Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[C:18](=[O:19])[C:17]3[CH:20]=[C:21]([CH2:23][CH3:24])[S:22][C:16]=3[NH:15][C:14]2=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[N:44]=[C:43](C(Cl)(Cl)Cl)[O:42][N:41]=2)=[CH:30][CH:29]=1.C(=O)([O-])[O-:50].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[C:18](=[O:19])[C:17]3[CH:20]=[C:21]([CH2:23][CH3:24])[S:22][C:16]=3[N:15]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:44][C:43](=[O:50])[O:42][N:41]=4)=[CH:30][CH:29]=3)[C:14]2=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(=O)n(CCc3ccc(OC)c(OC)c3)c(=O)[nH]c2s1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CCc3ccc(OC)c(OC)c3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A mixture of 3-[2-(3,4-dimethoxyphenyl)ethyl]-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.36 g), potassium carbonate (0.12 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from acetone-hexane to give the title compound as colorless crystals (0.3 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](Cl)=[O:37])=[CH:31][CH:30]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)[C:36](=[O:37])[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(N(C(=O)Cc2ccc(OC)cc2)c2ccc(Cl)cc2)CC1

Procedure:
To a stirred solution of 15 parts of ethyl 4-[(4-chlorophenyl)amino]-1-piperidinecarboxylate, 5.4 parts of N,N-diethylethanamine and 160 parts of benzene is added dropwise 11.07 parts of 4-methoxybenzeneacetyl chloride at a temperature between 32° to 40° C. After the addition is complete, the whole is stirred and refluxed for 3 hours. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate solution and water, dried, filtered and evaporated in vacuo. The oily residue is crystallized from a mixture of 56 parts of 1,1'-oxybisethane and 40 parts of hexane. The crude solid product is filtered off and recrystallized from a mixture of benzene and 1,1'-oxybisethane, yielding 3 parts of ethyl 4-{N-(4-chlorophenyl)-N-[(4-methoxyphenyl)acetyl]amino}-1-piperidinecarboxylate; mp. 137° C.
Reaction SMILES: [CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li+:8].[CH2:9]1[CH2:13]O[CH2:11][CH2:10]1>CCCCCC>[CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:11]([Li:8])[CH2:10][CH2:9][CH3:13]
Reactant: C1CCOC1
Reactant: [Li+]
Reactant: CC(C)[N-]C(C)C
Solvent: CCCCCC
Product: CC(C)NC(C)C
Product: [Li]CCCC

Procedure:
A solution of the ketone 26a (60 mg) in THF (0.5 ml) is added at -78° C. to a solution of lithium diisopropylamide, obtained from diisopropylamine (0.024 ml) and n-butyllithium (0.084 ml of a 2 molar solution in hexane) in THF (0.5 ml). The temperature is brought back to -40° C. for 10 minutes. A solution of phenylselenyl bromide (40 mg) in THF (0.5 ml) is then added dropwise at -78° C. Water and ether are added. The organic phase is washed with water, bicarbonate and brine, and dried. After concentration under vacuum, the residue is purified on silica gel (ether/hexane, 1:9), to give 40 mg of selenide 32a (50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=3[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CCC(CC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 2 h

Procedure:
To a solution of the product of Step B (50 mg, 0.16 mmol) and N-methylmorpholine (32 mg, 0.32 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (23 mg, 0.24 mmol) at room temperature. The mixture was stirred for 2 h, then diluted with water (15 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by PREP-TLC eluting with PE/EA (2/1, v/v) to give the title compound as a colorless solid. LC/MS m/z=391.0[M+H]+.
