Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@@H:6]1[CH:18]=[CH2:19].O.B(O[O-])=[O:34].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[OH:34][CH2:19][CH2:18][C@@H:6]1[C@H:5]([CH2:4][CH2:3][CH:2]([OH:1])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1
Reactant: O=BO[O-]
Reactant: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CCO)c2c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
33.4 cm3 of triethylamineborane complex were added with stirring, at a temperature in the region of 20° C., to a solution of 52.6 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)-3-vinylpiperidine in 500 cm3 of toluene and then the mixture was heated for 18 hours at a temperature in the region of 110° C. After having concentrated the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 45° C., the residue obtained was taken up in 500 cm3 of tetrahydrofuran. The solution which resulted therefrom had approximately 63 cm3 of water added over 20 minutes and then 47.5 g of sodium perborate were added portionwise over approximately 1 hour. The mixture was stirred for 4 hours at a temperature in the region of 20° C. and then 300 cm3 of a saturated ammonium chloride solution were added. The organic solution was separated by settling, dried over magnesium sulfate, and concentrated under the same conditions as above. The residue obtained was purified by chromatography on a column of silica gel (particle size 20-45 μm; diameter 9 cm; silica volume 2500 cm3), elution was carried out first with a dichloromethane/methanol (97.5/2.5 by volume) mixture, and 1-liter fractions were collected. Fractions 1 to 17 were separated and then elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, 1-liter fractions were collected. Fractions 30 to 35 were combined and, finally, elution was carried out with a dichloromethane/methanol (90/10 by volume) mixture, 1-liter fractions were collected. Fractions 36 to 41 were combined, while the combination of fractions 30 to 41 was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 20 g of (3R,4R)-3-(2-hydroxyethyl)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine were obtained in the form of an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](Cl)=[O:8])[CH2:3][CH2:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH:19]([C:23]([OH:25])=[O:24])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.Cl>ClCCl.O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:8])[CH:19]([C:23]([OH:25])=[O:24])[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Reactant: O=C(Cl)C1CCOCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCOCC2)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tetrahydropyran-4-carbonyl chloride was added drop wise to a mixture of piperazine-1,3-dicarboxylicacid 1-tert-butyl ester (123 g, Reference Example 63) and triethylamine (150 g) in dichloromethane (2000 ml) over a period of 0.45 hours. After stirring at room temperature for 3 days the reaction mixture was treated with water (1500 ml) and then acidified to pH 2 by addition of hydrochloric acid (37%). The organic phase was separated, then washed with aqueous sodium chloride solution (1%) and then evaporated under reduced pressure to give a yellow foam (157 g) which was recrystallised from diethyl ether and then from ethyl acetate to give the title compound (67.9 g) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([N+:15]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[H][H]>O1CCCC1.[C].[Pd]>[NH2:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(OC)cc1OC

Procedure:
A 4.00 g portion of methyl 2,4-dimethoxy-5-nitrobenzoate was dissolved in 200 ml of tetrahydrofuran, and 0.40 g of 10% palladium-carbon was added, followed by stirring for 12 hours at room temperature under normal pressure in an atmosphere of hydrogen. After removing insoluble matter by filtration, the solvent was evaporated under a reduced pressure to give 3.6 g of methyl 5-amino-2,4-dimethoxybenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:40]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:40])=[O:31])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 88.2 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammonium salt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-n-hexane to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.18 g, 90.0%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)[N:3]=1.[ClH:21]>>[ClH:21].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc(CCc2cccc(N)n2)cc1
Agent: Cl
Product: Nc1cccc(CCc2ccc(C(=O)O)cc2)n1
Temperature: 60 °C

