Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:10]1[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].[N:16]([CH2:19][C:20]([CH3:28])=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:17]=[N-:18]>>[ClH:1].[CH3:28][C:20](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][N:16]1[CH:9]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:10]2[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=2)[N:18]=[N:17]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCCCCCCc1c[nH]c(N)n1
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCCCCc2c[nH]c(N)n2)nn1
Yield: 64.5 %

Procedure:
4-Oct-7-ynyl-1H-imidazol-2-ylamine hydrochloride (0.098 g, 0.568 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.118 g, 0.681 mmol) following the general procedure for click reactions outlined above to produce 4-{6-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-hexyl}-1H-imidazol-2-ylamine hydrochloride (0.147 g, 85%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1H), δ 7.25-7.15 (m, 5H), δ 6.65 (s, 1H), δ 6.36 (s, 1H), δ 5.23 (s, 2H), δ 2.78 (t, 2H), δ 2.38 (t, 2H), δ 1.74 (s, 3H), δ 1.64 (m, 2H), δ 1.51 (m, 2H), δ 1.33 (m, 4H) ppm; 13C (75 MHz, CD3OD) δ 147.5, 136.3, 132.9, 132.8, 129.9, 128.9, 128.6, 128.5, 128.3, 127.7; HRMS (ESI) calcd for C21H29N6 (M+) 365.2448. Found 365.2448.
Reaction SMILES: C([O-])(O)=O.[Na+].[Br:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1.[CH2:14]([OH:17])[CH:15]=[CH2:16]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:16][CH2:15][CH:14]=[O:17])=[CH:9][CH:8]=1
Reactant: C=CCO
Reactant: Brc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=CCCc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
210 mg (0.86 mmol) Pd(OAc)2, 5.23 g (17.32 mmol) tetra-n-butylammonium chloride and 3.6 g NaHCO3 are added to a solution of 5.0 g (17.32 mmol) 4-bromo-iodo-benzene and 3.0 mL (43.67 mmol) allylalcohol in 30 mL DMF. The reaction solution is stirred for 2 h at 60° C. and diluted with 50 mL water. The aqueous phase is extracted with 50 mL EtOAc and the combined organic extracts are washed with 50 mL saturated NaCl solution. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (cyc/EtOAc 3:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:10]([OH:37])[CH2:11][C@@H:12]([NH:26]C(=O)OCC1C=CC=CC=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:26][C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[CH2:11][C@H:10]([OH:37])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product of Example 1C (4.2 g, 7.0 mmol) in a mixture of methanol (35 mL) and ethyl acetate (35 mL) was treated with Pd(OH)2 on carbon (1.4 g, 20% Pd by wt.) and HCl solution (1.8 mL, 4N in dioxane), and the reaction was stirred under a hydrogen atmosphere (balloon pressure) for 16 hours at 25° C. The reaction mixture was filtered through a bed of celite®, rinsed with methanol and concentrated to give the title compound as the hydrochloride salt (3.7 g).
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)C.[CH:13]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>C(O)C>[CH:13]1([C:18]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:12])=[CH:10][CH:9]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)C1CCCC1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)C2CCCC2)cc1

Procedure:
4-Aminobenzoic acid ethyl ester was reacted with cyclopentanecarboxylic acid by method E, and the resulting ester was hydrolyzed by boiling with sodium hydroxide in aqueous ethanol. The product with the molecular weight of 233.27 (C13H15NO3); MS (ESI): 234 (M+H+) was obtained in this way.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:36]([O:38][C:39](=[O:43])[N:40]([CH3:42])[NH2:41])[CH3:37]>O1CCCC1.C(Cl)(Cl)Cl>[CH2:36]([O:38][C:39](=[O:43])[N:40]([CH3:42])[NH:41][C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:37]
Reactant: CCOC(=O)N(C)N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 0.16 mole of t-butoxycarbonylalanylproline in 80 ml of dry tetrahydrofuran which has been cooled to -20° to -30° is added 2 ml of N-methylmorpholine and then 2.1 ml of isobutylchloroformate. After stirring for 10 minutes, 0.16 mole of 2-azaalanine ethyl ester and 60 ml of chloroform are added. The reaction mixture is allowed to warm to room temperature overnight, concentrated in vacuo, taken up in ethyl acetate and the insoluble material removed by filtration. Concentration of the filtrate in vacuo gives t-butoxycarbonylalanylprolyl-2-azaalanine ethyl ester.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([CH3:13])=[O:12])[CH:5]=1)=[O:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C(OCC)(=O)C.CCOCC>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:1][C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[CH3:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1

