Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:27])([CH3:26])[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][C:15]([CH3:27])([CH2:14][CH2:13][CH:12]=[O:11])[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)(CCCO)C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCC=O)C(=O)OCc1ccccc1
Reaction time: 0.42 h
Yield: 91.1 %

Procedure:
To a −78° C. solution of oxalyl chloride (4.80 g, 37.8 mmol) in DCM (200 mL) was add DMSO (5.91 g, 75.6 mmol) dropwise over 10 minutes. After 25 minutes of additional stirring, a −78° C. solution of benzyl 5-hydroxy-2,2-dimethylpentanoate (4.06 g, 17.2 mmol, Step B) in DCM (200 mL) was added via cannula over 75 minutes. After stirring for an additional 30 minutes, triethylamine (13.9 g, 137 mmol) was added slowly over 25 minutes. The cooling bath was allowed to warm, while the reaction stirred for an additional 18 hours. Reaction solvent was then removed in vacuo, and the residue was dissolved in a mixture of diethyl ether and water (containing enough HCl to remain acidic). The organics were then dried over sodium sulfated, filtered and concentrated in vacuo to give the title compound (3.67 g), which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.[OH-].[Na+:34]>CO>[Na+:34].[S:29]1[CH:30]=[CH:31][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@@H:8]4[CH2:9][CH2:10][CH2:11][N:7]4[CH2:6][CH2:5][CH2:4][C:3]([O-:32])=[O:2])=[CH:15][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28]1
Reactant: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])CCCN1CCC[C@H]1COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Temperature: 58 °C
Reaction time: 5.5 h
Yield: 68 %

Procedure:
To the product from step 1 (128 mg, 0.29 mmol) in methanol (5 mL) was added 1N NaOH (0.30 mL). The resulting solution was stirred at 58° C. for 5.5 h. The reaction mixture was concentrated in vacuo. The subsequent powder was washed with ether to afford the title compound (85 mg, 68%); LCMS; m/z: 436.9 (M+1); 1H NMR (400 MHz, DMSO-d6); δ 1.54-1.68 (m, 5H), 1.82-1.90 (m, 3H), 2.15-2.26 (m, 2H), 2.70-2.74 (m, 2H), 3.00-3.02 (m, 1H), 3.63-3.67 (m, 1H), 3.87-3.90 (m, 3H), 6.84 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.51 (dd, J1=5.2 Hz, J2=1.2 Hz, 1H), 7.60-7.62 (m, 3H), 7.78-7.79 (m, 1H):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Cl
Temperature: 25 °C

Procedure:
Fuming H2SO4 (25 mL) is added dropwise to a solution of crude 3-chloro-pyridine-1-oxide in concentrated H2SO4 (25 mL) under cold conditions (0° C.) with stirring. HNO3 (fuming, 90%, 60 mL) is added carefully to the above mixture with caution to keep the offset of any exotherm under control, and then allowed to warm to room temperature slowly. The resulting mixture is then heated at 120° C. for 4 h with stirring, cooled, poured into ice-cold water, and extracted with CHCl3. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 3-Chloro-4-nitro-pyridine-1-oxide as an yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.31 (d, J=1.5 Hz, 1H), 8.13 (dd, J=1.5, 5.4 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1c[nH]c2ccccc12)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 35 %

Procedure:
The title compound is prepared from 1H-indole-3-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 35% of theory; LC (method 4): tR=1.99 min; Mass spectrum (ESI+): m/z=317 [M+H]+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5]CCC.[Na+].[I-].[C:11]([O:15]O)(C)([CH3:13])[CH3:12].[O-:17]O>C(O)(C)(C)C.O>[CH2:12]([OH:17])[CH:11]([OH:15])[CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [O-]O
Reactant: CC(C)(C)OO
Reactant: C=CCCCCCC
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCC(O)CO