Reaction SMILES: C([C:3]1[C:8]([Br:9])=[CH:7][C:6]([Br:10])=C[N:4]=1)#N.[C:11]([OH:14])(=[O:13])[CH3:12].S(=O)(=O)(O)O>O>[Br:10][C:6]1[C:12]([C:11]([OH:14])=[O:13])=[N:4][CH:3]=[C:8]([Br:9])[CH:7]=1
Reactant: N#Cc1ncc(Br)cc1Br
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ncc(Br)cc1Br
Temperature: 140 °C

Procedure:
2-Cyano-3,5-dibromopyridine (prepared in the above (2)) 3.27 g is added to a mixture of acetic acid 14 ml, sulfuric acid 14 ml and water 14 ml, and the mixture is refluxed at 140° C. for 4 hours. The reaction mixture is cooled and water is added thereto. The resulting precipitate is filtered and washed with water. The precipitate is dissolved in ether, washed and dried. The solvent is removed in vacuo and crystallized from a mixture of ether and hexane to give 3,5-dibromopyridine-2-carboxylic acid. mp 170–171° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][N:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[Cl:18][C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@@H:31]([CH2:33][C:34](=[O:52])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:32][C:21]=2[CH:20]=1>>[Cl:18][C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@H:31]([CH2:33][C:34]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[C:8](=[O:17])[NH:9][C:10]5[C:15]([CH:16]=4)=[CH:14][N:13]=[CH:12][CH:11]=5)[CH2:5][CH2:6]3)=[O:52])[CH2:32][C:21]=2[CH:20]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c2ccncc2cc1C1CCNCC1
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cnccc4[nH]c3=O)CC2)C1=O
Yield: 27 %

Procedure:
3-(piperidin-4-yl)-1,6-naphthyridin-2(1H)-one (89 mg, 0.29 mmol) and [4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acid (95 mg, 0.26 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 27% yield. High resolution MS m/e (M+H)+=575.2538.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=O)[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH2:27]([O:29][NH2:30])[CH3:28].O>C(O)C>[Cl:1][C:2]1[C:3]([C:12](=[N:30][O:29][CH2:27][CH3:28])[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Reactant: CCON
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
To 214 mg of the N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-oxoethyl]phthalimide prepared in Step 2 in Synthetic Example 6 in 3 ml of ethanol, 84 mg of ethoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3), and the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 2:18 to 5:15) as the eluent to obtain 111 mg of the desired product as a brown resinous substance.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[Cl-].Cl[C:31](Cl)=[N+:32]([CH3:34])[CH3:33]>C(#N)C.CS(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:31]([N:32]([CH3:34])[CH3:33])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N(C)C)n(CC3CCOCC3)c12
Temperature: 120 °C
Yield: 77.1 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for preparation see intermediate 17) (50 mg, 0.131 mmol) and N-(dichloromethylene)-N-methylmethanaminium chloride (available from Aldrich) (42.5 mg, 0.261 mmol) were combined in anhydrous acetonitrile (0.5 ml) and heated at 120° C. for 10 min (microwave). The reaction mixture was reduced to dryness under a stream of nitrogen and the residue dissolved in DMSO (1 ml) and purified by MDAP (HpH). The solvent was evaporated under a stream of nitrogen to give 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-N,N-dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-c]quinolin-2-amine (44 mg, 0.101 mmol, 77% yield) as a yellow gum.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:20]#[CH:21])[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1([C:20]#[C:21][CH:32]([C:31]2[CH:34]=[CH:35][C:28]([CH3:27])=[CH:29][CH:30]=2)[OH:33])[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC1(COCc2ccccc2)CCC2(CC1)OCCO2
Reactant: Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C#CC2(COCc3ccccc3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
To a solution of 8-(benzyloxymethyl)-8-ethynyl-1,4-dioxaspiro[4.5]decane (Reference Example 87) (393 mg, 1.37 mmol) in tetrahydrofuran (4.6 mL), 2.6 M n-butyllithium (solution in hexane, 0.555 mL, 1.44 mmol) was added at −78° C., and the obtained solution was stirred for 10 minutes. Further, 4-methylbenzaldehyde (0.178 mL, 1.51 mmol) was added, and the obtained solution was allowed to warm gradually to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (459 mg, 1.13 mmol, 82%) as a colorless oily compound.
