Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([C:13]([CH2:15][N:16]1[N:20]=[CH:19][N:18]=[CH:17]1)=[O:14])([CH3:12])[CH3:11].C=O.N1CCCC[CH2:24]1>C1(C)C=CC=CC=1.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:24][CH:15]([N:16]2[CH:17]=[N:18][CH:19]=[N:20]2)[C:13](=[O:14])[C:10]([CH3:9])([CH3:11])[CH3:12])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: C1CCNCC1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C(=O)C(CSc1ccc(Cl)cc1)n1cncn1
Yield: 28 %

Procedure:
A mixture of 72.5 g (0.5 mol) of 4-chlorothiophenol, 100.2 g (0.6 mol) of 1,2,4-triazol-1-yl-pinacolin, 18 g (0.6 mol) of paraformaldehyde, 15 g of acetic acid and 5 ml of piperidine in 600 ml of toluene was heated under reflux in a water separator. After the water had been separated off, the reaction solution was washed with water, dried over sodium sulphate, filtered, and concentrated in vacuo. The oily residue was chromatographed over a silica gel column (mobile phase: chloroform). 45 g (28% of theory) of 1-(4-chlorophenylthio)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 67° C. were obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])[CH2:3][OH:4].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29]>O1CCCC1>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])[CH2:3][OH:4])=[O:29]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCOc1cc(C(C)(C)C)ccc1C(N)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C(CO)NC(=O)c1c(F)cccc1F
Yield: 86.1 %

Procedure:
A mixture of 23.6 g (0.10 mole) of 2-amino-2-(2-ethoxy-4-tert-butylphenyl)ethanol, 12.2 g (0.12 moles) of triethylamine and 200 ml of tetrahydrofuran was cooled and stirred, 17.7 g (0.10 mole) of 2,6-difluorobenzoyl chloride was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 32.5 g of N-(2,6-difluorobenzoyl)-2-amino-2-(2-ethoxy-4-tert-butylphenyl)ethanol.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:29]#[N:30])[CH2:26][CH2:27][CH2:28]4)=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(N)c1ccc(C2(C#N)CCC2)cc1
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C2(C#N)CCC2)cc1

Procedure:
2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyanocyclobutyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing (7-cyano-1H-benzimidazol-1-yl)acetic acid (95.0 mg, 0.475 mmol) prepared according to scheme 3, 1-[4-(1-aminoethyl)phenyl]cyclobutanecarbonitrile (95 mg, 0.475 mmol) prepared according to scheme 9, Et3N (144 mg, 1.43 mmol, 0.199 mL) and HATU (181 mg, 0.475 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (34.0 mg, 0.0888 mmol, 19%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.40 (d, J=7.03 Hz, 3H) 1.89-2.05 (m, 1 H) 2.15-2.34 (m, 1H) 2.52-2.66 (m, 2H) 2.66-2.80 (m, 2H) 4.88-5.01 (m, 1H) 5.25 (dd, J=22.66, 17.58 Hz, 2H) 7.31-7.46 (m, 5H) 7.71 (dd, J=7.62, 0.78 Hz, 1H) 8.01 (dd, J=8.01, 0.78 Hz, 1H) 8.36 (s, 1H) 8.87 (d, J=7.62 Hz, 1H); MS [M+H], calcd: 384.0. found: 384.2.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=O)C.C(OC([O-])=O)([O-])=O.[Na+].[Na+].C(O)(=O)C>CO>[C:25]([O:24][C:15]12[O:23][N:10]([CH2:11][CH:12]3[CH:14]1[N:13]3[C:28](=[O:30])[CH3:29])[C:9]1[C:17](=[C:5]([OH:4])[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=1)[CH:16]2[CH2:18][O:19][C:20](=[O:22])[NH2:21])(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Agent: O=C([O-])OC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(O)c1C2COC(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.2 %