Procedure:
Into a 100 ml 3-neck flask provided with condenser, addition funnel, and magnetic stirrer is charged t-butyl-alcohol (20.0 g), 1-octene (4.48 g), water (1.0 g), NaI (0.03 g) and 0.30 g of the Os(CO)12 /MgO supported catalyst prepared in accordance with Example 1. At ambient temperature (26° C.), 2.0 g of a solution of 90% by weight, tertiary butyl hydroperoxide dissolved in t-butyl alcohol is added dropwise over a period of 2 minutes with stirring. After 12 hours from completion of the addition, the reaction mixture is analyzed by GLC and complete conversion of the hydroperoxide is obtained with a selectivity to 1,2-octanediol of 84%. The results are summarized at Table 1.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.N[C:12]1[CH:20]=[C:19]2[C:15]([C:16](=CC3NC4CCN(CCN(CC)CC)C(=O)C=4C=3C)[C:17](=[O:21])[NH:18]2)=[CH:14][C:13]=1[F:41].[NH:42]1CCCCC1>O1CCCC1>[F:41][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([NH:42][CH:5]=[O:7])[CH:12]=1)[NH:18][C:17](=[O:21])[CH2:16]2
Reactant: C1CCNCC1
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1cc(F)cc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of acetic anhydride (1.6 ml) and formic acid (1.2 ml) was stirred for 1 hour at room temperature, and added with 6-amino-5-fluoro-1,3-dihydro-indol-2-one (4.0 g, 24 mmol) obtained from Example 7 in 60 ml of tetrahydrofuran and piperidine (0.04 ml). Upon the completion of the addition, the mixture was stirred for 3 hours at room temperature until a precipitate was formed. The solid was filtered and recrystallized from methanol to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide (4.6 g, 99%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:31][C@@H:27]5[CH2:28][NH:29][CH2:30][C@@H:26]5[CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].C=O.Cl.O1CCOC[CH2:36]1>C(O)=O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:31][C@@H:27]5[CH2:28][N:29]([CH3:36])[CH2:30][C@@H:26]5[CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@H]2CNC[C@H]2C1
Reactant: C1COCCO1
Agent: C=O
Agent: Cl
Solvent: O=CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@@H]2CN(C)C[C@@H]2C1
Temperature: 95 °C
Yield: 56 %

Procedure:
N-(3,4-Dichloro-phenyl)-6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclopenta-[c]pyrrol-5-yl]oxy}quinazolin-4-amine hydrochloride (0.20 g, 0.42 mmol) was solubilized in formic acid (5.0 mL) and 37% aqueous formaldehyde (1 mL) was added. The solution was heated to 95° C. for 12 h. The reaction mixture was concentrated in vacuo. The residue was taken up in a mixture of 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2×30 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent the product was taken up in a mixture of 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2×30 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated then the product was taken up in methanol and treated with 4.0 M hydrogen chloride in dioxane (1 eq.). Removal of solvent in vacuo provided 116 mg (56%) of N-(3,4-dichlorophenyl)-7-({[(3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]}oxy)-6-(methyloxy)quinazolin-4-amine hydrochloride. 1H NMR (400 MHz, d6-DMSO): 11.05 (bs, 1H), 8.90 (s, 1H), 8.44 (s, 1H), 8.18 (d, 1H), 7.84 (dd, 1H), 7.76 (s, 1H), 7.48 (s, 1H), 5.30 (m, 1H), 4.00 (s, 3H), 3.35 (m, 2H), 2.90 (m, 2H), 2.24 (m, 5H), 2.10 (m, 2H), 1.24 (m, 2H). MS (EI) for C23H24Cl2N4O2: 459, 461 (MH+).
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[Na].[C:6]([C:8]1[C:9]([SH:21])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:13]=1[CH3:14])#[N:7].II>C(O)C>[C:6]([C:8]1[C:9]([S:21][S:21][C:9]2[C:8]([C:6]#[N:7])=[C:13]([CH3:14])[CH:12]=[C:11]([C:3]3[CH:2]=[CH:20][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[N:10][C:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][C:13]=1[CH3:14])#[N:7]
Reactant: Cc1cc(-c2ccccc2)nc(S)c1C#N
Reactant: CC[O-]
Agent: II
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1cc(-c2ccccc2)nc(SSc2nc(-c3ccccc3)cc(C)c2C#N)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
An ethanolic solution containing sodium ethoxide was prepared by dissolving 0.74 g of metallic sodium in 70 ml of ethanol. To the solution was added 7.28 g of 3-cyano-4-methyl-6-phenyl-2-pyridinethiol. The mixture was stirred at room temperature for about 20 minutes to give a yellowish homogeneous solution. To this solution was added dropwise with stirring at room temperature 60 ml of ethanol containing 4.09 g of iodine. With addition, colorless crystals began to precipitate and there was obtained a suspension at the time of completion of the addition. After completion of the addition, stirring was continued for about 2 hours at room temperature. The reaction mixture was then filtered and the collected substance was dried to give 7.00 g of brownish crystals. The obtained crystals were recrystallized from benzene. The crystals recrystallized had a melting point of 200°~201° C and were identified by the elemental analyses and IR spectrum as bis(3-cyano-4-methyl-6-phenyl-2-pyridyl) disulfide.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:38]([C:37]2[CH:36]=[CH:35][C:34]([O:33][CH2:32][CH:29]3[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:25])[CH2:31][CH2:30]3)=[CH:42][CH:41]=2)=[O:39])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)CC1
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g), 4-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}benzoic acid obtained in Reference Example 6 (1.41 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (824 mg), 1-hydroxy-1H-benzotriazole monohydrate (659 mg), triethylamine (1.53 mL), and N,N-dimethylformamide (10 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (NH-silica gel, 10:90-0:100 hexane/ethyl acetate) to provide the title compound (1.6 g, 87%) as crystals.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](I)[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([C:22]4[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[CH3:33])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(I)cccc3c21
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)cccc3c21
Temperature: 80 °C
Reaction time: 48 h
Yield: 15.2 %