Procedure:
A mixture of 3-acetamidoacetophenone 7 (20 g, 112.9 mmol), dimethylformamide dimethyl acetal (40.3 g, 338.6 mmol) was refluxed under nitrogen for 1 hour. The reaction mixture was cooled, diluted with ethyl acetate (150 mL) and ether (150 mL). The solid was collected by filtration, triturated with a solution of ethyl acetate and hexane (1:1, 200 mL). Compound 8 was obtained as a red-orange solid (23.6 g, 101.6 mmol, 90%). GC/MS, m/z=232 at tR=15.11 min (100%). LC/MS, [M+H]′=233.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(OC([NH:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:51].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:51].[ClH:51].[NH2:33][C:34]([CH3:39])([CH3:38])[C:35]([N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1)=[O:36]
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CO
Product: CC(C)(N)C(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 60 °C
Yield: 0 %

Procedure:
The product obtained using Compound 18 (300 mg, 0.90 mmol), 2-(tert-butoxycarbonyl)amino-2-methylpropionic acid (153 mg, 0.75 mmol), 1-hydroxybenzotriazole monohydrate (132 mg, 0.98 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.05 mmol) and N-methylmorpholine (0.16 mL, 1.50 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 131 (0.10 mg, 23%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[CH2:1]([N:8]([CH2:9][C:10]([F:12])([F:11])[F:13])[C:23]([C:19]1[CH:18]=[C:17]([Cl:16])[N:22]=[CH:21][N:20]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: FC(F)(F)CNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N(Cc1ccccc1)CC(F)(F)F
Reaction time: 2 h

Procedure:
1.04 g (5.5 mmol) benzyl-(2,2,2-trifluoroethyl)-amine and 5.5 mL (5.5 mmol) of a 1M sodium hydroxide solution were added dropwise to 1.0 g (5.65 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane while cooling with a bath of ice and ethanol. The mixture was first stirred for 2 h with cooling and then for 1 h at RT. 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for 10 min. The organic phase was separated off, washed with water and 1M hydrochloric acid, dried on sodium sulphate, filtered and evaporated down i.vac.
Reaction SMILES: [OH:1][NH:2][CH:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[C:27](OC(=O)C)(=[O:29])C>C1COCC1.C(O)=O>[CH:27]([N:2]([CH:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[OH:1])=[O:29]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(NO)c1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine (338 mg, 0.89 mmol) in THF (5 ml) and formic acid (2 ml) was added a preformed mixture of formic acid (2 ml) and acetic anhydride (0.5 ml). The mixture was stirred at room temperature for one hour. The mixture was evaporated in vacuo and toluene (2×5 ml) was added and evaporated in vacuo. The residue was taken in CH2Cl2-methanol (6 ml, 9:1) and silica (1 g) was added. The mixture was stirred for 18 hours. The silica was filtered off and rinsed with CH2Cl2-methanol (9:1). The residue was purified on silica gel (eluant: CH2Cl2-MeOH 4%) to give the title compound as a light orange solid (220 mg, 61%).
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[C:3]#[N:4].C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CC#N.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])[C:3]#[N:4])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CC(Br)c1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(C#N)c2ccccc2Cl)CC1
Yield: 64.6 %

Procedure:
To a solution of bromo-(2-chloro-phenyl)-acetonitrile (1)(1.5 g, 6.45 mmol) in MeCN (25 mL) was added K2CO3 (1.78 g, 12.91 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.32 g, 7.10 mmol) and tetrabutylammonium iodide (0.02 g, 0.06 mmol). The reaction mixture was allowed to reflux for 24 h. The reaction mixture was then diluted with EtOAc (100 mL) and washed with brine (100 mL). The organic phase was concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with a gradient of 5% EtOAc in hexanes to 1:1 hexanes/EtOAc) yielding 1.4 g (65%) of pure product.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9]([C:11]1[CH:12]=[C:13]([CH:17]([CH3:21])[C:18]([OH:20])=O)[CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C(OCC)C.Cl>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:18](=[O:20])[CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]([C:2]2[S:1][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[CH:3]=2)=[O:10])[CH:12]=1)[CH3:21]
Reactant: CN(C)CCN
Reactant: CC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Agent: Cl
Solvent: CCOCC
Product: CC(C(=O)NCCN(C)C)c1cccc(C(=O)c2cc3ccsc3s2)c1
Reaction time: 20 h
Yield: 37.3 %