Reaction SMILES: [C:1]1([CH:7]2[O:17][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][N:9]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[CH3:36])([CH3:25])[CH3:24].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:14]2[CH2:15][CH2:16][C:11]3([O:17][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][N:9]([CH2:18][C:19]([F:21])([F:22])[F:20])[CH2:10]3)[CH2:12][CH2:13]2)=[O:32])=[CH:29][C:28]=1[CH3:36])([CH3:25])[CH3:24]
Reactant: FC(F)(F)CN1CC(c2ccccc2)OC2(CCNCC2)C1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(CC(F)(F)F)CC(c2ccccc2)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane (hydrochloride salt) (150 mg, 0.39 mmol) and 4-isopropoxy-3-methyl-benzoic acid (75 mg, 0.39 mmol) in DMF (1 mL) was added at room temperature O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (162 mg, 0.43 mmol) and diisopropylethylamine (337 μL, 1.94 mmol) and reaction mixture was stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate and washed with 1M NaOH and then brine solution. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 10-60% EtOAc/hexane to give the desired compound as a white foam (147 mg, 73%) ESI-MS m/z calc. 490.2. found 491.4 (M+1)+; Retention time: 2.42 minutes (3 min run).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:51][C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH2:66][CH2:67][CH2:68][O:69][CH3:70])[CH:58]=1)[CH:53]([CH3:55])[CH3:54])[C@@H:34]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:35][C@@H:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:31])([CH3:28])([CH3:27])[CH3:26].[CH2:71]([NH2:78])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1.CCOC(C)=O>C(#N)C.CN(C=O)C>[C:25]([O:29][C:30](=[O:31])[NH:32][C@@H:33]([CH2:51][C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH2:66][CH2:67][CH2:68][O:69][CH3:70])[CH:58]=1)[CH:53]([CH3:54])[CH3:55])[C@@H:34]([O:43][Si:44]([C:47]([CH3:48])([CH3:50])[CH3:49])([CH3:45])[CH3:46])[CH2:35][C@H:36]([C:37](=[O:38])[NH:78][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[CH:40]([CH3:41])[CH3:42])([CH3:26])([CH3:28])[CH3:27]
Reactant: NCc1ccccc1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@H](C(=O)O)C(C)C)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@H](C(=O)NCc2ccccc2)C(C)C)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
HBTU (400 mg, 1.03 mmol, 1.2 equiv.) is added to a solution of (2S,4S,5S,7S)-5-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (575 mg, 0.86 mmol, 1.0 equiv.) in acetonitrile (CH3CN) (15 mL) and DMF (1 mL) at 0° C. After 5 minutes, a solution of benzylamine (94 μL, 0.86 mmol, 1.0 equiv.) and Net3 (1.2 mL, 8.6 mmol, 10 equiv.) in CH3CN (3 mL) is added and the reaction mixture is stirred at room temperature for 5 minutes. For workup EtOAc is added and the organic layer is washed with 1 N HCl, a saturated solution of sodium bicarbonate (NaHCO3) and brine. Drying (Na2SO4) of the organic phase and evaporation of the solvent affords the crude product which is purified by flash column chromatography [50 g SiO2, hexane:EtOAc (4:1)] to afford the desired product as a colorless foam. MS (LC-MS): 780.4 [M+Na]+; Rf [hexane:EtOAc (1:1)]: 0.65 minutes.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=c1[nH]cc(Br)cc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cn1cc(Br)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
