Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16])=[O:23]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)c1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1ncc[nH]1
Yield: 58 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.20 g, 0.87 mmol), 1H-imidazole-2-carboxylic acid obtained in Example (3a) (91 mg, 0.81 mmol), WSC hydrochloride (0.36 g, 1.88 mmol) and DMAP (10 mg, 0.083 mmol), to obtain 138 mg of the title compound as a white solid (58%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[NH:4][C:5](=[S:20])[N:6]([CH:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)[CH3:10])[C:7]=1[NH2:8].[C:22](O)(=O)C.C(N)=N>CS(C)=O>[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[CH:9]([N:6]1[C:7]2[N:8]=[CH:22][NH:1][C:2]=2[C:3](=[O:21])[NH:4][C:5]1=[S:20])[CH3:10]
Reactant: CC(c1nc2ccccc2[nH]1)n1c(N)c(N)c(=O)[nH]c1=S
Reactant: CC(=O)O
Agent: N=CN
Solvent: CS(C)=O
Product: CC(c1nc2ccccc2[nH]1)n1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 80 °C
Yield: 11 %

Procedure:
To 5,6-diamino-1-[1-(1H-benzimidazol-2-yl)ethyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (obtained from Example 9(c)) in DMSO (2 mL) was added formamidine acetate (0.058 g, 0.56 mmol) and the reaction was heated to 80° C. for 2 h and 10 min. Purification of the crude product using preparative HPLC gave the title compound (0.025 g, 11%) as a solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].CC(O)=O>C1COCC1>[C:9]1([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[OH:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC(c1ccccc1)c1ccccc1

Procedure:
1 mmole (182 mg) of benzophenone dissolved in 5 mL THF was stirred with 0.5 g of 12% Li-AG and solid state proton sources such as NH4Cl, (NH4)2HPO4, or dropwise addition of glacial AcOH at room temperature after a deep blue colored solution is produced. The color of the reaction vessel gradually fades and becomes grey at the end indicating complete consumption of lithium. The reaction mixture was filtered, the solids washed with hexane, and the solvent was removed from the combined organic solutions under vacuum to obtain a white solid corresponding to diphenyl methanol as confirmed by 1H, 13C NMR and ESI-MS. See FIGS. 3A-3C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.OC1C=C[C:24]([C:25]([O:27][CH3:28])=O)=[CH:23]C=1.COC1C=CC(CCO)=CC=1>>[CH3:28][O:27][C:25]1[CH:2]=[CH:3][C:1]([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)=[CH:23][CH:24]=1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: COc1ccc(CCO)cc1
Product: COc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Yield: 79 %

Procedure:
Reactions similar to those described in Example 1 (1a) and (1b) were conducted using methyl 4-hydroxybenzoate (4.56 g, 30.0 mmol) and 2-(4-methoxyphenyl)ethanol (5.03 g, 33.0 mmol) to give 7.80 g of the title compound (white powder, yield: 79%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C(Cl)(Cl)Cl.Br.[Br:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>O>[Br:12][CH2:13][CH2:14][NH:15][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: NCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)NCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.4 g. (0.1 mole) of diketene in 150 ml. of chloroform is added 21 g. (0.11 mole) of 2-bromoethylamine hydrobromide in 30 ml. of water, and the resulting mixture stirred vigorously at 0° C. while 4.1 g. (0.11 mole) of sodium hydroxide in 20 ml. of water is added dropwise over a period of 20 minutes. The reaction mixture is allowed to stir at room temperature for 1 hour, after which the chloroform layer is separated, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to yield the intermediate, N-(2-bromoethyl)acetoacetamide, as a white crystalline residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17]CC3C=CC=CC=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([N:27]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([OH:17])[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([N:27]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OCc3ccccc3)cnc21
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(O)cnc21
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
To the solution of 0.3 g (0.64 mmol) 5-benzyloxy-2-(4,4-difluoro-piperidine-1-carbonyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester in 3 ml methanol and 4 ml ethyl acetate 45 mg palladium on activated charcoal (10%) was added and the suspension was hydrogenated at 1.3 bar for 15 min. The suspension was filtered over Dicalite Speed Plus®(Aldrich), the filtercake was washed with ethyl acetate and methanol and the filtrate evaporated. The residue was purified by flash column chromatography on silica gel with ethyl acetate:n-heptane (2:1) as eluant to give 0.19 g (78%) of the desired compound as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[H-].[Na+].[I:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1>CN(C=O)C.[Cl-].[Na+].O>[I:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH2:2][CH2:3][O:4][CH3:5])[C:16]2[N:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:13][CH:14]=1
Reactant: COCCBr
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 2-bromoethylmethyl ether (0.14 ml) and sodium hydride (48 mg) were added to a solution of N-(4-iodophenyl)pyrimidin-2-amine (300 mg) in anhydrous DMF (1 ml), and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform, followed by drying the organic layer over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/chloroform=1/10) to obtain N-(4-iodophenyl)-N-(2-methoxyethyl)pyrimidin-2-amine (233 mg). NMR (H1, CDCl3): δ 3.32(3H, s), 3.63 (2H, t, J=5.9 Hz), 4.14 (2H, t, J=5.9 Hz), 6.59 (1H, t, J=4.9 Hz), 7.09-7.13 (2H, m), 7.70-7.73 (2H, m), 8.32 (2H, d, J=4.9 Hz)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([OH:31])[C:19]#[C:20][C:21]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2].[K].[CH3:45]I>CS(C)=O.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([O:31][CH3:45])[C:19]#[C:20][C:21]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@H](O)C#CC(C)(C)OC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: CI
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CO[C@H](C#CC(C)(C)OC1CCCCO1)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 90 %