Procedure:
N,N'-Carbonyldiimidazole (3.8 g) is added to 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (7.25 g) [prepared as described in a previous Example] in solution in diethyl ether (70 cc). When the evolution of gas has ceased, 2-dimethylaminoethylamine (2.1 g) in solution in diethyl ether (25 cc) is then added. After 20 hours at 25° C., the reaction mixture is evaporated. The residue, dissolved in methylene chloride (100 cc), is washed four times with a 5% (w/v) aqueous sodium chloride solution (total 400 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. The oil obtained (5.4 g) is dissolved in N aqueous hydrochloric acid solution (50 cc). This solution is washed three times with diethyl ether (total 150 cc) and then rendered alkaline to pH 11 by the addition of 1N aqueous sodium hydroxide solution (55 cc). The resulting precipitate is extracted three times with methylene chloride (total 150 cc). The combined methylene chloride solutions are washed three times with distilled water (total 150 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. N-(2-Dimethylaminoethyl) 2-{3-(thieno-[2,3-b]thien-2-yl)carbonyl-phenyl}propionamide (3.3 g), in the form of an oil, is thus obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.Cl[S:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:12])=[O:11]>ClCCl.[Cl-].[Na+].O>[CH3:1][N:2]([CH3:3])[S:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:12])=[O:11]
Reactant: CNC
Reactant: COC(=O)CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CS(=O)(=O)N(C)C
Temperature: 0 °C