A 1-L round-bottomed flask equipped with a magnetic stirrer was charged with 3,5-dibromo-1H-pyridin-2-one (7.0 g, 27.7 mmol), anhydrous DMF (280 mL) and powdered potassium carbonate (−350 mesh, 8.4 g, 61.1 mmol), and the suspension stirred for 15 min at ambient temperature. After this time, methyl iodide (4.3 g, 30.5 mmol) was added, and the mixture was stirred at room temperature under nitrogen for a further 18 h. The reaction mixture was then diluted with water (200 mL), extracted with ethyl acetate (3×250 mL), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica to give an 84% yield (6.2 g) of 3,5-dibromo-1-methyl-1H-pyridin-2-one (1) as an off-white solid: mp 87-88° C.; MS (ESI+) m/z 266 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Mg].O1CCCC1.[C:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C>[ClH:8].[Cl:8][C:4]1[CH:3]=[C:2]([C:24]2([OH:28])[CH2:25][CH2:26][CH2:27][N:22]([CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:23]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Br)c1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cl
Product: OC1(c2cccc(Cl)c2)CCCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred and refluxed Grignard complex previously prepared starting from a mixture of 4.2 parts of 1-bromo-3-chlorobenzene, 5.4 parts of magnesium and 135 parts of tetrahydrofuran were added dropwise 19 parts of 1-(phenylmethyl)-3-piperidinone. Upon completion, stirring was continued for 1 hour at reflux temperature. After cooling, the reaction mixture was poured into ice water and 12.5 parts of acetic acid. The layers were separated. The aqueous phase was extracted with trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol. the salt was filtered off and dried, yielding 26 parts (76%) of 3-(3-chlorophenyl)-1-(phenylmethyl)-3-piperidinol hydrochloride (intermediate 27).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1>CN(C=O)C>[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[CH:12][CH:11]=1
Reactant: O=C1CCCN1
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1ccc(I)cc1
Temperature: 25 °C

Procedure:
To 140 μl (1.68 mmol) 2-pyrrolidone in 5 mL DMF are added 110 mg (2.53 mmol) sodium hydride. Then 500 mg (1.68 mmol) 4-iodobenzyl bromide are added by several portions and the resulting mixture is stirred at r.t. over night. The solvent is removed in vacuo and the residue is resolved in DCM and water. The layers are separated and the organic layer is dried with Na2SO4, filtrated and the solvent is removed in vacuo. The crude product is purified by HPLC.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(#N)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:47][CH2:48][NH:49][CH2:50][CH2:51]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)NCc2cccc(-c3cccc(CN4CCNCC4)c3)c2)cc1
Yield: 52.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3′-{[({4-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)-amino]methyl}-3-biphenylyl)methyl]-1-piperazinecarboxylate (0.130 g, 0.16 mmol) in acetonitrile (7.2 mL) and H2O (4800 μL) was added TFA (100 μL, 0.160 mmol). The resultant mixture was applied to a GeneVac EZ-2 evaporator at 45° C. for 8 h. The mixture was further purified using a Gilson HPLC (with 0.1% TFA) and the product-containing fraction concentrated on a GeneVav EZ-2 evaporator at 45° C. for 8 h. The extra TFA was removed by re-dissolving the resultant mixture in DCM and passing it though an amino cartridge. The mixture was concentrated down again by Glas-Col evaporator to afford the title compound 0.0600 g (52%). LC-MS m/z 716 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.53 Hz, 3 H) 1.48 (t, J=7.15 Hz, 3 H) 1.81-1.97 (m, 2 H) 2.09 (d, J=12.05 Hz, 2 H) 3.16 (q, J=7.45 Hz, 2 H) 3.56 (s, 8 H) 3.68 (t, J=11.42 Hz, 2 H) 3.99-4.11 (m, J=8.41, 3.14 Hz, 2 H) 4.29-4.41 (m, J=4.27 Hz, 1 H) 4.43-4.53 (m, 4 H) 4.64 (s, 2 H) 4.71 (s, 2 H) 7.35-7.46 (m, 2 H) 7.47-7.61 (m, 3 H) 7.65 (s, 1 H) 7.74 (d, J=7.53 Hz, 1 H) 7.81 (s, 1 H) 7.92-8.03 (m, 4 H) 8.28 (s, 1 H).