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (52 mg) in methanol (5 ml) was added sodium dicarbonate (10 mg) in an ice-water bath. The mixture was stirred for 30 minutes in an ice-water bath and for additional 2.5 hours at ambient temperature. To the reaction mixture was added acetic acid to adjust the pH value to about 6 in an ice-water bath and the mixture was evaporated in vacuo. The residue was extracted with a mixture of chloroform and methanol (5:1, v/v) (5 ml×3). The extracts were combined and evaporated in vacuo. The residue was subjected to silica gel column chromatography and elution was carried out with a mixture of chloroform and methanol (50:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (26 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[C:6]([N:8]([CH3:15])[C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH:7]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])#[N:18]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:16][C:4]1[CH:5]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[N:13][CH:12]=[N:11][CH:10]=2)[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:23])#[N:18]
Reactant: CN(c1cncnc1)c1cc(N)cc(F)c1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(c1cncnc1)c1cc(F)cc(NC(=O)c2cccc(C#N)c2)c1
Reaction time: 0.08 h
Yield: 26.2 %

Procedure:
Compound 32 (15 mg, 0.069 mmol, 1.0 eq) was dissolved in CH2Cl2 (0.5 mL) and DMAP (9.2 mg, 0.075 mmol, 1.1 eq) was added and the reaction stirred for 5 min. 3-Cyanobenzoyl chloride (11 mg, 0.066 mmol, 1.0 eq) was added and the reaction was stirred until determination of completion by LCMS. The reaction was diluted with CH2Cl2, washed with water (1×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 6 mg (47%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 8.82 (s, 1H), 8.63 (s, 2H), 8.34 (s, 1H), (8.19 (d, J=8.0 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.44 (d, J=11.0 Hz, 1H), 7.22 (s, 1H), 6.79-6.73 (m, 1H), 3.34 (s, 3H); ES-MS [M+1]+: 348.2.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[H-].[Na+].[Na].[CH3:10][CH:11](Br)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH:21]([CH3:24])[CH2:22][CH3:23])=[CH:16][CH:15]=1>>[CH3:10][CH:11]([S:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1)[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20][CH:21]([CH3:24])[CH2:22][CH3:23])=[CH:18][CH:19]=1
Reactant: SC1=NCCS1
Reactant: CCC(C)Sc1ccc(OCC(C)Br)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: CCC(C)Sc1ccc(OCC(C)SC2=NCCS2)cc1

Procedure:
