Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]3[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29](C)([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)[C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(OC(Cl)=O)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]3[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]4)[C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1ncnc2c1ccc(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1Oc1ncnc2c1ccc(=O)n2C1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(4-(2-methylpyridin-3-yloxy)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate from Example 116C (56 mg, 0.13 mmol) in 4 mL methylene chloride was added 4 mL of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 1 h and then was concentrated in vacuo. The residue was taken up in 4 mL of methylene chloride and then there was added triethylamine (0.054 mL, 0.38 mmol) and isopropylchloroformate (0.13 mL of a 1M solution in toluene, 0.13 mmol). The resulting mixture was allowed to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with sat'd aq sodium bicarbonate and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated. The residue was purified by silica gel chromatography (12 g ISCO cartridge, 0-100% ethyl acetate/hexane) to afford 28 mg (49%) of Example L16 as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 1.21 (d, J=6.05 Hz, 6 H) 1.55-1.61 (m, 2 H) 2.37 (s, 3 H) 2.80-2.93 (m, 4 H) 4.20-4.36 (m, 2 H) 4.85-4.92 (m, 1 H) 5.57 (s, 1 Ft) 6.70 (d, J=9.35 Hz, 1 H) 7.21 (dd, J=7.97, 4.67 Hz, 1 H) 7.40 (d, J=6.60 Hz, 1 H) 8.02 (d, J=9.35 Hz, 1 H) 8.42 (d, J=4.95 Hz, 1 H) 8.46 (s, 1 H). LRMS (ESI): 424.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=[O:11].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([Sn](C)(C)C)[CH2:33][CH2:32]2.C(OCC)(=O)C>C1(C)C=CC=CC=1.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.[Cu]I>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[O:11])=[C:2]([C:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=3)[CH:35]=2)[CH:7]=1
Reactant: COc1ccc2c(c1)CCC([Sn](C)(C)C)=C2
Reactant: COc1ccc(C(=O)c2ccc(OCCN3CCCCC3)cc2)c(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCC(c1cc(OC)ccc1C(=O)c1ccc(OCCN3CCCCC3)cc1)=C2
Temperature: 100 °C
Reaction time: 5 h
Yield: 38.8 %

Procedure:
A suspension of (2-bromo-4-methoxyphenyl)[4-(2-piperidin-1-ylethoxy)phenyl]methanone (570 mg), (6-methoxy-3,4-dihydronaphthalen-2-yl)trimethyltin (542 mg), tetrakis(triphenylphosphine)palladium(0) (80 mg) and copper(I) iodide (25 mg) in toluene (10 ml) was stirred for 5 hours at 100° C. under a nitrogen atmosphere. Ethyl acetate was added thereto, the insoluble material was removed by filtration, the solvent was evaporated in vacuo, and the resulting residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (263 mg).
Reaction SMILES: [CH2:1]([CH:5]([CH:9]1[O:11][CH2:10]1)[C:6](=O)[CH3:7])[CH2:2][CH2:3][CH3:4].Cl>C(Cl)(Cl)Cl>[CH3:10][C:9]1[O:11][CH:7]=[CH:6][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C(C)=O)C1CO1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCc1ccoc1C
Yield: 35 %

