Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:39])[O:13][CH2:14][C@@H:15]([N:25]([CH3:38])[C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=2[Cl:37])=[O:27])[CH2:16][C@@H:17]([OH:24])[CH2:18][O:19][P:20]([OH:23])([OH:22])=[O:21])[N:2]=1.[OH-].[Na+:41]>CO>[P:20]([O-:23])([O-:22])([O:19][CH2:18][C@H:17]([OH:24])[CH2:16][C@H:15]([N:25]([CH3:38])[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[Cl:37])=[O:27])[CH2:14][O:13][C:12](=[O:39])[NH:11][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:21].[Na+:41].[Na+:41]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)C[C@@H](O)COP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)C[C@@H](O)COP(=O)([O-])[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-hydroxy-5-(phosphonooxy)pentyl isoquinolin-3-ylcarbamate in MeOH (50 mL) at 0° C. was added NaOH solution (0.5 N, 16 mL, 2 equiv.) dropwise. The solution was stirred at 0° C. for 1 h and concentrated to give sodium (2R,4S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-2-hydroxy-5-(isoquinolin-3-ylcarbamoyloxy)pentyl phosphate as a white solid (quant.). The solid could be further crystallized by trituration with EtOH, followed by re-crystallization from EtOH—H2O (6:1) to give the crystalline form. LRMS (M−2Na+3H+) m/z 585.5.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[CH:30]=[CH:31][C:32](=[O:43])[C@@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH3:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.CCOC(C)=O>C1COCC1>[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[CH:30]=[CH:31][C@H:32]([OH:43])[C@@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH3:34])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)C=Cc1ccc(F)cc1OCc1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)C=Cc1ccc(F)cc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
1M solution of L-selectride in THF (11.5 ml) was added dropwise below −30° C. to a solution of (S)-1-(2-benzyloxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-1-penten-3-one (3.94 g) in THF (18 ml). The mixture was stirred at −20° C. for 30 min. Water and EtOAc were added and the organic layer was washed with brine, dried and evaporated. The residue was chromatographed over silica gel (100 g) eluting with a mixture of hexane and EtOAc (30:1) to afford a pale yellow oil of (3S,4S)-1-(2-benzyloxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-1-penten-3-ol (2.64 g, 66.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.C([NH:32][CH2:33][CH:34]1[O:38][C:37]2[CH:39]=[CH:40][C:41]([NH2:43])=[CH:42][C:36]=2[O:35]1)(OC(C)(C)C)=O>C(O)(=O)C>[NH2:32][CH2:33][CH:34]1[O:38][C:37]2[CH:39]=[CH:40][C:41]([NH:43][C:14]3[N:15]=[CH:16][C:11]4[CH:10]=[C:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])[C:22](=[O:23])[N:21]([CH3:24])[C:12]=4[N:13]=3)=[CH:42][C:36]=2[O:35]1
Reactant: CC(C)(C)OC(=O)NCC1Oc2ccc(N)cc2O1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4c(c3)OC(CN)O4)nc21

Procedure:
A mixture of 0.384 g of compound of formula (II), 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 0.266 g of compound of formula (III), (R/S)-2-(N-Boc-aminomethyl)-1,3-benzodioxol-5-ylamine, is heated in 4 ml of acetic acid at 80° C. for 2 h. The reaction medium is subsequently concentrated by half under vacuum, then taken up in water and ethyl acetate and brought to pH 6 with a saturated NaHCO3 solution; the organic phase is separated by settling, washed with water and then a saturated NaCl solution, dried over sodium sulfate and evaporated. The crude product obtained is purified by flash chromatography on silica with a gradient of 0 to 1% of methanol in dichloromethane. 0.252 g of expected product is obtained in the form of a yellow powder.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:5][CH2:4]1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:12](=[O:14])[CH2:11][CH2:10][O:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=3)(=[O:16])=[O:17])[CH2:4][CH2:5]2)[CH2:31][CH2:30]1
Reactant: OC1CCNCC1
Reactant: CN([C@H]1CC[C@H](OCCC(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN([C@H]1CC[C@H](OCCC(=O)N2CCC(O)CC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
100 mg (0.24 mmol) of trans-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid in 3 mL of CH2Cl2 were treated with 21.3 mg (0.36 mmol, 1.5 eq) of 4-hydroxypiperidine and 0.40 mL (0.36 mmol, 1.5 eq) of NMM. The solution was cooled to 0° C. and 60.9 mg (0.31 mmol, 1.3 eq) of EDCI and 7.5 mg (0.05 mmol, 0.2 eq) of HOBT were added. The mixture was stirred at RT over night, and was then partitioned between CH2Cl2 and a saturated aqueous solution of Na2CO3. The organic phase was washed with a solution of KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with CH2Cl2:MeOH 98:2 gave 97.1 mg (81%) of trans-N-{4-[3-(4-hydroxy-piperidin-1-yl)-3-oxo-propoxy]-cyclohexyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as white powder, MS: 493 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:2]1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccsc1Br
Temperature: 23 °C
Yield: 94.6 %