Procedure:
100 mg of (22S)-1α,3β-diacetoxy-25-tetrahydropyranyloxy-cholest-5-en-23-yn-22-ol (IIIa1) obtained in Example 1 (1) was dissolved in 1.5 ml of dimethylsulfoxide, and after adding thereto 13.2 mg of powderous potassium hydroxyde and 31 μl of methyl iodide, the mixture was stirred for 3.5 hours at room temperature. The reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatgraphy (solvent; n-hexane:ethyl acetate=7:1) for purification to give 92 mg of (22S)-1α,3β-diacetoxy-22-methoxy-25-tetrahydropyranyloxy-cholest-5-en-23-yn (IVb1) (yield: 90%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.C([N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1)(=O)C>C(#N)C>[CH3:25][C:23]1[NH:22][C:21]([CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]3)=[N:20][CH:24]=1
Reactant: COC(=O)c1ccc2cc(CBr)ccc2c1
Reactant: CC(=O)n1cnc(C)c1
Solvent: CC#N
Product: COC(=O)c1ccc2cc(Cc3ncc(C)[nH]3)ccc2c1
Yield: 69.8 %

Procedure:
2 g (7.16 mmol) of methyl 6-bromomethyl-2-naphthoate and 1.07 g (8.6 mmol) of 1-acetyl-4-methylimidazole are heated under reflux in absolute acetonitrile (8 hours). After the reaction solution has been evaporated, the residue is taken up in 2N HCl, and the solution is extracted with ethyl acetate. The ethyl acetate phases are discarded. After the aqueous phase has been neutralized with sodium carbonate, it is extracted with ethyl acetate, and the ethyl acetate phase is dried and evaporated in vacuo. 1.4 g (70%) of methyl 6-(5-methyl-1-imidazolylmethyl)-2-naphthoate are obtained by trituration of the residue with ether. Melting point 101°-102° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=2)[CH2:10]1)[CH3:4]>O1CCCC1.O>[CH2:3]([O:5][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:10]1)[CH3:4]
Reactant: CCOC(=O)c1ccc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ccc(C(=O)O)cn2)C1
Temperature: 60 °C
Yield: 98.8 %

Procedure:
Aqueous 1N sodium hydroxide solution (27.1 mL, 27.0 mmol) was added to a stirred solution of ethyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinate (2.5 g, 6.8 mmol) in tetrahydrofuran (20 mL) at 0° C. The reaction mixture was heated to 60° C. for 18 h. The mixture was then diluted with water (25 mL) and was washed with ethyl acetate (2×50 mL). The aqueous layer was acidified with citric acid solution (pH-2) and was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude solid material was purified by washing with ether and hexane to afford (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinic acid (2.3 g) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.57 (d, 1H), 7.87 (dd, 1H), 7.03 (dd, 1H), 6.90 (m, 3H), 6.79 (d, 1H), 4.29 (m, 1H), 4.16 (m, 1H), 3.91 (m, 2H), 3.76 (m, 1H), 3.59 (m, 2H), 2.01 (m, 1H), 1.81 (m, 2H), 1.51 (m, 1H), 1.23 (t, 3H). MS (ES+) 343.2 (M+H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31](Br)[C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=1)[CH3:20]>CN(C)C=O.O>[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]([CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:31]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=1)[CH3:20]
Reactant: Sc1ccccc1
Reactant: COC(=O)C(Br)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccccc1
Temperature: 25 °C

Procedure:
Thiophenol (0.92 mL) was added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in oil, 0.38 g) in dry N,N-dimethylformamide (60 mL). The mixture was allowed to warm to room temperature over 30 minutes prior to the addition of a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-bromopropanoate (3.85 g) in N,N-dimethylformamide (40 mL) and the mixture was then heated at 80° C. for 72 hrs, cooled and diluted with water (1 L). The mixture was extracted with ethyl acetate (3×250 mL) and the combined organic solutions washed with water (3×1 L) and brine (1 L), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using a gradient of 1% methanol to 2% methanol in dichloromethane as eluent to afford the title compound, mp 78°-9° C. (dichloromethane-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[S:13](Cl)(=[O:15])=[O:14].[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[S:13]([NH:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: COC(=O)c1sccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 69.9 %