Procedure:
15.6 Grams of 3-butyl-4,5-epoxy-pentan-2-one was added to chloroform (300 ml), and then conc. hydrochloric acid (3 ml) was added thereto, followed by refluxing for 10 hours. The chloroform layer was washed with water and then with an aqueous sodium hydrogen carbonate solution, followed by concentrating. The residue was column chromatographed on silica gel to obtain 4.8 g of 2-methyl-3-butylfuran.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:35])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18][CH2:17]3)[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:57]2[C@H:58]([CH3:81])[C@H:59]3[C@@H:76]([C@H:77]([OH:79])[CH3:78])[C:75](=[O:80])[N:60]3[C:61]=2[C:62]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][C:69]([N+:72]([O-:74])=[O:73])=[CH:68][CH:67]=2)=[O:63])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:24][C:22]([N:19]2[CH2:18][CH2:17][CH:16]([NH:15][C:14]([C:12]3[N:13]=[C:9]([N:7]4[CH2:6][CH:5]([S:4][C:57]5[C@H:58]([CH3:81])[C@@H:59]6[C@@H:76]([C@H:77]([OH:79])[CH3:78])[C:75](=[O:80])[N:60]6[C:61]=5[C:62]([O:64][CH2:65][C:66]5[CH:71]=[CH:70][C:69]([N+:72]([O-:74])=[O:73])=[CH:68][CH:67]=5)=[O:63])[CH2:8]4)[S:10][CH:11]=3)=[O:35])[CH2:21][CH2:20]2)=[O:23])=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: CC(=O)SC1CN(c2nc(C(=O)NC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)cs2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NC5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)CC5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 3-acetylthio-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (260 mg, 0.500 mmol) (obtained as described in Reference Example 51) in dimethylformamide (13 ml) was added hydrazine acetate (55 mg, 0.600 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (297 mg, 0.500 mmol) in acetonitrile (15 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (348 μl, 2.00 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (9:1) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (348 mg, yield 85%) as a pale yellow solid.
Reaction SMILES: Cl.[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22]>C(Cl)Cl>[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH:9][C:18](=[O:25])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])[CH2:5][CH2:4]1
Reactant: NC1CCC(F)(F)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCC(F)(F)CC1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Treat a 0° C. mixture of 4,4-difluorocyclohexylamine hydrochloride (3.29 g, 19.2 mmol) and triethylamine (5.88 mL, 42.2 mmol) in CH2Cl2 (192 mL) with 2,2,2-trichloroethyl carbonochloridate (2.91 mL, 21.1 mmol) dropwise. After 1 h, allow the reaction mixture to warm to ambient temperature and stir overnight. Partition the reaction mixture between H2O and CH2Cl2 and separate the layers. Dry the organic layer over Na2SO4, filter, and concentrate under reduced pressure to provide the title compound as an off-white solid (5.75 g, 97%). GC/MS m/z 35Cl 309 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1
Reactant: O=CCc1c(Cl)nc2ccnn2c1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCCc1c(Cl)nc2ccnn2c1Cl
Reaction time: 0.5 h
Yield: 146.1 %

Procedure:
The above aldehyde (1.82 mmol) was dissolved in methanol (27 mL), and sodium borohydride (302 mg, 7.98 mmol) was added to this solution with ice-cooling. After this mixture was stirred for 30 min, aqueous ammonium chloride was added here. The resultant mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off, and the residue was purified with column chromatography (15% ethyl acetate-hexane) to obtain the title compound (617 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:29])=[CH:26][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:29])=[CH:37][CH:38]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Yield: 46.6 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138), 0.04 g (0.18 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide, 0.04 g (0.23 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (30:70), followed by recrystallization from ethyl acetate-hexanes-methanol to give 0.036 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-143).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]CC)=[O:12])=[CH:6][CH:5]=1.C(C1C=CC(CC(OCC)=O)=CC=1)#N.[CH2:30]([O:34][C:35]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:36]=1[C:37](Cl)=[O:38])[CH2:31][CH2:32][CH3:33].Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C(N(CC)CC)C>[CH2:30]([O:34][C:35]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:36]=1[C:37]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)=[O:38])[CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)Cc1ccc(CN)cc1
Reactant: CCCCOc1ccc(Cl)cc1C(=O)Cl
Agent: CCOC(=O)Cc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(Cl)cc1C(=O)NCc1ccc(CC(=O)O)cc1

