Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:5]([NH:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:11][CH2:10][C:9]1[O:12][C:5]([C:4]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([Cl:1])[CH:3]=2)=[N:7][N:8]=1
Reactant: O=C(CCl)NNC(=O)c1ccc(Cl)c(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: ClCc1nnc(-c2ccc(Cl)c(Cl)c2)o1
Yield: 72.8 %

Procedure:
To a mixture of 3,4-dichlorobenzohydrazide 8 (0.5 mg, 2.43 mmol) and K2CO3 (0.61 g, 4.4 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.41 g, 3.66 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, Washed with H2O and ether, and dried to afford 3,4-dichloro-N′-(2-chloroacetyl)benzohydrazide 9 (0.59 g, 85%) which was used for the next step without further purification. A mixture of compound 9 (0.5.9 g, 2.24 mmol) and phosphorous oxychloride (0.51 g, 3.36 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 10 (0.43 g). Yield: 78%.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8](I)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([Zn]C#N)#[N:15].O.CCOC(C)=O>CN(C=O)C.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>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:14]#[N:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: N#C[Zn]C#N
Reactant: COC(=O)c1c(I)cc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(C#N)cc(Cl)nc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium (34.8 mg, 0.03 mmol), methyl 2,6-dichloro-4-iodonicotinate (100 mg, 0.301 mmol) and dicyanozinc (38.9 mg, 0.331 mmol) in DMF (2 mL) was stirred at 100° C. overnight under N2 atmosphere. To the resulting mixture were added H2O and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with H2O and brine, dried over MgSO4 and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a white solid (28 mg, 40%). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H), 8.44 (s, 1H).
Reaction SMILES: [CH:1]1([N:7]2[CH:12]3[CH2:13][CH2:14][CH:8]2[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([N:7]2[CH:8]3[CH2:14][CH2:13][CH:12]2[CH2:11][CH:10]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:9]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(C2=CC3CCC(C2)N3C2CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C2CC3CCC(C2)N3C2CCCCC2)cc1

Procedure:
A solution of 8-cyclohexyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene (230 mg; 0.74 mmol; 1.0 eq.) in EtOH (7 mL) was passed twice at 1 mL/min through the H-Cube using a cartridge of Pd/C under full H2 at 250. The solution was then concentrated under reduced pressure to give the title compound as a 66:33 mixture of the endo:exo isomers (163 mg; 78%). 1H NMR (DMSO) δ 6.94 (d, J=8.3 Hz, 1.3H), 6.87 (d, J=8.3 Hz, 0.7H), 6.48-6.45 (m, 2H), 4.78 (bs, 2H), 3.47 (m, 2H), 2.84-2.70 (m, 1H), 2.19-2.07 (m, 2H), 1.90-1.82 (m, 3H), 1.72-1.63 (m, 5H), 1.54-1.46 (m, 2H), 1.40-1.33 (m, 2H), 1.27-0.98 (m, 5H). HPLC (max plot) 65.3%; Rt %2.25 min. UPLC/MS: (MS+) 285.4.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([N:16]([OH:31])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[CH:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:15])=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([N:16]([O:31][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[CH:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:15])=[CH:11][CH:12]=1
Reactant: C#CCOc1ccc(CCN(O)C(=O)Cc2ccc(Cl)cc2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(CCN(OS(C)(=O)=O)C(=O)Cc2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.022 ml, 0.286 mmol) is added dropwise to a solution of 2-(4-chloro-phenyl)-N-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (0.1 g, 0.26 mmol), and Et3N (0.036 ml, 0.26 mmol) in 1 ml CH2Cl2 at 0° C. The reaction mixture is allowed to warm to room temperature and stirred for another 2 hours. The reaction mixture is then washed with water, 1N HCl, and brine and dried over Na2SO4. After rotary evaporation, the product is purified by flash chromatography (ethyl acetate:hexane, 1:2) to yield 2-(4-chloro-phenyl)-N-mesyloxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide as a solid, mp. 91-93° C.
Reaction SMILES: O1CCCC1.[CH:6](=[O:12])[C:7]1[O:11][CH:10]=[CH:9][CH:8]=1.[CH:13](=[O:19])[CH:14]1[O:18][CH2:17][CH2:16][CH2:15]1>CCCCCCCCCCCCCCCC>[CH:9]1[CH:8]=[C:7]([CH:6]([OH:12])[C:13]([C:14]2[O:18][CH:17]=[CH:16][CH:15]=2)=[O:19])[O:11][CH:10]=1
Reactant: O=Cc1ccco1
Reactant: O=CC1CCCO1
Solvent: C1CCOC1
Solvent: CCCCCCCCCCCCCCCC
Product: O=C(c1ccco1)C(O)c1ccco1

