Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[CH2:16]([SH:19])[CH2:17][SH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[S:18]1[C:12]2([CH2:13][CH2:14][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[OH:1])[CH2:10][CH2:11]2)[S:19][CH2:16][CH2:17]1
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Reactant: SCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(C2CCC3(CC2)SCCS3)c(O)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added 4-(2,4-dihydroxyphenyl)cyclohexanone (1 g) and toluene (40 ml). To the stirred solution was added ethane-1,2-dithiol (0.49 ml) and a few crystals of p-toluenesulfonic acid monohydrate and the reaction mixture was heated under reflux for 3.5 hr. The reaction mixture was cooled to room temperature, saturated sodium hydrogencarbonate solution (20 ml) was added, and the layers were separated. The aqueous layer was diluted with water (40 ml) and extracted into ethyl acetate (3×30 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether 2:3 v/v) furnished the title compound (1.34 g, 98%) as a white solid. δH (CD3OD): 1.59-1.73 (2H, m), 1.75-1.84 (2H, m), 1.98-2.08 (2H, m), 2.14-2.22 (2H, m), 2.77 (1H, tt), 3.22-3.32 (4H, m), 6.18-6.24 (2H, m), 6.85 (1H, d); m/z (ES+) 283 (M+H)+.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH3:27][O:28][C:29]([C:31]1([CH2:46]O)[CH:35]([CH3:36])[C:34](=[O:37])[N:33]([C:38]2[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:45])[CH2:32]1)=[O:30]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:27][O:28][C:29]([C:31]1([CH2:46][I:25])[CH:35]([CH3:36])[C:34](=[O:37])[N:33]([C:38]2[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:45])[CH2:32]1)=[O:30]
Reactant: COC(=O)C1(CO)CN(c2c(C)cccc2C)C(=O)C1C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1(CI)CN(c2c(C)cccc2C)C(=O)C1C
Temperature: 100 °C
Yield: 83.1 %

Procedure:
Imidazole (261.5 mg, 3.84 mmol), triphenyiphosphine (670.7 mg, 2.56 mmol) and I2 (487.3 mg, 1.92 mmol) were added sequentially to a solution of 1-(2,6-dimethylphenyl)-3-hydroxymethyl-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step c, 373 mg, 1.28 mmol) in toluene (15 mL) and resulting reaction mixture was heated at 100° C. with stirring for an hour. The reaction mixture was then cooled to room temperature and diluted with EtOAc (50 mL), washed with water (30 mL), saturated NH4Cl (30 mL), dried (Na2SO4) and evaporated. The residue was then purified by flash chromatography (SiO2, 20→70% EtOAc/hexanes) to obtain 1-(2,6-dimethylphenyl)-3-iodomethyl-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (427 mg, 83% yield). LC-MS: Rt (retention time): 2.32 min, MS: (ES) m/z 402.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:18]O>CS(O)(=O)=O>[CH2:1]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:16][OH:18])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: OO
Reactant: CCCCCCCCCNC(=O)CCC(=O)O
Agent: CS(=O)(=O)O
Product: CCCCCCCCCNC(=O)CCC(=O)OO
Temperature: -15 °C
Yield: 89.3 %

Procedure:
A 500 mL beaker was charged with 50.0 g (0.205 mol) of 4-nonylamino-4-oxobutyric acid and 100 mL of 98% methanesulfonic acid. The resulting solution was cooled in an ice bath and, with stirring, 38.8 g of 90% hydrogen peroxide (34.9 g, 1.03 mol of hydrogen peroxide) was added dropwise at a rate such that the temperature of the reaction mixture did not rise above 20° C. (required 10 minutes). The solution was stirred at room temperature for 1.5 hours, cooled to -15° C., and poured over ice. The precipitated solid was collected by filtration and washed with water. The filter cake was reslurried with water, filtered, and washed with water. The wet filter cake was dissolved in 250 mL of 60° C. ethyl acetate, the water layer removed with a pipet, and the ethyl acetate solution cooled to -15° C. The crystals which formed were collected by filtration, washed with -15° C. ethyl acetate, and air dried to yield 47.5 g of 4-nonylamino-4-oxoperoxybutyric acid (1), mp 85°-91° C., analysis for available oxygen (AvO)=5.61%. Theoretical yield=53.2 g having an AvO of 6.17%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12].[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(CCc1ccccc1F)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCc1ccccc1F)C(=O)O
Yield: 101.3 %