Procedure:
Dimethylamine in THF (57.9 ml, 116 mmol) was dissolved in dichloromethane (29.0 ml) and cooled to 0° C. Then, methyl (chlorosulfonyl)acetate (prepared according to: Szymonifka, M. J.; Heck, J. V. Tet. Lett. 1989, 30, 2869-72.) (10.0 g, 57.9 mmol) was added dropwise as a solution in dichloromethane (29.0 ml), while maintaining the temperature below 5° C. The resulting solution was allowed to warm to room temperature over the course of 2 h. Then, brine (200 mL) was added and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow liquid. 1H NMR (600 MHz, DMSO-D6) δ 4.25 (s, 2H); 3.68 (s, 3H); 2.78 (s, 6H). LRMS (APCI) calculated for C5H12NO4S [M+H]+, 182.0; found 182.0.
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@H:17]2[CH2:21][C:20](=[O:22])[C@H:19]([OH:23])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.C(OCC)(=O)C>[C:24]([O:23][C@@H:19]1[CH2:18][C@@H:17]([C@@:7]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8](=[O:10])[O:9][C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:6]2)[CH2:21][C:20]1=[O:22])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@H]2CC(=O)[C@H](O)C2)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1C[C@@H]([C@]2(c3ccccc3)O[C@@H](C(C)(C)C)OC2=O)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 32 mg of (2R,5R)-2-(t-butyl)-5-((1R,3R)-3-hydroxy-4-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in 1 ml of pyridine, 0.5 ml of acetic anhydride was added, followed by 1 hour's stirring at room temperature. The reaction liquid was diluted with ethyl acetate, washed successively with water, 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue obtained was purified on preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/acetone=20/1) to provide 27 mg of the title compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([C@H:13]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[O:37](C(OC(C)(C)C)=O)[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=O>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([C@H:13]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:9]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:37])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](c1ccccc1)[C@H]1CC[C@@H](c2ccc(Br)cc2)N1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)CC[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of the title compound from Step C (1.20 g, 2.61 mmol) and N,N-diisopropylethylamine (0.910 ml, 5.21 mmol) in CH2Cl2 (15 ml) was added BOC2O (1.21 ml, 5.21 mmol) and the mixture was stirred at RT for overnight. The mixture was diluted with ethyl acetate (200 mL), washed with aqueous sodium hydrogen carbonate (saturated, 2×100 mL), with brine (100 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/isohexane 0%-10% to afford title compound as a colorless solid. Yield is 96%. LC-MS: m/z (E/S) 562.1 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]([OH:6])=[O:5])[Cl:3].[CH2:7]=[CH:8][CH2:9][CH2:10]O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(OC)(C)(C)C.O>[CH3:1][CH:2]([C:4]([O:6][CH2:10][CH2:9][CH:8]=[CH2:7])=[O:5])[Cl:3]
Reactant: C=CCCO
Reactant: CC(Cl)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: C=CCCOC(=O)C(C)Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
CH3CHClCOOH (50 g) and CH2═CHCH2CH2OH (75 ml) were put into a flask, and 10 ml of concentrated sulfuric acid was added dropwise, followed by stirring at room temperature for 10 minutes. The reaction solution was poured into 250 ml of a saturated sodium carbonate aqueous solution. 150 ml of water and 150 ml of t-butylmethyl ether were added for liquid separation to obtain a t-butylmethyl ether layer as an organic layer. The organic layer was washed with 150 ml of water, dried over magnesium sulfate and then subjected to filtration to obtain a crude liquid. The crude liquid was concentrated to obtain CH3CHClCOOCH2CH2CH═CH2.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:40]=[C:41](F)[CH:42]=1)[CH2:5][C@H:6]([C:25](N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H:7]([C@H:9]1[CH2:13][C@@H:12](OCC=C)CN1C(OC(C)(C)C)=O)O.[F:44][C:45]1[CH:46]=[C:47]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:48][C@H:49]1[C@@H:53]([CH:54]2[CH2:59][O:58][CH2:57][CH2:56][N:55]2C(OC(C)(C)C)=O)[O:52][C:51](=[O:67])[NH:50]1.FC1C=C(C=C(F)C=1)C[C@@H]([C@@H](C1COCCN1C(OC(C)(C)C)=O)O)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:71][C:69]1[CH:68]=[C:47]([CH:46]=[C:45]([F:44])[CH:70]=1)[CH2:48][C@H:49]1[C@@H:53]([C@H:54]2[CH2:59][C@H:57]([OH:58])[CH2:56][N:55]2[CH:5]([C:4]2[CH:3]=[CH:2][CH:42]=[CH:41][CH:40]=2)[C:6]2[CH:7]=[CH:9][CH:13]=[CH:12][CH:25]=2)[O:52][C:51](=[O:67])[NH:50]1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CCOCC1[C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1
Agent: CC(C)(C)OC(=O)N1CCOCC1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Step D (5): tert-Butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)morpholine-4-carboxylate. To a solution of (2S,3S)-2-(3,5-difluorobenzyl)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)-3-hydroxypropanoic acid (step D (4)), 1.6 g, 4 mmol) in toluene (100 mL) was added diphenylphosphoryl azide (1.65 g, 6 mmol) and triethyl amine (1.01 g, 10 mmol.). This reaction mixture was stirred at 80° C. for 4 h. Ethyl acetate (500 mL) was added. The mixture was washed with sodium carbonate solution, H2O, dried over Na2SO4 and concentrated. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 800 mg of the title compound: MS (ESI) (M−H)− 397.12.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)=[CH:5][N:4]=[CH:3]1.C([Li])CCC.C([Sn](Cl)(CCCC)CCCC)CCC.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[C:53](I)[CH:54]=3)[N:49]=[CH:48][N:47]=2)=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ag-]=O>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[C:53]([C:3]4[N:2]([CH3:1])[C:6]([CH:7]5[O:11][CH2:10][CH2:9][O:8]5)=[CH:5][N:4]=4)[CH:54]=3)[N:49]=[CH:48][N:47]=2)=[CH:43][CH:44]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Ic1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: Cn1cncc1C1OCCO1
Agent: Cl[Pd]Cl
Agent: O=[Ag-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cn1c(C2OCCO2)cnc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
1-Methyl-5-(1,3-dioxolan-2-yl)-imidazole (0.09 g) in dry THF (5 ml) under N2 was cooled to −78° C. and treated with n-butyl lithium (0.4 ml, 1.6 M). After 30 minutes, tributyl tin chloride (0.17 ml) was added, the mixture allowed to warm to 20° C. and stirred for 1 hour. (4-Benzyloxy-phenyl)-(6-iodoquinazolin-4-yl)-amine (0.191 g), catalytic quantities of 1.4-bis-(diphenylphosphino)-butane palladium (II) chloride and silver (I) oxide (0.052 g) were added and the mixture heated at reflux for 18 hours. The mixture was absorbed onto silica and chromatographed to give the title compound (0.045 g); m/z (M+1)+ 480.
Reaction SMILES: Br.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[SH:13][C:14]1[NH:15][C:16]2[C:17](=[CH:19][S:20][CH:21]=2)[N:18]=1.CC(C)=O>CC(N(C)C)=O>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:13][C:14]1[NH:18][C:17]2=[CH:19][S:20][CH:21]=[C:16]2[N:15]=1
Reactant: Sc1nc2cscc2[nH]1
Reactant: CN(C)c1ccccc1CBr
Agent: Br
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccccc1CSc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.9 g of 2-dimethylaminobenzyl bromide hydrobromide are added to a solution of 1.56 g of 2-mercaptothieno[3,4-d]imidazole in 20 ml of anhydrous dimethylacetamide. A crystalline precipitate separates out in a weakly exothermic reaction. The mixture is stirred at room temperature for one hour, acetone is added, and the crystals are filtered off and dried in a stream of air. The crystalline solid is then introduced into saturated aqueous NaHCO3 solution, the mixture is heated briefly on a steam bath and, after stirring at room temperature, the crystals are filtered off. Treatment with active charcoal in ethanol and concentration is followed by solution being induced to crystallize with a little acetone.