Generally following the procedure of Example 7, 2-mercapto-2-thiazoline (0.67 g, 5.6 mmol) is treated with sodium hydride (0.35 g, 7.3 mmol), with cooling, and the resulting sodium salt is reacted with 1-methyl-2-[4-(1methylpropylthio)phenoxy]ethyl bromide (1.70 g, 5.6 mmol) at RT to give 2-{1-methyl-2-[4-(1-methylpropylthio)phenoxy]ethylthio}-2-thiazoline.
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=C[C:2]=1[S:15](Cl)(=O)=[O:16].[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C([O:41][C:42](=[O:48])[C@H:43]([CH:45](C)[CH3:46])[NH2:44])(C)(C)C.C(OC(=O)[C@H](CCSC)N)(C)(C)C>>[CH3:2][S:15]([CH2:46][CH2:45][C@H:43]([NH:44][S:33]([C:20]1[CH:21]=[CH:22][C:23]2[O:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:31][C:32]=2[CH:19]=1)(=[O:35])=[O:34])[C:42]([OH:41])=[O:48])=[O:16]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Agent: CSCC[C@H](N)C(=O)OC(C)(C)C
Product: CS(=O)CC[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-methionine-t-butyl ester, (S)-4-methanesulfinyl-2-(phenoxathiine-2-sulfonylamino)-butyric acid is obtained as a white solid;
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([NH2:8])=[O:7])[CH2:4][OH:5].[C:9]([O:24][C@H:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:26][C:27](O)=[O:28])(=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(Cl)Cl>[C:9]([O:24][C@H:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:26][C:27]([NH:8][C:6](=[O:7])[C@H:3]([CH2:4][OH:5])[NH2:2])=[O:28])(=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: NC(=O)[C@@H](N)CO
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NC(=O)[C@@H](N)CO
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A suspension of L-serinamide hydrochloride (0.157 g, 1.18 mmol) and (R)-3-tetradecanoyloxytetradecanoic acid (0.61 g, 1.34 mmol) in CH2Cl2 (6 mL) was treated with triethylamine (0.18 mL, 1.3 mmol) and the resulting solution was stirred with 4 Å molecular sieves for 30 min. EEDQ (0.437 g, 1.77 mmol) was then added and the mixture was stirred for 16 h at room temperature. The product that precipitated was collected and washed with CH2Cl2 (2×25 mL) to give 0.455 g (71%) of N-[(R)-3-tetradecanoyloxytetradecanoyl]-L -serinamide as a colorless powder: mp 126-130° C.; 1H NMR (CDCl3) δ 0.88 (t, 6H, J=˜7 Hz), 1.15-1.7 (m, 42 H), 2.31 (t, 2 H, J=7.5 Hz), 2.51 (d, 2 H, J=6.3 Hz), 3.56 (br s, 1 H), 3.65 (dd, 1 H, J=1 1.2, 5.5 Hz), 3.86 (dd, 1 H, J=1 1.2, 4.5 Hz), 4.21 (s, 2 H), 4.40 (m, 1 H), 5.22 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:21]1([O:27][CH2:28][C@@H:29]2[O:31][CH2:30]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH:20][CH2:30][C@@H:29]([OH:31])[CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cccc(NCCN)c2)c1
Reactant: c1ccc(OC[C@H]2CO2)cc1
Product: COC(=O)c1cccc(-c2cccc(NCCNC[C@@H](O)COc3ccccc3)c2)c1