Procedure:
A mixture of diethyl 2-(2-(2-fluorophenyl)ethyl)malonate (381.8 g, 1.35 mol) and potassium hydroxide (227.3 g, 4.1 mol) and potassium hydroxide (227.3 g, 4.1 mol) in ethanol (500 mL) and water (500 mL) was refluxed for 24 h. The reaction mixture was placed in an ice bath and hydrochloric acid (6N, 442 mL) was added. The ethanol was removed in vacuo and the aqueous residue was extracted with diethyl ether. The extracts were dried (MgSO4) and concentrated in vacuo to give 309.3 g (100%) of 2-(2-(2-fluorophenyl)ethyl)malonic acid as an off-white solid. This product was used without further purification. NMR (DMSO-d6): d 6.8-6.2 (m, 4H, ArH), 2.4 (t, 1H, CH), 1.9 (q, 2H, CH2), 1.3 (t, 2H, CH2). IR (KBr) 1691 CM-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25][C:26]1[C:27]([N+:35]([O-:37])=[O:36])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].ClCCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([OH:25])[C:27]=1[N+:35]([O-:37])=[O:36]
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 82.3 %

Procedure:
12.9 g of L-proline methyl ester and 21.0 g of N,N'-dicyclohexylcarbodiimide were successively added to an ice-cooled and constantly stirred solution of 18.3 g of 3-hydroxy-2-nitrobenzoic acid dissolved in a mixture consisting of 360 ml of dichloromethane and 30 ml of N,N'-dimethylformamide, and then the same treatment as in Example 1 was carried out. Thus, there was obtained 24.2 g of 1-(3-hydroxy-2-nitrobenzoyl)-L-proline methyl ester as a yellow-colored needle-like crystal having a melting point of 114° to 116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.C(O[C:35](=O)[N:36]([CH2:38][CH2:39][NH2:40])C)(C)(C)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:40][CH2:39][CH2:38][NH:36][CH3:35])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21
Agent: Cl
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure I, the coupling of {6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with HCl, the title compound.
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21]CC(=O)[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].F[C:24]([F:35])([F:34])[CH2:25]N(OS(=O)(=O)O)CC>C(Cl)(Cl)Cl>[C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:25][C:24]([F:34])([F:35])[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]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(=O)C2)O1
Reactant: CCN(CC(F)(F)F)OS(=O)(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(F)(F)C2)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2.8 g of (2R,5R)-2-(t-butyl)-5-((1R)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in 30 ml of chloroform, 4.89 ml of trifluorodiethylaminosulfuric acid was added under cooling with ice, followed by 20 hours' stirring at room temperature. The reaction liquid was diluted with chloroform, washed successively with water and with saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to provide 2.4 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1cccn1-c1ncccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)cn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To a solution of 1.0 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine in 15 ml of N,N-dimethylformamide was added 0.68 g of N-chlorosuccinimide. The resulting mixture was stirred at 50° C. for 2 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 4-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[CH2:17]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-tert-butoxycarbonylpiperidin-4-ol (25 g, 0.124 mol) in 100 ml anhydrous THF was added to a suspension of sodium hydride (5.96 g, 0.15 mol, pentane washed) in 100 ml anhydrous THF at 0° C. The reaction was stirred at 0° C. for 1 hour, then treated with a solution of benzyl bromide (25.65 g, 0.15 mol) in 20 ml anhydrous THF. The reaction was allowed to stand for 20 h at room temperature, cooled to 0° C., and 50 ml water was added cautiously. The product was extracted using ethyl acetate, the combined organic extracts were washed with water, dried (MgSO4) and concentrated. Chromatography using petroleum ether→20% ethyl acetate-petroleum ether gave 4-benzyloxy-1-tert-butoxycarbonyl-piperidine as a colourless solid. δH (250 MHz, CDCl3) 1.45 (9H, s), 1.51-1.65 (2H, m), 1.80-1.94 (2H, m), 3.04-3.15 (2H, m), 3.51-3.61 (1H, m), 3.70-3.84 (2H, m), 4.56 (2H, m), 7.26-7.35 (5H, m). m/e (ES) 292.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:4]1=[O:32])=[CH:22][CH:21]=[CH:20][CH:19]=3.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:2][C@@H:3]1[C@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[C:4]1=[O:32])=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 84 %