Procedure:
A suspension of ester 9-5 (625 mg, 2.31 mmol) in 6N HCl (12 ml) was heated to 60° C. After ~20 h, the reaction was concentrated to give acid 9-6 as a tan solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:29]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:31]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:15]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:16]=1)=[O:10])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:33]([O:32][C:30]1[CH:29]=[C:8]([CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:31]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1)=[O:10])[CH:34]([CH3:36])[CH3:35]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cc(OCC(C)C)cc(OCC(C)C)c2)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)COc1cc(OCC(C)C)cc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
In 9 ml of ethanol is dissolved 1.74 g of ethyl 3-[5-(3,5-diisobutoxybenzoyl)-2-isobutoxyphenyl]-propanoate. After adding 2 ml of 5 mol/L solution of sodium hydroxide, the mixture thus obtained is stirred at ambient temperature for one hour. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 1.53 g of 3-[5-(3,5-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoic acid is obtained as a white solid product.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCCc1cccc(F)c1F
Product: CN1c2cc(OCCc3cccc(F)c3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(2,3-difluorophenyl)ethanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:27])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:15][CH:14]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 86.6 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) was cooled to −78° C. and then treated with a solution of (4-benzyloxy-phenyl)-acetic acid methyl ester (1.66 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 g, 7.13 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. At this time, the reaction mixture was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) afforded 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.90 g, 86.6%) as a white wax: mp 55-57° C.; EI-HRMS m/e calcd for C22H26O3 (M+) 338.1881 found 228.1878.
Reaction SMILES: C(N(CC)CC)C.CS(C)=O.[OH:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:28][CH:27]=3)=[CH:20][N:19]2[C:41]=1[CH3:42]>O>[CH3:42][C:41]1[N:19]2[CH:20]=[C:21]([NH:24][C:25](=[O:40])[C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:30][CH:31]=3)[CH:22]=[CH:23][C:18]2=[N:17][C:16]=1[CH2:15][CH2:14][CH:13]=[O:12]
Reactant: Cc1c(CCCO)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(CCC=O)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Reaction time: 11 h
Yield: 54.3 %

Procedure:
Triethylamine (87.9 μL) and sulfur trioxide-pyridine complex (46.3 mg) were added to a DMSO solution (3 mL) of the compound (20.0 mg) obtained in Example 14, at room temperature. After stirred for 11 hours, the reaction liquid was poured into saturated saline water, and extracted with chloroform. The organic layer was dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel chromatography (methanol/chloroform=1/25 to 1/8) to obtain N-[3-methyl-2-(3-oxopropyl)imidazo[1,2-a]pyridin-6-yl]-4-(pyridin-2-ylmethoxy)benzamide (10.8 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[CH2:14][CH2:15][O:16][C:12]=2[C:11]([OH:17])=[C:10]([CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[H-].[Na+].[H][H].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][Cl:28]>CS(C)=O>[ClH:28].[ClH:28].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][O:17][C:11]1[C:14]2[CH2:15][O:16][CH2:12][C:13]=2[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH3:18]
Reactant: Cc1nc(Cc2ccccc2)c2c(c1O)OCC2
Reactant: CN(C)CCCl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Product: Cc1nc(Cc2ccccc2)c2c(c1OCCN(C)C)COC2
Product: Cl
Reaction time: 15 h

Procedure:
12.1 g (50 millimoles) of 4-benzyl-6-methyl-1,3-dihydro-furo[3,2-c]pyridin-7-ol are suspended in 40 ml of dry dimethylsulfoxide and converted to the sodium salt by adding 1.75 g (60 millimoles) of sodium hydride (85% strength in oil) at 20° C. When the evolution of hydrogen has ceased, 8.1 g (75 millimoles) of freshly distilled β-dimethylaminoethyl chloride are added dropwise and the mixture is left to stand for 15 hours at 10° C. The dimethylsulfoxide is distilled off in a high vacuum. The residue is taken up in methylene chloride, the salts and unconverted pyridinol are washed out with dilute sodium hydroxide solution, and the organic phase is dried and concentrated under reduced pressure. The residue is converted to the hydrochloride by means of dilute hydrochloric acid, and the hydrochloride is recrystallized from ethanol/ether. 10.0 g of 4-benzyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-yl β-dimethylaminoethyl ether bis-hydrochloride are obtained; melting point 213°-214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[C-:17]1([CH2:22][C:23]([OH:25])=O)[CH:21]=[CH:20][CH:19]=[CH:18]1.[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:23](=[O:25])[CH2:22][C-:17]1[CH:18]=[CH:19][CH:20]=[CH:21]1)[CH2:9][CH2:8]2.[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31]
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: O=C(O)C[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(C(=O)C[c-]1cccc1)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A4-4 when using 360 mg (1.6 mmol) N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and 240 mg (0.99 mmol) ferrocenylacetic acid (A3-7: W=OH, Cy=ferrocenyl). Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 10/1 gave the crude product N-(8-methoxytetralin-2-yl)-N-propyl-2-ferrocenylacetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:32][CH2:31][CH:27]([C:28]([Cl:30])=[O:29])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[ClH:30].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][CH:27]([C:28]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:17])=[O:29])[CH2:31][CH2:32]2)=[CH:20][CH:19]=1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1F
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: Cl
Product: O=C(Nc1ccccc1F)c1ccccc1NC(=O)C1CCN(c2ccncc2)CC1
Yield: 34.8 %