Procedure:
Electrospray MS (positive ion): (M+H) 421.1; from methyl-3′-[(2-aminoethyl)amino]-[1,1′-biphenyl]-3-carboxylate (117 mg) and (R)-(-)-3-(phenyloxy)-1,2-epoxypropane (54 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[C:21]([CH3:31])[CH:20]=1>>[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[CH:28][C:22](/[CH:23]=[CH:24]/[C:25]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[C:21]([CH3:31])[CH:20]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1cc(C)c(C=CC(=O)O)cc1C
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(C)c(OC)cc3C)nc2n(CCC)c1=O
Yield: 45 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.5 g (11.1 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.51 g (12.17 mmol) of 4-methoxy-2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.98 g (yield 45%) of Compound 44 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14](CC2C=CC(OC)=CC=2)[C:13](=[O:27])[N:12]=[C:11]3[CH:28]2[CH2:30][CH2:29]2)[CH:5]=[CH:6][CH:7]=1.[O-]S([C:35](F)(F)F)(=O)=O.[Mg+2].[O-]S(C(F)(F)F)(=O)=O.C[Mg]Br>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:27])[NH:12][C:11]3([CH:28]2[CH2:29][CH2:30]2)[CH3:35])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COc1ccc(Cn2c(=O)nc(C3CC3)c3cc(-c4cccc(Cl)c4)ccc32)cc1
Agent: C[Mg]Br
Agent: [Mg+2]
Solvent: CCOCC
Product: CC1(C2CC2)NC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
To a solution of 6-(3-chlorophenyl)-4-cyclopropyl-1-(4-methoxybenzyl)-1H-quinazolin-2-one (0.25 g, 0.6 mmol) in anhydrous ether was added, at ambient temperature under nitrogen, magnesium triflate (0.78 g, 2.4 mmol). The mixture was stirred for 30 minutes and treated with a solution of methylmagnesium bromide in ether (3.0 M, 1.0 mL, 3.0 mmol). The reaction mixture was kept at room temperature under nitrogen for 3 hours and quenched with a mixture of a saturated aqueous ammonium chloride solution (10 mL) and 1N aqueous HCl solution (5 mL). The mixture was stirred at room temperature for 20 minutes and ethyl acetate (40 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and dried (MgSO4). The solvent was removed and a half portion of the residue was dissolved in TFA (3 mL) and was stirred under nitrogen at room temperature for 72 hours. The solution was poured onto ice-water and the white precipitate obtained was collected on a filter. The solid was washed with water and then purified by a flash chromatography (methylene chloride:methanol/25:1, silica gel) to give 6-(3-chlorophenyl)-4-cyclopropyl-4-methyl-3,4-dihydro-1H-quinazolin-2-one as off-white solid (40 mg, 43%): mp 125-127° C.; 1H-NMR (DMSO-d6) δ 9.21 (s, 1H), 7.71 (s, 1H), 7.61 (d, 1H, J=7.8 Hz), 7.55 (d, 1H, J=1.6 Hz), 7.47 (dd, 1H, J=8.3, 1.8 Hz), 7.45 (t, 1H, J=7.8 Hz), 7.36 (d, 1H, J=8.1 Hz), 6.84 (d, 1H, J=8.2 Hz), 6.79 (s, 1H), 1.54 (s, 3H), 1.11 (m, 1H), 0.42 (m, 1H), 0.15-0.20 (i, 3H); MS (ESI) m/z 313([M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@@:17]3(OC)[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C:19]([CH2:28][OH:29])([CH2:26][OH:27])[O:18]3)[CH:13]=[CH:14][C:15]=2[Cl:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@@:17]34[O:18][C@@:19]([CH2:28][OH:29])([CH2:26][O:27]3)[C@@H:20]([OH:25])[C@H:21]([OH:24])[C@H:22]4[OH:23])[CH:13]=[CH:14][C:15]=2[Cl:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3R,4S,55)-2-(3-(4-(allyloxy)benzyl)-4-chlorophenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (0.5 g, 1.04 mmol) in dry DCM (20 mL), was added trifluoracetic acid (4.6 mL, 62.43 mmol) dropwise at 0° C. and the reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as monitored by TLC, the reaction mixture was diluted with ethyl acetate (100 mL) and washed sequentially with water (2×10 mL) and NaHCO3 (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The crude compound was used as such in the next reaction (440 mg, 94.3%).
Reaction SMILES: [CH3:1][OH:2].[F:3][C:4]1[CH:12]=[C:11]([CH3:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6](Cl)=[O:7]>C(OCC)(=O)C>[F:3][C:4]1[CH:12]=[C:11]([CH3:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([O:2][CH3:1])=[O:7]
Reactant: Cc1cc(F)c(C(=O)Cl)cc1F
Reactant: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(C)cc1F
Yield: 62 %