Procedure:
11.5 g Ethyl 4-aminomethylphenylacetate hydrochloride (m.p. 172° C.; prepared by the catalytic hydrogenation of ethyl 4-cyanophenylacetate) are suspended in 200 ml toluene. After the addition of 13.9 ml triethylamine, there is added dropwise, while cooling, a solution of 12.4 g 2-butoxy-5-chlorobenzoyl chloride in 10 ml toluene. The reaction mixture is subsequently heated under reflux for 2 hours, while stirring. After cooling, the toluene phase is treated successively with dilute hydrochloric acid, aqueous sodium bicarbonate solution and water and then evaporated. The evaporation residue is heated on a steambath with 2 N aqueous sodium hydroxide solution and the solution then filtered. The filtrate is acidified with dilute hydrochloric acid. The precipitated 4-(2-butoxy-5-chlorobenzamidomethyl)-phenylacetic acid is reprecipitated via its sodium salt and recrystallized from ethanol. The yield is 3.9 g (20% of theory); m.p. 198° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO>[F:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:20]=1
Reactant: COc1ccc(F)cc1C1(O)CCN(Cc2ccccc2)CC1
Solvent: CO
Product: COc1ccc(F)cc1C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.2 %

Procedure:
In a round bottom flask at room temperature was placed with 1.95 g (6.18 mmole) 1-benzyl-4-(5-fluoro-2-methoxy-phenyl)-4-hydroxypiperidine, dry MeOH (40 mL), and the system purged with N2 for 5 min. To the solution, 1.95 g of 10% palladium on carbon was added. The system was again purged with N2 for 5 minutes followed by addition of 2 mL formic acid (88%). The resulting mixture was stirred at room temperature under N2 for one day. At this point, a further 2 mL of formic acid (88%) was added. The reaction was continued for 2.5 days. The mixture was filtered through celite, and concentrated to afford of 4-(5-fluoro-2-methoxy-phenyl)-4-hydroxypiperidine (0.95 g, 69% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22][CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([C:32]2[CH:37]=[CH:36][C:35]([O:14][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[Cl:18])=[CH:34][CH:33]=2)=[O:39])=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(O)cc2)cc1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(OCc4ccccc4)cc3Cl)cc2)cc1
Yield: 93.1 %

Procedure:
In 50 mL of methylene chloride, 1.84 g (7.0 mmol) of 4-benzyloxy-2-chloro-benzoic acid, 1.90 g (6.7 mmol) of 4-hydroxy-benzoic acid 4-pentyl-phenyl ester, and 0.082 g (0.67 mmol) of 4-dimethylaminopyridine were dissolved. Then, 1.45 g (7.0 mmol) of dicyclohexylcarbodiimide was added while stirring the solution under argon. After being stirred for 8 hours under argon, the solution was filtered and the filtered liquid was concentrated. The residue was purified by silica-gel column chromatography. As a result, 3.3 g of a white solid was obtained.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:13](C=O)([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:27]([Mg]Br)=[CH2:28]>C1COCC1>[CH:27]([CH:14]([OH:15])[C@H:13]1[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10][C@@H:9]1[O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])=[CH2:28]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](C=O)(CO)O2)c(=O)[nH]c1=O
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
3'-O-t-Butyldimethylsilyl thymidine 4'-aldehyde (5.0 g; azeotroped twice with toluene, 25 ml) was dissolved in dry THF (60 ml) and cooled to -78° C., followed by addition of 1.0M solution of vinylmagnesium bromide (2.5 eq.) in THF. The reaction mixture was stirred for 30 minutes and then quenched with saturated aqueous NH4Cl, diluted with ethyl acetate, washed with water (2×100 ml) and then with brine. Then the organic layer was dried. The title compound was purified by flash chromatography using 30% ethyl acetate/hexane, affording a 43% yield of the desired alcohol.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])C.C(OC(C1NC2C(C=1)=CC(O)=CC=2)=O)C.C(N1CCC(O)CC1)(C)C>>[CH:22]([N:19]1[CH2:18][CH2:17][CH:16]([O:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)[CH2:21][CH2:20]1)([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2[nH]1
Agent: CC(C)N1CCC(O)CC1
Agent: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)CC1