Procedure:
Tert-butyl thien-3-ylcarbamate (37 g, 0.19 mol) and N-bromosuccinimide (33 g, 0.19 mol) were combined in carbon tetrachloride (900 mL) and heated at reflux for 3 h. At this time, the mixture was cooled to 23° C. and filtered. The filtrate was washed with water (5×900 mL) to remove succinimide, dried (Na2SO4), and concentrated in vacuo to give the title compound (50 g, 96%, m.p. 68-70° C.) as a tan solid which was pure enough for further use.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[CH2:3][CH:4]([C:9]#[N:10])[CH2:5][C:6]([OH:8])=[O:7]>CO.[OH-].[Pd+2].[OH-]>[NH2:10][CH2:9][CH:4]([CH2:3][Si:2]([CH3:11])([CH3:1])[CH3:12])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: C[Si](C)(C)CC(C#N)CC(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[Si](C)(C)CC(CN)CC(=O)O
Yield: 94.4 %

Procedure:
A suspension of 4-(trimethylsilyl)-3-cyanobutanoic acid (178 mg, 0.962 mmol) and palladium hydroxide (20% on carbon, wetted with ca. 50% water, 36 mg) in methanol (10 ml) was subjected to catalytic reduction under a hydrogen atmosphere [0.45 MPa (gauge pressure)] for 48 hours. The reaction mixture was filtered through Celite, the solvent was evaporated, and then the residue was recrystallized to obtain 4-amino-3-(trimethylsilylmethyl)butanoic acid (172 mg, 95%) mentioned in the title as colorless fine prism crystals.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:20]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1cccc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cccc(CO)c1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 1,3-phenylenedimethanol (10.00 g, 72.38 mmol, Aldrich) in DCM (200 mL) was added 1H-imidazole (5.17 g, 76.0 mmol, Aldrich), followed by the addition of tert-butylchlorodiphenylsilane (19.8 mL, 76.0 mmol, Aldrich) and 4-dimethylaminopyridine (0.88 g, 7.2 mmol, Aldrich). After stirring overnight, the reaction was partitioned between DCM and water, the organic layer was dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography (gradient elution, 0 to 20% EtOAc/hexanes). Yield: (7.9 g, 29%).
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][C:21](Cl)=[N:20]3)=[O:16])[C:9]=1[F:28])OC(C)(C)C.Cl.[O:31]1CCOC[CH2:32]1>CO>[F:28][C:9]1[C:8]([OH:7])=[CH:13][CH:12]=[C:11]([F:14])[C:10]=1[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([O:31][CH3:32])=[N:20]2)=[O:16]
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COc1cnc2ccc(C(=O)c3c(F)ccc(O)c3F)cc2n1
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of tert-butyl (3-(3-chloroquinoxaline-6-carbonyl)-2,4-difluorophenyl) carbonate (55 mg, 0.13 mmol, 1 eq.) in MeOH (5 mL) was added HCl/dioxane (3 N, 5 mL). The resulting mixture was stirred overnight, then concentrated. The residue was purified via flash column chromatography (PE/EA=1/1, v/v) to afford (2,6-difluoro-3-hydroxyphenyl)(3-methoxyquinoxalin-6-yl)methanone (20.3 mg, 49%). LCMS (M−H+) m/z calculated 315.1, found 315.0. 1H NMR (CD3OD, 400 MHz) δ 8.49 (s, 1 H), 8.01-8.06 (m, 3 H), 7.01-7.07 (m, 1 H), 6.86-6.91 (m, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26])([O-:17])=[O:16]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:25]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N+:15]([O-:17])=[O:16])=[O:26])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Product: O=C(NCC1CCN(c2ccncc2)CC1)Nc1ccccc1[N+](=O)[O-]
Yield: 63.8 %