Procedure:
A mixture of 2.6 g of (±)-cis-2,3-dihydro-3-hydroxy-5-[3-(dimethylamino)propyl]-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride and 25 mL of acetic anhydride was stirred and heated at 100° for 17 hours. The excess of reagent was removed under reduced pressure and the residue was dissolved in water. The aqueous solution was made basic with concentrated ammonium hydroxide and extracted with ethyl acetate (3×75 mL). The combined ethyl acetate solutions were washed with brine (50 mL) and dried (magnesium sulfate). Removal of the solvent gave 2.2 g (84%) (±)-cis-3-(acetyloxy)-2,3-dihydro-5-[3-(dimethylamino)propyl]-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one. A sample of this compound was crystallized from ether, mp 98°-99°.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:12][C:13]([CH3:15])=O>CO>[CH3:12][C:13]([CH3:15])=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9]
Reactant: CC(C)=O
Reactant: N#CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=C(C#N)c1ccccc1
Temperature: 65 °C
Yield: 47 %

Procedure:
Benzyl cyanide (50.0 g, 0.43 mol) is dissolved in a mixture of acetone (150 ml) and methanol (20 ml) and then KOH (10 g, 0.15 mol) is added under stirring. After complete dissolution the brown mixture is heated to 65° C. (oil bath) during 90 min. The mixture is concentrated in a rotary evaporator, the residue is dissolved in toluene and washed 3 times with half saturated aq. NaCl-solution. The organic layer is dried over MgSO4, the solvent removed under reduced pressure and the residue distilled over a short-path apparatus at 0.07 mbar. The fraction distilling at 77° C. is collected (33 g) and subjected to a fine distillation over a Widmer-column to yield 31.3 g (47%) of 3-methyl-2-phenyl-but-2-ene nitrile as colourless oil (b.p. 85° C./0.05 mbar).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:67]([O:71][CH3:72])(=[O:70])[CH:68]=[CH2:69]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](/[CH:69]=[CH:68]/[C:67]([O:71][CH3:72])=[O:70])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(/C=C/C(=O)OC)cn2)CN1C(=O)OC(C)(C)C
Temperature: 150 °C
Yield: 74.7 %

Procedure:
(2R,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.5 mmol), palladium(II) acetate (15 mg, 0.05 mmol), tri(o-tolyl)phosphine (36 mg, 0.1 mmol), triethylamine (0.2 mL, 1.5 mmol), and methyl acrylate (0.15 mL, 1.5 mmol) are dissolved in DMF (5 mL) and heated in a microwave at 150° C. for 30 minutes. The reaction mixture is filtered through Celite with EtOAc and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-((E)-2methoxycarbonyl-vinyl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (225 mg, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)[CH:14]([CH3:16])[CH3:15])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[O:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:38]([O:34][CH2:12][C@@H:13]([CH2:17][CH:10]([OH:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)[CH:14]([CH3:16])[CH3:15])[CH:14]([CH3:16])[CH3:15])[C:37]1[CH:3]=[CH:1][CH:2]=[CH:35][CH:36]=1
Reactant: COCCCOc1cc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)ccc1OC
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(O)C[C@H](COCc2ccccc2)C(C)C)C(C)C)ccc1OC
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
The reaction mixture is stirred for a further 20 minutes at 55° C. and then cooled to 5° C. A solution of 2(S)-(tert-butoxycarbonyl)amino-4(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-5-methyl-hexanal (190 g) in tetrahydrofuran (700 ml) is then added dropwise. The reaction mixture is stirred for a further 3 hours at room temperature, then at 5° C. saturated ammonium chloride solution is added and the mixture is extracted with diethyl ether. The organic phases are concentrated and purified by FC (4 kg of silica gel, ethyl acetate/hexane 1:3). The title compound is obtained in the form of a colourless oil (139 g): Rf (ethyl acetate/hexane 1:2)=0.26; HPLC Rt =22.7 and 22.8 min ((4:6)-diastereoisomeric mixture).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O>C(O)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][CH:7]1[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: Nc1nccs1
Reactant: O=Cc1ccccc1C(=O)O
Solvent: CCO
Product: O=C1OC(Nc2nccs2)c2ccccc21
Yield: 81.3 %