Procedure:
Using the procedure described in Example 138, N-(2-fluorophenyl)-2-aminobenzamide (0.89 mmol) and N-(4-pyridyl)isonipecotoyl chloride (2.23 mmol), purifying with RPHPLC Method A, yielded 141 mg (35%) of the title compound.
Reaction SMILES: [S-2:1].[Li+].[Li+].F[C:5]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].Cl.C(OCC)(=O)C>CS(C)=O.O>[F:19][C:16]1[CH:17]=[CH:18][C:5]([SH:1])=[C:6]([C:7](=[O:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=1
Reactant: O=C(c1ccccc1)c1cc(F)ccc1F
Reactant: [S-2]
Agent: Cl
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cc(F)ccc1S
Temperature: 120 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Lithium sulfide (3.5 g) (supplied from Aldrich) was added to a solution of 10.1 g of 2,5-difluorobenzophenone in 200 mL of DMSO, and stirred at 120° C. under a nitrogen atmosphere for 3 hours. Under ice cooling, 200 mL of 1 N hydrochloric acid was added to the reaction solution. Further 400 mL of ethyl acetate and 200 mL of water were added thereto, and the mixture was separated into two liquid phases. The organic layer was washed with 400 mL of water, and then washed with 200 mL of saturated brine. The organic layer was dried on sodium sulfate anhydrate and subsequently concentrated, to yield 10.54 g of the title compound.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[CH:11]1([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.N1C=CC=CC=1>ClCCl>[CH:11]1([CH2:16][CH2:17][O:18][S:2](=[O:3])(=[O:4])[NH2:5])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OCCC1CCCC1
Solvent: O=CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)OCCC1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To chlorosulfonyl isocyanate (275 mL, 3.15 mol) at 0° C. was added formic acid (119 mL, 3.15 mol), dropwise. The resulting solid was allowed to stir at 0° C. for a further 20 minutes. The residue was diluted with dichloromethane (875 mL) and warmed to room temperature for one hour. The reaction mixture was cooled in an ice/salt bath and a solution of 2-cyclopentyl ethanol (240 g, 2.1 mol) in pyridine (255 mL, 3.15 mol) and dichloromethane (2.1 L) was added, keeping the temperature below 7° C. After 2 hours, the reaction was concentrated in vacuo, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a colourless oil. The residue was purified by column chromatography on silica gel, eluting with 90:10 to 50:50 heptane:ethyl acetate, to afford the title compound as a colourless oil in 95% yield (276 g).
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].[Cl:14][C:15]1[C:16]([F:55])=[C:17]([C@@H:21]2[C@:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:24]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:23][C@H:22]2[C:41]([NH:43][C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][C:45]=2[O:53][CH3:54])=[O:42])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:14][C:15]1[C:16]([F:55])=[C:17]([C@@H:21]2[C@:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:24]([CH2:36][C:37]([CH3:39])([CH3:40])[CH3:38])[NH:23][C@H:22]2[C:41]([NH:43][C:44]2[CH:52]=[CH:51][C:47]([C:48]([O:50][CH:3]([O:2][C:1]([O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)=[O:13])[CH3:4])=[O:49])=[CH:46][C:45]=2[O:53][CH3:54])=[O:42])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(=O)OC2CCCCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 70.5 %