Procedure:
This has as a consequence that if we use stoichiometric ratios, which means 2 moles of furfural and 1 mol of acetone (since the acetone can react at both ends), between 16 and 37% of components with only 5 carbon atoms would be obtained that have a very limited interest as components for gasoline (App. Catal. B Environ. 2006, 66, 111-118). A second product with 8 carbon atoms which is usually one third of the mix appears in other conditions. This condensation product is hydrogenated to n-octane that does not have an interesting application in gasoline for having linear chain, or in diesel for the low molecular weight. To increase the selectivity to 85% with a yield of 71% the condensation has to be carried out in an aqueous phase, and the hydrogenation in hexadecane as a solvent at 120° C. which is a more expensive method (Appl. Catal. B Environ. 2006, 66, 111-118). The own authors realized the drawbacks caused by the selectivity and proposed as an alternative the hydrogenation of the furane ring to tetrahydrofurane since these derivatives are able to carry out an aldol condensation with themselves which would ensure a high selectivity. However, chemoselective hydrogenation of, e.g., furfural to tetrahydrofurfural in one step is still a challenge and is currently carried out in several stages. In any case, if a multi-stage method is accepted, molecules with a total of 10 carbon atoms can be obtained (Science 2005, 308, 1446-1450) the same as by furoin formation.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3C(OC(C)(C)C)=O)[CH:15]=[CH:14][N:13]=2)=[N:3]1.C(OCC)(=O)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[NH:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1nc(-c2cc(C3CCCN3)ccn2)sc2ccccc12
Reaction time: 0.5 h
Yield: 31 %

Procedure:
tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]-1-pyrrolidinecarboxylate (0.40 g, 0.97 mmol) was dissolved in ethyl acetate (25 ml), and 4 N hydrogen chloride-ethyl acetate solution (8 ml) was added dropwise thereto at room temperature. The mixture was stirred at the same temperature for 30 minutes. The precipitates were collected by filtration and recrystallized from diethyl ether-methanol to give the titled compound (0.10 g, 31%) as white crystals.
Reaction SMILES: [Na].[I-:2].C([O-])(=O)C.[NH4+].C(OO)(=O)C.C([Sn](CCCC)(CCCC)[C:18]1[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:19]=1)CCC.C(#N)C>[OH-].[Na+].C(O)C>[I:2][C:18]1[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(CCCCCCCCCC(=O)O)no1
Reactant: [I-]
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCO
Product: O=C(O)CCCCCCCCCc1cc(I)on1
Reaction time: 0.25 h

Procedure:
To sodium [123I] iodide, received in 5-20 μL 0.05M sodium hydroxide is added ammonium acetate buffer (100 μL pH 4.0, 0.2M), sodium [127I] iodide (10 μL, 1 mM solution in 0.01M sodium hydroxide, 1×10−8 moles), peracetic acid (PAA) solution (10 μL 1 mM solution, 1×10−8 moles) and finally 10-(5-tributylstannyl-isoxazol-3-yl)-decanoic acid solution in ethanol or acetonitrile (53 μg, 1×10−7 moles). The reaction mixture is allowed to stand at room temperature for 15 minutes and the iodinated product 10-(4-iodo-[1,2,3]triazol-1-yl)-decanoic acid purified by HPLC.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1.[BH4-].[Na+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:22])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)c1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(Cc1cccc(OCc2ccccc2)c1)c1ccco1

Procedure:
1-(Furan-2-yl)-2-(3-benzyloxyphenyl)ethan-1-one (4 kg, 13.69 mol) was dissolved in MeOH (35 L), and NaBH4 (520 g, 13.75 mol) was slowly added to the solution at 5° C. After the reaction was completed, the solution was quenched with H2O, and the MeOH was evaporated. The residue was extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4, and evaporated to give the 1-(furan-2-yl)-2-(3-benzyloxyphenyl)ethan-1-ol as yellow oil: 3.97 kg (crude yield: 98%)
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH2:3].Cl.[C:22](=O)(O)[O-].[Na+]>CO>[CH3:22][O:13][C:12](=[O:14])[CH2:11][N:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1N(CC(=O)O)c1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCc1ccccc1N(CC(=O)OC)c1ccccc1