Procedure:
1-(1-Ethylpropyl)-6-iodo-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline (200 mg, 0.526 mmol), mesitylboric acid (95 mg, 0.579 mmol), barium hydroxide octahydrate (249 mg, 0.782 mmol) and tetrakistriphenylphosphinepalladium (12 mg, 0.01 mmol) were suspended into a mixture of dimethoxyethane (6 mL) and water (1 mL), followed by stirring at 80° C. for two days in nitrogen atmosphere. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was purified by silica gel column chromatogrpahy (ethyl acetate), to give the title compound (28 mg, 0.08 mmol) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[C:16]2=[CH:15][N:14]=1.Cl.C(Cl)(=O)C.C(N(CC)C(C)C)(C)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>CO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH2:28][N:27]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:26][CH2:25]4)[C:16]2=[CH:15][N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CCN(C(=O)OC(C)(C)C)C5)n[nH]c3n2)c1F
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CCN(S(C)(=O)=O)C5)n[nH]c3n2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 6-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (10.0 mg, 0.0191 mmol) in methanol (0.10 mL) was treated at r.t. with HCl solution previously prepared from acetyl chloride (0.1 mL) and methanol (0.1 mL) at 0° C. The mixture was stirred at r.t. for 1 h. The volatiles were evaporated. The residue was dissolved in acetonitrile (0.5 mL) and N,N-diisopropylethylamine (30.0 μL, 0.172 mmol). To the mixture was added methanesulfonyl chloride (2.0 μL, 0.026 mmol). The mixture was stirred at r.t. for 1 h. The volatiles were removed. The residue was dissolved in methanol (0.5 mL) and treated with sodium methoxide (25%, 0.060 mL). After 1 h, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=502.1. 1H NMR (300 MHz, DMSO-d6) δ: 9.39 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.07 (t, J=8.1 Hz, 1H), 4.40 (s, 2H), 3.92 (s, 6H), 3.48 (t, J=5.7 Hz, 2H), 3.04 (d, J=5.7 Hz, 3H), 2.97 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[NH2:17][OH:18]>>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1CCN(CCN2CCOCC2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CCN2CCOCC2)CC1