Procedure:
Synthesized as described for 3 using 2,6-dichloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (2.5 g; 7.97 mmol), methyl 3-aminothiophene-2-carboxylate (1.14 g; 7.25 mmol), 4-dimethylaminopyridine (221.4 mg; 1.81 mmol), pyridine (11.81 mL; 145.0 mmol) and anhydrous dichloromethane (50 mL). Purification by automated silica gel chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) afforded the title compound as a white solid (2.20 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH3:23][S:24]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)(=[O:26])=[O:25]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 180 step C) and methanesulfonyl chloride. White solid. MS (ESI): 393.2 (MH+).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[C:11]([O:14][C@@H:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([OH:18])=O)(=[O:13])[CH3:12].Cl.[C:26]1([C:32]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@@H:40]3[C@@H:36]([CH2:37][NH:38][CH2:39]3)[C@@:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])([OH:41])[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:50]1([C:32]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:40]3[C@@H:36]([CH2:37][N:38]([C:16](=[O:18])[C@@H:15]([O:14][C:11](=[O:13])[CH3:12])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:39]3)[C@@:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])([OH:41])[CH2:34][CH2:33]2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CC(=O)O[C@H](C(=O)O)c1ccccc1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)[C@@H](OC(C)=O)c3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
0.024 g of 1-hydroxybenzotriazole and 0.33 g of (S)-2-acetyloxy-2-phenylacetic acid are added to a suspension of 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 60 cm3 of dry methylene chloride, this solution is then cooled to +5° C. and a suspension of 0.4 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in 20 cm3 of dry methylene chloride is rapidly added, followed by a solution of 0.63 cm3 of diisopropylethylamine in 20 cm3 of dry methylene chloride. The reaction mixture is stirred at +5° C. for 2 hours and at room temperature for 24 hours, diluted with 120 cm3 of methylene chloride, washed with 100 cm3 of water and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.5 cm, height 39 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting fractions of 60 cm3. Fractions 6 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.96 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[2-acetyloxy-2-phenyl-(S)-acetyl]-perhydroisoindol-4-ol are obtained in the form of a white foam.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:13]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.NCC(N[C@H](B1O[C@@H]2C[C@@H]3C[C@H]([C@]2(C)O1)C3(C)C)CC(C)C)=O>C(Cl)Cl>[C:4]([NH2:13])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccccc1Br
Agent: CC(C)C[C@H](NC(=O)CN)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: NC(=O)c1ccccc1
Reaction time: 2 h
Yield: 292.9 %

Procedure:
To a solution of 2-bromobenzoic acid (0.124 g, 0.62 mmol) in DCM (2.25 mL) were added EDCI (0.119 g, 0.62 mmol), HOBt (0.084 g, 0.62 mmol), N-methyl morpholine (0.185 mL, 1.68 mmol) and 2-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}acetamide (0.2 g, 0.56 mmol). The reaction mixture was allowed to stir for 2 h and was concentrated. The residue was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 2-bromo-N-[2-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (0.22 g, 78%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reaction time: 0.5 h

Procedure:
N-methylpiperazine 3.6 mL, N,N-diisopropylethylamine 5.7 mL and tetrahydrofuran 31 mL were mixed and dropped into a solution of 4-chloro-3-nitrobenzenesulfonyl chloride 8.19 g in tetrahydrofuran 51 mL, under cooling with ice, followed by stirring for 30 minutes under cooling with ice. The stirring was then continued for 17 hours at room temperature. The solvent was distilled off and the residue was poured in water, of which pH was raised to 9 with saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate-tetrahydrofuran mixed solvent. The organic layer was washed with saturated brine, dried over magnesium sulfate, and from which the solvent was distilled off. Recrystallizing the crude product from ethyl acetate-hexane mixed solvent, 4.29 g of the title compound was obtained.
Reaction SMILES: [C:1]([Si:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:26][CH2:11][CH2:10][C:9]#[C:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](OCC#CCCO)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC#CCCBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of compound 5 (1.09 g, 3.22 mmol) and CBr4 (1.28 g, 3.86 mmol) in CH2Cl2 (70 mL) was treated with a solution of Ph3P (1.27 g, 4.84 mmol) in CH2Cl2 (30 mL) dropwise at −78° C. After 30 min, the reaction mixture was slowly warmed up to room temperature for 2 h and then stirred for overnight. The reaction mixture was poured to the silica gel pad. The filtrate was concentrated to dryness. After concentration, the residue was purified with 0˜2% EtOAc in hexanes by silica gel column chromatography to give 1.28 g of product 6 (3.19 mmol, 99% yield); 1H NMR (CDCl3) δ 7.80˜7.65 (m, 4H), 7.50˜7.32 (m, 6H), 4.34 (t, J=1.9 Hz, 1H), 3.35 (t, J=5.8 Hz, 2H), 2.73 (tt, J=2.1, 6.0 Hz, 2H) 1.08 (s, 9H).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>N1C=CC=CC=1.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:19][C:18]([NH:20][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=4)=[N:17][N:16]=3)=[CH:13][CH:14]=2)[CH:3]=1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1cccc(OC(F)(F)F)c1
Reaction time: 3 h
Yield: 17.5 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 3-trifluoromethoxybenzoyl chloride (117 uL) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (38.8 mg). Yield 17.5%.