Procedure:
A solution of 0.06 mol of N-(2-allylphenyl)phenylglycine, prepared as described by A. Padwa, H. L. Gingrich, and R. Lim in J. Org. Chem.,1982, 47, 2447-2456, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(2-allylphenyl)phenylglycine methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.[CH3:16]I.[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:10]([CH3:16])[S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)NC(C)c1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N(C)C(C)c1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-41, N-(1-(5-bromopyridin-3-yl)ethyl)ethanesulfonamide (intermediate A-37) was reacted with MeI in presence of NaH (60% in mineral oil) to give the title compound as a light yellow solid. MS: 307.1 and 309.2 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[CH2:22][CH2:21][C:20]([F:26])([C:23]([OH:25])=O)[CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=[O:9])[CH3:6].[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:26][C:20]1([C:23](=[O:25])[NH:31][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][CH2:18][N:17]([CH:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([O:7][CH2:5][CH3:6])=[O:9])[CH2:11][CH2:12]2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)N
Reactant: CCOC(=O)N1CCCC(N2CCC(F)(C(=O)O)CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCCC(N2CCC(F)(C(=O)NC(C)(C)C)CC2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 22.6 %

Procedure:
Thionyl chloride (4 mL) was added to a solution of 1-[1-(ethoxycarbonyl)azepan-4-yl]-4-fluoropiperidine-4-carboxylic acid (1.24 g, assume 3.92 mmol) and the reaction was stirred at 90° C. for 3 h. The reaction mixture was cooled to rt and concentrated in vacuo. DCM (4 mL) was added to a portion of the residue (0.65 mmol) followed by tert-butylamine (0.14 mL, 1.31 mmol) and DIPEA (0.57 ml, 3.27 mmol), the reaction mixture was stirred at rt for 48 h. The solvents were removed in vacuo, and the residue was partitioned between DCM (50 mL) and sat. NaHCO3 sol. (25 mL), organic layer washed with sat. NaCl sol. (25 mL) and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 7% MeOH in DCM]) to give ethyl 4-(4-fluoro-4-((tert-butyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (0.11 g, 46.8%) as a yellow oil.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:42][C@@H:43]1[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])[C@H:45]([CH:61]2[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([N+:77]([O-:79])=[O:78])=[CH:73][CH:72]=3)=[O:68])[CH2:63][CH2:62]2)[CH2:44]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:42][C@@H:43]3[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[C@H:45]([CH:61]4[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]5[CH:72]=[CH:73][C:74]([N+:77]([O-:79])=[O:78])=[CH:75][CH:76]=5)=[O:68])[CH2:63][CH2:62]4)[CH2:44]3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 76.3 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (270 mg, 0.46 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidine (216 mg, 0.40 mmol, compound of Reference Example 32) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)piperidin-4-yl]pyrrolidin-4ylthio]-1-carbapen-2-em-3-carboxylate (267 mg, yield: 65.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:17](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:18])[C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].OO.[OH-].[Li+].S([O-])(O)=[O:37].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C@@H:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:17]([OH:18])=[O:37])=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: O=S([O-])O
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of [(1S,2R)-1-((S)-2-oxo-4-phenyl-oxazolidine-3-carbonyl)-2-phenyl-propyl]-carbamic acid tert-butyl ester (710 mg, 1.7 mmol) in tetrahydrofuran (18 mL) and water (4 ml) at 0° C. was added 30% aqueous hydrogen peroxide (1.5 mL, 15.1 mmol) followed by 1M aqueous lithium hydroxide (5.0 mL, 5.0 mmol). The mixture was stirred overnight at room temperature. The excess hydrogen peroxide was quenched with 2.0 M aqueous sodium hydrogen sulfite (15 mL, 30.1 mmol). Stirring was continued for 1 hour followed by extraction with dichloromethane. The aqueous layer was acidified with 10% aqueous citric acid and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water, brine and dried over magnesium sulfate and evaporated to give (2S,3R)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid (420 mg, 90% yield).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.Cl[C:19]1[C:20]2[C:21]3[C@H:22]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][CH2:24][CH2:25][C:26]=3[S:27][C:28]=2[N:29]=[CH:30][N:31]=1>C1COCC1>[C:13]([O:12][C:11]([NH:10][CH:7]1[CH2:8][CH2:9][CH:4]([O:3][C:19]2[C:20]3[C:21]4[C@H:22]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][CH2:24][CH2:25][C:26]=4[S:27][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:5][CH2:6]1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C[C@@H]1CCCc2sc3ncnc(Cl)c3c21
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCCc2sc3ncnc(OC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
NaH (60% dispersion in mineral oil, 438 mg, 10.95 mmol, 4.00 equiv) was treated with tert-butyl N-(4-hydroxycyclohexyl)carbamate (710 mg, 3.30 mmol, 1.20 equiv) in freshly distilled THF at 50° C. for 30 min under nitrogen. Then a solution of ethyl 2-[(13S)-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-13-yl]acetate (850 mg, 2.73 mmol, 1.00 equiv) in THF (10 mL) was added via syringe and stirred for 2 h at 60° C. After cooling, the reaction was quenched with brine, extracted with ethyl acetate (80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give 800 mg (60%) of ethyl 2-[(13S)-3-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-13-yl]acetate as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:21])[CH2:6][CH2:7][NH:8][C:9]([CH:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:13]([CH3:20])([CH3:19])[O:12]1)=[O:10].[C:22](Cl)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(N(CC)CC)C>O1CCCC1>[CH3:19][C:13]1([CH3:20])[O:12][CH:11]([C:9]([NH:8][CH2:7][CH2:6][C:5](=[O:21])[NH:4][CH2:3][CH2:2][NH:1][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:10])[C:16]([CH3:17])([CH3:18])[CH2:15][O:14]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)NCCN)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCNC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 19.4 %