Procedure:
Using a similar procedure to that described for Example 48, Part A, 1-(4-pyridyl)piperidine-4-methylamine (1.34 g, 7.01 mmol) and 2-nitrophenyl isocyanate (1.21 g, 7.40 mmol) yielded 1.59 g (64%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[C:7]([Br:14])[CH:6]=1
Reactant: BrBr
Reactant: COC(=O)Cc1ccc(SC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(SC)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl ester (5.11 g, 26.03 mmol) in carbon tetrachloride (130 mL) was slowly treated with bromine (1.74 mL, 33.84 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h, at which time, thin layer chromatography still indicated the presence of a substantial amount of starting material. The reaction mixture was treated with more bromine (1.74 mL, 33.84 mmol). The reaction mixture was stirred an additional 4 h at 25° C. and then quenched with a 10% aqueous sodium bisulfite solution (150 mL). The reaction mixture was concentrated in vacuo to remove carbon tetrachloride. The resulting aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl acetate) afforded (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (6.10 g, 85%) as a light yellow oil: EI-HRMS m/e calcd for C10H11BrO2S (M+) 273.9663, found 273.9661.
Reaction SMILES: [Br:1][C:2]1([C:31]2[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=2)[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>Br>[Br:1][C:2]1([C:31]2[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=2)[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(C2(Br)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1
Agent: Br
Product: Oc1ccc(C2(Br)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1

Procedure:
44.44 g (0.08 mol) of 5-bromo-1,2,3,4-tetraphenyl-5-p-methoxyphenylcyclopenta-1,3-diene in 400 ml of concentrated HBr were refluxed for 24 h. The product was filtered off with suction and washed with water. It was recrystallized in toluene. (Yield: 35.05 g (81%); elemental analysis for C35H25OBr: found: C, 77.60%, H, 4.58%. calculated: C, 77.64%, H, 4.65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N1C(C)=CC=CC=1C.CN1CCCC1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:43]3[N:44]=[CH:45][N:46]=[C:47](Cl)[C:42]=3[CH:41]=2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:43]3[N:44]=[CH:45][N:46]=[C:47]([O:11][C:4]4[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=4)[C:42]=3[CH:41]=2)=[CH:38][CH:39]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CN1CCCC1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ncnc21
Temperature: 130 °C
Reaction time: 24 h
Yield: 76.5 %

Procedure:
After adding 248 mg of 3-fluoro-4-nitrophenol, 0.208 ml of 2,6-lutidine and 1 ml of N-methylpyrrolidine to 490 mg of 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 130° C. for 24 hours. After returning it to room temperature, water was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the organic layer was washed with saturated brine, dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (ethyl acetate) to obtain 472 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:23]1[S:27][C:26]([C:28]2[CH2:32][CH:31]([CH2:33][OH:34])[O:30][N:29]=2)=[CH:25][CH:24]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:34][CH2:33][CH:31]1[O:30][N:29]=[C:28]([C:26]2[S:27][C:23]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][C@H:11]([CH2:13][N:14]5[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]5)[O:10][C:9]4=[O:20])=[CH:4][CH:3]=3)=[CH:24][CH:25]=2)[CH2:32]1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)cc3)C(=O)O2)nn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO)C5)s4)cc3)C(=O)O2)nn1
Temperature: 90 °C
Yield: 35.4 %

