][CH2:83][CH2:82][CH2:81]4)=[CH:7][N:6]4[CH:8]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=[C:5]4[CH:4]=3)[N:27]=[C:20]2[C:21]([CH3:26])=[N:22][CH:23]=1
Reactant: Cc1ncc(C)n2nc(-c3cc4nc(-c5ccccc5)cn4cc3Br)nc12
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ncc(C)n2nc(-c3cc4nc(-c5ccccc5)cn4cc3N3CCCC3)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
A 2.0-5.0 mL microwave vial was charged with 2-(6-bromo-2-phenylimidazo[1,2-a]pyridin-7-yl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (45 mg, 0.107 mmol) and dissolved in toluene (1073 μL). To that stirring solution was added sodium tert-butoxide (36.1 mg, 0.376 mmol), BINAP (6.68 mg, 10.73 μmol), pyrrolidine (22.90 mg, 0.322 mmol), and palladium(II) acetate (2.410 mg, 10.73 μmol). The vial was sealed and degassed using ultra pure argon under sonication for 1 minute. Once purged, the vial was placed in a reaction block preheated to 110° C. The reaction was let stir overnight. After 19 hours at 110° C. the reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The contents of the vial were filtered through a pad of diatomaceous earth (Celite®) and the layers were separated. The organic layer was concentrated under reduced pressure to remove excess pyrrolidine and then rediluted with ethyl acetate and transferred into a separatory funnel. The organic was washed with brine (×2), dried with magnesium sulfate, concentrated under reduced pressure, and purified by prepHPLC: Column: Waters XBridge C18 100×30 mm 5 μm, Solvents: water/acetonitrile/TFA, % B gradient (time): 0% (2 min), 0-100% (12 min), 100% (1 min), Flow Rate: 42 mL/min, 3 injections (1 mL DMSO). The desired fractions were collected and neutralized using a saturated solution of sodium bicarbonate and then diluted with ethyl acetate. The layers were separated and the organic was concentrated under reduced pressure and then diluted with methanol and passed through a Phenomenex STRATA-XC 1 g cartridge and was with several volumes of methanol. The product was eluted with 25 mL of 2.0M ammonia in methanol to give 5,8-dimethyl-2-(2-phenyl-6-(pyrrolidin-1-yl)imidazo[1,2-a]pyridin-7-yl)-[1,2,4]triazolo[1,5-a]pyrazine (4.7 mg, 0.01079 mmol, 10% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.97 (d, J=7.0 Hz, 2H), 7.87 (s, 1H), 7.46 (t, J=7.5 Hz, 2H), 7.38-7.30 (m, 1H), 2.98-2.87 (m, 4H), 2.85 (s, 3H), 2.74 (s, 3H), 1.84-1.78 (m, 4H). Mass found 410 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].N1C=CC=CC=1.Cl.[CH2:15]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:15]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:1][C:2]([CH3:7])([C:3]([OH:5])=[O:4])[CH3:6])=[O:37])=[CH:39][CH:40]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(C)(N)C(=O)O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.24 g. of α-aminoisobutyric acid, 50 ml. of pyridine, and 25 ml. of H2O was stirred while 21.1 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride was added. The mixture was stirred for 18 hours at ambient temperature and filtered. The filtrate was evaporated and the residual yellow glass was dissolved in 1N NaOH solution. The solution was extracted with diethyl ether and then acidified with 6N HCl. The precipitate was collected, dried, and recrystallized from acetone, melting point 199°-202° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1([C:15](=[NH:18])[NH:16][OH:17])[CH2:11][CH:10]1[CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].[C:20](C1NC=CN=1)(C1NC=CN=1)=[O:21]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1([C:15]2[NH:18][C:20](=[O:21])[O:17][N:16]=2)[CH2:11][CH:10]1[CH:12]([CH3:14])[CH3:13])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(=N)NO
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)C1CC1(CNC(=O)OC(C)(C)C)c1noc(=O)[nH]1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of [1-(N-hydroxycarbamimidoyl)-2-isopropyl-cyclopropylmethyl]-carbamic acid tert-butyl ester (5.0 g, 18.5 mmol) in dry THF (185 mL) was added dropwise a solution of carbonyl diimidazole (4.5 g, 27.8 mmol) in dry THF (185 mL). The reaction mixture was heated to reflux for 12 hours and allowed to cool to room temperature. Excess of solvents was removed in vacuo and the residue was partitioned between ether (100 mL) and 1N NaOH (100 mL) solution. The ethereal solution was extracted with 1N NaOH (2×50 mL) and the combined aqueous layers were acidified to pH=3 with 4N HCl solution. The aqueous solution was extracted with EtOAc (3×100 mL) and the combined organic phase was washed with brine and dried over Na2SO4. Removal of excess of solvent, followed by purification of the residue by flash column chromatography using hexanes/EtOAc (1:1) as an eluant gave 3.3 g (61%) of {2-isopropyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclopropylmethyl}-carbamic acid tert-butyl ester as a colorless foam: 1H NMR (300 MHz, CD3OD) δ 0.87 (dd, J=5.4, 6.8 Hz, 1H), 1.00 (m, 1H), 1.05 (d, J=5.2. Hz, 3H), 1.07 (d, J=5.1 Hz, 3H), 1.35 (m, 1H), 1.42 (s, 9H), 1.48 (m, 1H), 3.25 (d, J=14.7 Hz, 1H), 3.69 (d, J=14.7 Hz, 1H), 4.92 (s, 1H); 13C NMR (75 MHz, CD3OD) δ 17.6, 23.2, 23.5, 24.7, 29.1, 30.3, 36.3, 41.3, 86.8, 158.7, 162.8, 164.4; MS (ACPI) m/z, 298 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:32]([CH3:34])[CH3:33])[C:6]2[O:10][C:9]([C:11]3[CH:30]=[CH:29][C:14]([C:15]([NH:17][CH2:18]OC(N4CCCOCC4)=O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:31]=1)#[N:2].[CH3:35][OH:36]>[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:32]([CH3:34])[CH3:33])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][C@H:5]4[O:36][CH2:35][CH2:9][NH:8][CH2:7][CH2:6]4)=[O:16])=[CH:29][CH:30]=3)=[N:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCOC(=O)N4CCCOCC4)cc3)oc12
Reactant: CO
Agent: [Pd]
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCNCCO4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of benzyl(7S)-7-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl-1,4-oxazepane-4-carboxylate (211 mg) in 30 ml methanol was added 10% palladium on carbon (40 mg). The mixture was stirred under an atmosphere of hydrogen (via balloon) overnight at room temperature. The mixture was then filtered through a small plug of Celite and concentrated in vacuo to provide the title compound (133 mg, 83%). Mass spectrum (ESI) 419.3 (M+1).