Procedure:
1-(2-(4-Morpholinyl)ethyl)-4-piperidone oxime is prepared from 1-(2-(4-morpholinyl)ethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(N(CC)CC)C>C(O)(C)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)C2CNCCO2)no1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(NC(=O)C2CN(c3ccc(C(F)(F)F)cn3)CCO2)no1
Temperature: 175 °C
Reaction time: 18 h

Procedure:
A microwave vial is charged with morpholine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (75 mg; 0.259 mmol), 2-bromo-5-trifluoromethylpyridine (58.8 mg; 0.26 mmol), triethylamine (0.072 mL; 0.52 mmol) and t-butanol (0.5 mL). The vial is heated in microwave at 175° C. for 1 hour then left standing at room temperature for 18 hours. After this time, the reaction mixture is concentrated in vacuo. Purification by flash chromatography using methanol/methylene chloride provides the title compound, m/z 399 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](=[CH2:15])[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][C:33]=1[CH3:39].C(N(CC)CC)C.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSC>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:14]([CH2:15][S:38][C:35]2[CH:36]=[CH:37][C:32]([F:31])=[C:33]([CH3:39])[CH:34]=2)[C@H:13]([OH:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(S)ccc1F
Reactant: C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CCN(CC)CC
Solvent: CSC
Solvent: CCOCC
Product: Cc1cc(SC[C@@H]2[C@H](O)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
Di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-methylene-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (8 g, 18.9 mmol) in diethyl ether (80 mL) is bubbled with nitrogen gas for 10 minutes. 4-fluoro-3-methyl-benzenethiol (2.7 g, 18.9 mmol) and triethylamine (0.26 mL, 1.89 mmol) are added. The mixture is warmed to 40° C. and stirred for 15 minutes. The mixture is then allowed to cool to ambient temperature, transferred to addition funnel and added slowly over 2 hours to a 200 ml ether solution at −10° C. which contains S-(−)-2-methyl-CBS-oxazaborolidine (1M in tetrahydrofuran) (5.67 mL, 5.67 mmol) and borane-methyl sulfide complex (2M in tetrahydrofuran, 8.5 mL, 17 mmol). The mixture is stirred for an additional hour after final addition. Silica gel (40 g) is added over 30 minutes and the reaction mixture is gradually warmed to ambient temperature. The suspension is filtered, and washed with 300 ml of diethyl ether. The solvent is concentrated under reduced pressure giving a residue. The residue is purified by flash chromatography, eluting with (0 to 25% ethyl acetate/hexanes) to give the title compound (9.8 g, 17.3 mmol, 91.5% yield). MS (m/z): 565.8 (M−H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:60]=[CH:59][C:51]([CH2:52][NH:53][CH2:54][CH2:55][CH2:56][CH:57]=[CH2:58])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][N:53]([CH2:54][CH2:55][CH2:56][CH:57]=[CH2:58])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:59][CH:60]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: C=CCCCNCc1ccc(C(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 69 mg (0.3 mmol) of (4-tert-butyl-benzyl)-pent-4-enyl-amine in 1 ml DMF was added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (8 g silica gel; heptane/EtOAc 6:1) to give 62 mg (53%) of a light yellow viscous oil. MS (ISP) 375.5 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:5]([CH3:7])[CH:6]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][N:5]1[CH:6]=[C:2]([C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)[N:3]=[C:4]1[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: OB(O)c1ccsc1
Reactant: Cn1cc(Br)nc1CCc1ccc2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccsc2)nc1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
A suspension of 2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)ethyl)quinoline (0.31 g, 0.980 mmol), thiophen-3-ylboronic acid (0.25 g, 1.960 mmol), and Pd(PPh3)4 (0.022 g, 0.441 mmol) in 1,4-dioxane (6 mL) under N2 was stirred at room temperature for 0.5 h and then Na2CO3 (0.3105 g, 2.94 mmol) in water (1 mL) was added. The mixture was refluxed overnight. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate (EtOAc). The separated organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 55.6 mg of the desired compound. LC-MS: m/z 320 (M+H+).