Procedure:
(5R)-3-(4-Iodophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (222 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (90 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:32][C@@H:33]([C@@H:40]1[C@@:44]2([CH3:62])[CH2:45][CH2:46][CH:47]3[C@@:52]4([CH3:61])[CH2:53][CH2:54][CH:55]([O:57][C:58](Cl)=[O:59])[CH2:56][C:51]4=[CH:50][CH2:49][CH:48]3[CH:43]2[CH2:42][CH2:41]1)[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:58]([O:57][CH:55]1[CH2:56][C:51]2[C:52]([CH3:61])([CH:47]3[CH:48]([CH2:49][CH:50]=2)[CH:43]2[C:44]([CH3:62])([CH:40]([CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:41][CH2:42]2)[CH2:45][CH2:46]3)[CH2:53][CH2:54]1)=[O:59])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCNC(=O)OC1CCC2(C)C(=CCC3C2CCC2(C)C(C(C)CCCC(C)C)CCC32)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The hydrochloride salt of 3-[(6-Amino-hexanoyl)-ethoxycarbonylmethyl-amino]-propionic acid ethyl ester AC (4.7 g, 14.8 mmol) was taken up in dichloromethane. The suspension was cooled to 0° C. on ice. To the suspension diisopropylethylamine (3.87 g, 5.2 mL, 30 mmol) was added. To the resulting solution cholesteryl chloroformate (6.675 g, 14.8 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and washed with 10% hydrochloric acid. The product was purified by flash chromatography (10.3 g, 92%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:20](OC1C=CC(Cl)=C(Cl)C=1Cl)(=[O:25])[CH2:21][C:22]([O-])=[O:23]>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:12]2[CH:17]=[CH:16][N:15]3[C:20](=[O:25])[CH2:21][C:22](=[O:23])[N:18]=[C:14]3[CH:13]=2)=[O:19])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])CC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Reactant: CC(C)(C)c1csc(NC(=O)c2ccnc(N)c2)n1
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1csc(NC(=O)C2=CC3=NC(=O)CC(=O)N3C=C2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
N4-[4-(tert-Butyl)-1,3-thiazol-2-yl]-2-aminoisonicotinamide (200 mg, 0.724 mmol) was added with xylene (20 ml) and trichlorophenyl malonate (370 mg, 0.796 mmol) and refluxed by heating at 130° C. The reaction solution was stirred for 1 hour, then returned to room temperature and concentrated under reduced pressure. The resulting orange crystals was taken by filtration, washed with chloroform, dried under reduced pressure to obtain 209 mg (84%) of the title compound as orange crystals without purification.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([N:15]2[CH2:20][CH2:19][N:18](S(CC)(=O)=O)[CH2:17][CH2:16]2)=[N:4][C:3]=1[C:26]1[CH:27]=[C:28]([O:33][CH3:34])[C:29]([NH2:32])=[N:30][CH:31]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[N:4][C:3]=1[C:26]1[CH:27]=[C:28]([O:33][CH3:34])[C:29]([NH2:32])=[N:30][CH:31]=1
Reactant: CCS(=O)(=O)N1CCN(c2nc(-c3cnc(N)c(OC)c3)c(Br)n2COCC[Si](C)(C)C)CC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(-c2nc(N3CCNCC3)n(COCC[Si](C)(C)C)c2Br)cnc1N

Procedure:
Preparation of 5-(5-bromo-2-(4-(ethylsulfonyl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine: In a 10 mL round-bottomed flask was 5-(5-bromo-2-(piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine (22 mg, 0.046 mmol) in THF (1.2 ml) and DMF (0.2 mL) under Ar at 0° C. to give a colorless solution. Ethanesulfonyl chloride (8.62 μl, 0.091 mmol) and triethylamine (0.014 ml, 0.100 mmol) were added. The ice bath was removed and the mixture was stirred at ambient temperature for 30 min. The mixture was quenched with water (3 mL) and diluted with EtOAc (10 mL). The aq layer was extracted with EtOAc (2×10 mL). The combined org layers were washed with sat aq NaHCO3 solution (1×30 mL), brine (1×30 mL), dried over Na2SO4, filtered and conc in vacuo. The crude material was directly used in the next step without purification: LCMS (m/z): 577.2 (MH+), tR=0.82 min.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:7]2)[C@H:3]1[OH:22].C(N(CC)CC)C.[C:30]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])([CH3:32])[CH3:31]>CN(C1C=CN=CC=1)C.ClCCl>[Si:34]([O:12][CH2:11][C@H:10]1[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[S:7]2)[C@@H:3]([OH:22])[C@@H:2]1[OH:1])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:36])[CH3:35]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
To a mixture of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(methyl)carbamate (30 g, 90 mmol), DMAP (550 mg, 4.5 mmol) and triethylamine (18.2 g, 180 mmol) in dichloromethane (200 mL) was added tert-butylchlorodimethylsilane (16.3 g, 108 mmol) at 0° C. The resulting solution was stirred for 4 h at room temperature, and then concentrated under vacuum to provide a residue, which was purified by silica gel column, eluted with 1% methanol in dichloromethane to give compound 26 as a white solid (20 g, 50%). (ES, m/z): [M+H]+ 449.0; 1H NMR (300 MHz, CDCl3) δ 6.10-6.12 (d, J=6.9 Hz, 1H), 4.15-4.24 (m, 2H), 3.83-3.97 (m, 5H), 3.60 (m, 1H), 2.58-2.66 (m, 2H), 1.55 (s, 9H), 1.18 (m, 3H), 0.91 (s, 9H), 0.09 (s,
Reaction SMILES: [C:1]([C:5]1[NH:10][C:9]2[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[N:12]=[N:13][C:8]=2[C:7](=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:36]>>[C:1]([C:5]1[N:6]=[C:7]([Cl:36])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3Cl)c2[nH]1
Solvent: CCN(CC)c1ccccc1
Product: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
A mixture of 5-tert-butyl-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (12.3 mg, 38.7 μmol) and N,N-diethylaniline (12.3 μL, 77.4 μmol) in POCl3 (250 μL, 2.73 mmol) was refluxed for 3 h under N2 atmosphere. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with cold H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.