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood Products, 1.99 g, 1.5 mL, 13.9 mmol) was reacted with cyclohexanol (Alfa Aesar, 1.33 g, 1.4 mL, 13.3 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at −78° C. for 3 h to give 1-chloroethyl cyclohexyl carbonate. A portion of 1-chloroethyl cyclohexyl carbonate (253 mg, 1.22 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.3 mg, 0.244 mmol) in the presence of cesium carbonate (487.4 mg, 1.5 mmol) in dimethylformamide (5 mL) overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 1-(cyclohexyloxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (135.4 mg, 70% yield). MS (ES+) m/z calcd. for C40H44Cl2F2N3O7: [(M+H)+]: 786, found: 786
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2(O)[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[H-].[Na+].[CH2:22]([SH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[ClH:1].[CH2:22]([S:28][C:2]1[C:3]([C:8]2[CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][CH:13]=2)=[N:4][CH:5]=[CH:6][N:7]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CN1CCCC(O)(c2nccnc2Cl)C1
Reactant: CCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCSc1nccnc1C1=CCCN(C)C1
Product: Cl
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of 1.1 g (0.0048 mol) of (1) and 7 ml of thionyl chloride was stirred 1 h, the excess thionyl chloride was evaporated, and the residue was treated with ice-water. The solution was made basic with 5 N NaOH and the mixture extracted 3× with 25 ml of CH2Cl2. The solvent was evaporated from the dried extracts, the residue was dissolved in 10 ml of THF, and the solution was added to a suspension of sodium hexylthiolate in THF prepared from 0.21 g (0.0091 mol) NaH, 2 ml (0.014 mol) hexanethiol, and 30 ml of THF. The reaction was heated to reflux for 20 min followed by distillation of most of the THF from the reaction mixture. The solvents were evaporated, the residue treated with water, and the mixture extracted 3× with 25 ml of CH2Cl2. The solvent was evaporated from the dried extracts and the residue purified by radial chromatography eluting with 5% ethanol/0.5% NH4OH/CHCl3. The hydrochloride salt (35), 0.33 g, 21% yield crystallized from ethyl acetate as a white solid, mp 120.5°-122° C. NMR ppm(CDCl3) 0.9 (3H,t), 1.31 (4H, m), 1.44 (2H, m), 1.67 (2H, m), 2.6-2.7 (1H, m), 2.96 (3H, d), 3.05-3.22 (4H, m), 3.54-3.64 (1H, m), 3.72-3.8 (1H, m), 4.4-4.45 (1H, d), 6.8 (1H, m), 8.15 (1H, d), 8.28 (1H, d). Anal. C16H25N3S-HCl requires C: 58.61; H: 7.99; N: 12.81%. Found C: 58.48; H: 7.93; N: 12.84%.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])O.C([O:14][C:15](OCC)([O:17]CC)[CH3:16])C.[C:23](O)(=O)[CH2:24]CC>C(O)C>[CH3:23][CH2:24][CH:1]([O:17][C:15]([CH3:16])=[O:14])/[CH:2]=[C:3](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])\[CH3:5]
Reactant: CCCC(=O)O
Reactant: CCOC(C)(OCC)OCC
Reactant: C=CC(C)(O)CCC=C(C)C
Solvent: CCO
Product: CCC(/C=C(\C)CCC=C(C)C)OC(C)=O
Yield: 92.6 %

Procedure:
154 Grams of linalool (3.7-dimethyl-1,6-octadien-3-ol), 324 g of 1,1,1-triethoxy ethane and 4.6 g of butyric acid are placed in a three-necked flask having 500 ml of inner capacity, and reacted for 8 hours with stirring under heating at 140° to 145° C. and with removal of ethanol formed during the reaction. The liquid reaction product is directly distilled to remove the low boiling material such as butyric acid, whereby the unreacted 1,1,1-triethoxy ethane is recovered. The residue is distilled under high vacuum to give the ethyl geranyl acetate as a distillate boiling at 120° to 122° C./3.3 mm Hg. The yield is 92.6%.