Procedure:
A mixture of 1.1 g of N-[3-[(2aminoethyl)amino]-3-oxopropyl]-2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamide, 1.1 g of oleoyl chloride and 3 ml of triethylamine in 100 ml of tetrahydrofuran was reacted as described in Example 11. The crude product was purified by flash chromatography, eluting with dichloromethane:methane (50:1, then 20:1), giving 400 mg of the desired product as a white solid, mp 110-112° C.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(Cl)Cl.[N:19]1([CH2:29][CH2:30][OH:31])[C@H:28]2[C@@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[NH:22][CH2:21][CH2:20]1>O>[Si:8]([O:31][CH2:30][CH2:29][N:19]1[C@H:28]2[C@@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[NH:22][CH2:21][CH2:20]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCN1CCN[C@@H]2CCCC[C@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN1CCN[C@@H]2CCCC[C@H]21
Yield: 71 %

Procedure:
Triethylamine (4.61 mL, 33.0 mmol) and subsequently tert-butyldimethylsilyl chloride (4.27 g, 28.3 mmol) were added to a methylene chloride (40 mL) solution of 2-(trans -decahydroquinoxalin-1-yl)ethanol (1.74 g, 9.44 mmol) with ice-cooling and stirring, and the mixture was stirred overnight at room temperature. To the reaction mixture, water (100 mL) was added to terminate the reaction. The product was extracted with methylene chloride (100 mL). The organic layer was washed with water twice and with saturated saline once, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride/methanol) to obtain trans-1-[2-(tert-butyldimethylsilyloxy)ethyl]decahydroquinoxaline (2.00 g, yield: 71%) in a light brown oil form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[C:43]([CH3:56])=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[C:43]([CH3:56])=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][O:53][CH2:54][CH2:55]6)=[O:49])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1c(Br)cccc1C(=O)N1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCOCC4)c3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (3-bromo-2-methyl-phenyl)-morpholin-4-yl-methanone (164 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-phenyl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-157) as a pale brown powder (50 mg, 54%).
Reaction SMILES: Br[C:2]1[C:3](=[O:33])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCO[C:43]2[CH:51]=[C:50]3[C:46]([C:47](C4C=CC=CC=4)=C(Br)C3=O)=[CH:45][CH:44]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25][CH2:24]3)=[CH:7][CH:8]=2)[C:3](=[O:33])[C:2]=1[C:43]1[CH:51]=[CH:50][C:46]([CH3:47])=[CH:45][CH:44]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Yield: 76 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[3-(4-(methylsulfonyl)piperazin-1-yl)propoxy]-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and p-tolylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (76%).