Procedure:
2-Aminothiazole (I31) (1.0 equiv., 5.00 mmol, 0.500 g) and 2-formylbenzoic acid (I32) (1.2 equiv., 6.00 mmol, 0.900 g) were mixed in ethanol (8 ml) and heated at reflux for 2 h. Upon cooling, a precipitate was formed. The product was isolated by filtration and washed with isopropyl ether to afford 3-(2-thiazolylamino)-isobenzofuran-1(3H)-one (I33) (0.944 g, yield=81%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:17][CH2:16]1
Reactant: Clc1cc2ccccc2cn1
Reactant: OCCN1CCNCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: OCCN1CCN(c2cc3ccccc3cn2)CC1

Procedure:
Prepared analogously to Example 1 from 3-chloroisoquinoline and N-(2-hydroxyethyl)-piperazine. Melting point of base 134°-136° C.; melting point of dihydrochloride 282°-283° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[C:16]1[CH:17]=[C:18]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.[Cl:28][C:29]1[C:30]([C:55]([F:58])([F:57])[F:56])=[C:31]([CH:52]=[CH:53][CH:54]=1)[CH2:32][N:33]([CH2:38][CH:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:34][CH2:35][CH2:36][OH:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)C>[ClH:28].[Cl:28][C:29]1[C:30]([C:55]([F:56])([F:57])[F:58])=[C:31]([CH:52]=[CH:53][CH:54]=1)[CH2:32][N:33]([CH2:38][CH:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:34][CH2:35][CH2:36][O:37][C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][C:18]=1[S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23]
Reactant: CN(C)S(=O)(=O)c1cccc(O)c1
Reactant: OCCCN(Cc1cccc(Cl)c1C(F)(F)F)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1ccccc1OCCCN(Cc1cccc(Cl)c1C(F)(F)F)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
DIAD (48 uL, 0.24 mmol) was added dropwise to a RT solution of 3-hydroxy-N,N,-dimethyl-benzenesulfonamide (0.040 g, 0.2 mmol), 3-[(3-chloro-2-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol (0.088 g, 0.2 mmol) and triphenylphosphine (0.063 g, 0.24 mmol). The mixture was stirred for 48 at rt than was concentrated and purified by reverse phase HPLC to provide a solid which was dissolved in CH2Cl2 and treated with excess 4M HCl in diethyl ether. The mixture was concentrated to provide 35 mg (25%) of the title compound. MS (ESI) 632 (M+H+).
Reaction SMILES: [O:1]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:8]1)=[O:6].C[CH2:23][OH:24].C=O>O>[OH:24][CH2:23][CH:3]([NH:4][C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:12]1)=[O:6])[C:2](=[O:1])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)N1CCC(C(=O)NCC(=O)c2ccccc2)CC1
Reactant: CCO
Agent: C=O
Solvent: O
Product: CC(=O)N1CCC(C(=O)NC(CO)C(=O)c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 6 h

Procedure:
A solution of 1-Acetyl-piperidine-4-carboxylic acid (2-oxo-2-phenyl-ethyl)-amide (40.66 g, 141 mmol), prepared as in Intermediate 2A, in 2:1 EtOH: H2O (160 mL EtOH, 80 mL H2O) is treated with 37% aqueous formaldehyde (21.1 mL, 282 mmol) and NaCHO3 (1.18 g, 14.1 mmol). The reaction mixture is stirred at 23° C. for 6 h, and the resulting precipitate is removed by filtration. The filtrate is cooled to 0° C. and diluted with H2O (100 mL), and a second crop of 1-Acetyl-piperidine-4-carboxylic acid (1-hydroxymethyl-2-oxo-2-phenyl-ethyl)-amide is obtained by filtration.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](O)[CH2:9][C@H:8]1[CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:52]([OH:60])(=[S:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:59][C:52](=[O:60])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:9][C@H:8]1[CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:6])[CH:2]=[CH2:3]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1CCCn1ccnc1
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-[3-(imidazol-1-yl)propyl]pyrrolidine (12.5 g) in tetrahydrofuran (125 ml) were added successively triphenylphosphine (17.6 g) and diethyl azodicarboxylate (10.6 ml) at -10° C. and the solution was stirred at the same temperature for 30 minutes. Then thiobenzoic acid (9.5 ml) was added at the same temperature and the solution was stirred for 3 hours. To the solution was added ethyl acetate (125 ml) and washed with saturated aqueous sodium hydrogen carbonate (125 ml×2) and brine (250 ml). The solution was dried over magnesium sulfate and the solvent was evaporated to give a yellow oil. The oil was chromatographed on a 500 g of silica gel to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-[3-(imidazol-1-yl)propyl]pyrrolidine (15.3 g) as a yellow paste.