Procedure:
Methanol (10 mL) was added to 2,5-difluoro-4-methyl-benzoyl chloride (500 mg, 2.6 mmol) and the solution evaporated to give an oil. The oil was dissolved in ethyl acetate and extracted with saturated aqueous sodium carbonate solution (20 mL) and brine (2×20 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound as clear colourless solid (300 mg, 62%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12](Br)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([O-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+].O.C1C2C(=CC=CC=2)C=CN=1>C1CCCCC1.[Cu-]=O>[CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-]c1ccccc1
Reactant: Fc1ccc(COCc2ccccc2)cc1Br
Agent: O=[Cu-]
Agent: [Na+]
Solvent: O
Solvent: c1ccc2cnccc2c1
Solvent: C1CCCCC1
Product: Fc1ccc(COCc2ccccc2)cc1Oc1ccccc1
Yield: 75 %

Procedure:
A mixture of 1 mol of 3-bromo-4-fluoro-benzyl benzyl ether, 1.1 mol of sodium phenolate, 0.12 mol of copper(I) oxide, 80 g of 4 MgCO3.Mg(OH)2.4 H2O and 1,500 ml of isoquinoline was heated to 160° C. for 12 hours. The reaction mixture was then cooled, diluted with cyclohexane and filtered. The filtrate was washed with dilute hydrochloric acid and water, dried over sodium sulphate and filtered and the filtrate was distilled. 4-Fluoro-3-phenoxy-benzyl benzyl ether was obtained in the form of a yellow oil of boiling point 135° C./1 mbar in a yield of 75% of theory.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(NC(C)C)(C)C.CO>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[CH2:9][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCC1=CCN(Cc2ccc(N)cc2)C1=O
Solvent: CO
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)CCC1=CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
10 mg of 3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (h) prepared by above Step 1 was dissolved in methylene chloride solution (0.04 mM) at room temperature. And then 8.5 μl of benzoyl chloride (0.07 mM) and 19.1 μl of diisopropylamine (0.11 mM) were added thereto and the mixture was stirred for 2 hrs at 0° C. The reaction was stopped by adding methanol and the mixture was extracted three times with 10 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with ethyl acetate and hexane (1:2) as an eluant to give 12 mg of 3-[1-(4-benzoylamino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (i) (yield: 87%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[I:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCOCC>C1S(=O)(=O)CCC1>[I-:22].[C:28]1([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N+:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[C:10]([S:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:20])([F:1])[F:21])[CH:11]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ICCCCCc1ccccc1
Reactant: FC(F)(F)c1ccccc1Sc1cnc2ccccc2c1
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: FC(F)(F)c1ccccc1Sc1cc2ccccc2[n+](CCCCCc2ccccc2)c1
Product: [I-]
Temperature: 100 °C
Yield: 90.1 %

Procedure:
A mixture of 3-(2-trifluoromethyl-phenylsulfanyl)-quinoline (370 mg, 1.21 mmol), (5-iodo-pentyl)-benzene (520 mg, 1.9 mmol) in tetramethylene sulfone (1 mL) was sealed in a tube and heated at 100° C. for 12 h. Ether (10 mL) was added resulting in a solid product. The product was crystallized from MeOH-Et2O to yield 1-(5-phenyl-pentyl)-3-(2-trifluoromethyl-phenylsulfanyl)-quinolinium iodide (632 mg, 90%). Mp 227-229° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[N:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:12]1)=[O:4].[OH-].[Li+].CO.O>O1CCOCC1>[CH2:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C:14]2([N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([OH:4])=[O:2])[C:15]2=[O:16])[CH2:21][CH2:20]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1ccccc1N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of benzyl 3-(2-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.35 g, 4.7 mmol, 1 equiv.) and lithium hydroxide (394.4 mg, 9.4 mmol, 2 equiv) in a 3:1 mixture of methanol and water (20 ml t/v) was stirred at 60° C. for 16 hrs. Some dioxane was added to remove the turbidity in the reaction mixture and the stirring was continued for another 20 h. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated and dried in vacuo to afford the title compound as a cream solid (2.28 g, quant); 1H NMR (400 MHz, DMSO-d6): δ 1.88 (d, 2H, J=14 Hz); 2.38-2.45 (m, 2H); 3.52 (bs, 2H); 3.97-4.05 (m, 2H); 5.08 (s, 2H); 5.15 (d, 2H, J=16.4 Hz); 6.79-6.84 (m, 3H); 7.20-7.24 (m, 2H); 7.33-7.39 (m, 5H); 7.49-7.53 (m, 1H); 7.61 (dd, 1H, J=0.8 Hz); 7.68-7.72 (m, 1H); 791 (dd, 1H, J=1.6 Hz); 13.1 (bs, 1H); MS for C28H27N3O5 m/z 486.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[CH2:38]([NH2:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>O1CCCC1.C(OCC)(=O)C>[CH2:38]([NH:50][C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3](=[O:17])[C:2]([F:1])([F:19])[F:18])=[CH:16][CH:15]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: O=C(O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCN
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A solution of (E)-4-(4,4,4-trifluoro-3-oxo-1-butenyl)phenoxyacetic acid (0.810 g, 2.95 mmol) in tetrahydrofuran (20 ml) was treated with EEDQ (0.767 g, 3.10 mmol) and dodecylamine (0.575 g, 3.10 mmol). After 2 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed with water, 0.1N hydrochloric acid, saturated sodium bicarbonate, brine and dried. Evaporation of the solvent under reduced pressure gave a solid which was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (8:12) gave 0.750 g (58%) of the title material as white needles after recrystallization from ethyl acetate-hexane: mp 78.5-79° C.