Procedure:
According to the procedure described for the synthesis of Example 5/step 1 5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid ethyl ester was synthesized from 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (commercially available) and 1-isopropyl-piperidin-4-ol (commercially available). The title compound was yielded in 33% as off-white solid. MS (m/e): 331.1 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH:23][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12]
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: Cc1cccc(Cl)c1N
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(C)cccc1Cl)c1ccccc1CO2
Yield: 80.2 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.40 g of Compound A and 0.72 g of 2-chloro-6-methylaniline in place of aniline to obtain 1.54 g of Compound 8.
Reaction SMILES: [Br:1][C:2]1[C:3](C)=[C:4]([CH:6]=[CH:7][CH:8]=1)N.[CH3:10][NH:11][CH3:12]>>[Br:1][C:2]1[C:8]([CH3:7])=[C:10]([NH:11][CH:12]2[CH2:4][CH2:3][CH2:2][CH2:8][CH2:7]2)[CH:6]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1c(N)cccc1Br
Product: Cc1c(Br)cccc1NC1CCCCC1

Procedure:
The title compound was prepared by substituting cyclohexanone for EXAMPLE 64B and 3-bromo-2-methylaniline for dimethylamine in EXAMPLE 68A.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][S:26][CH2:27][C@H:28]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:3](=[O:24])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:25][S:26][CH2:27][C@H:28]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:3](=[O:24])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][P:16](=[O:17])([OH:23])[OH:20]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OCCCCCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl(14R,18R)-14-amino-18-(dodecyloxy)-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonate (1 eq) in DCM (0.1 M) was added trimethylsilyl bromide (20 eq). The reaction mixture was stirred at room temperature overnight and then concentrated. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 50-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to give the title compound as a white solid. 1H NMR (CDCl3): δ 8.73 (br s, 1H), 4.17 (br s, 1H), 3.70-3.83 (m, 3H), 3.57-3.70 (m, 10H), 3.50-3.57 (m, 4H), 3.45-3.50 (m, 2H), 3.33-3.45 (m, 4H), 3.02-3.16 (m, 2H), 2.65-2.79 (m, 2H), 1.90 (dd, 2H), 1.47-1.61 (m, 4H), 1.16-1.36 (m, 36H), 0.88 (t, 6H). LRMS [M+H]=771.5.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([N:20]1[C:23](=[O:24])[CH2:22][C@H:21]1[C:25]([OH:27])=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOCC.CCCCCC>[Si:13]([N:20]1[C:23](=[O:24])[C@H:22]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:21]1[C:25]([OH:27])=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@H](Cc2ccccc2)[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
In 6 ml of THF was dissolved 836.3 mg of diisopropylamine and the solution was cooled to 0° C. in a nitrogen atmosphere. To the solution was gradually added 5.2 ml of a n-hexane solution containing 530 mg of n-butyl lithium at 0° C. The mixture was stirred for 10 minutes at the same temperature. Then, a solution of 920 mg of (S)-1-t-butyldimethylsilyl-4-oxo-2-azetidinecarboxylic acid (1) in 8 ml of dry THF was added to the mixture at 0° C. followed by stirring at room temperature for 30 minutes. The solution was cooled to 0° C. and 820.8 mg of benzyl bromide was added to the solution. The mixture was then stirred at room temperature for 30 minutes. The solution was again cooled to 0° C. and a 10% citric acid solution was added thereto to render acidic. Ether was added to the mixture to separate from the aqueous phase. After the ethereal phase was dried, the solvent was removed by distillation to obtain 858 mg of (2S,3R)-1-t-butyldimethylsilyl-3-benzyl-4-oxo-2-azetidinecarboxylic acid (2) showing a melting point of 99°~102° C. as colorless crystals.