Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:16](=[O:17])[O:15][CH2:14]2.[Cl-].[NH4+]>CCOCC.O1CCCC1>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([Br:10])[CH:20]=[CH:19][C:18]=1[C:16]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A Grignard-solution prepared from 220 grams (1.15 mol) of p-chlorobromobenzene and 29 grams of magnesium turnings (1.2 mol) in 1500 milliliters of dry ether was added dropwise in the course of one hour to a suspension of 213 grams of 5-bromphthalide (1 mol) in 1500 milliliters of dry tetrahydrofuran. The temperature was not allowed to rise over 10 degrees Centigrade. After the addition was completed the reaction mixture was stirred for three hours at room temperature. The mixture was then poured into 2 liters of icewater and 100 milliliters of saturated aqueous ammonium chloride were added. The etherphase was separated and the water-tetrahydrofuranphase extracted once with 500 milliliters of ether. The etherphase was washed with water, dried over anhydrous magnesiumsulphate, filtered and evaporated in vacuum to yield 320 grams of 2-hydroxymethyl-4-bromo-4'-chloro-benzophenone in the form of a yellow oil which was not purified further but used directly in the next step. The 320 grams of oil were dissolved in 200 milliliters of dry tetrahydrofuran and added dropwise to a great excess of N,N-dimethylaminopropyl magnesium chloride in tetrahydrofuran under gentle reflux. After completed addition the mixture was refluxed over night. The reaction mixture was then poured into 5 liters of icewater and 200 milliliters of saturated aqueous ammonium chloride solution added. The mixture was extracted with a total of 2500 milliliters of ether. The etherphase was then extracted with 20% aqueous acetic acid to acid reaction, whereupon the acetic acid solution was made alkaline with 10 N sodiumhydroxide solution. After cooling, the oil, which separated out, was extracted twice with 500 milliliters of ether. The combined ether extracts were dried over anhydrous potassium carbonate, treated with active carbon and evaporated in vacuum. The remaining oil consists of somewhat impure (4-bromo-2-(hydroxymethyl)phenyl)-(4-chlorophenyl)-(3-dimethylaminopropyl)methanol which was used in the next step without further purification. Yield: 219 grams.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:36][NH2:37])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CO>[CH3:1][O:2][C:3]([C:5]1[N:37]([CH2:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][N:30]2[C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.7 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester (539 mg) in methanol (10 ml) was added 2-aminomethylpiperidine-1-carboxylic acid tert-butyl ester (1.07 g), and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and 4N hydrogen chloride-ethyl acetate solution (5 ml) was added to the obtained residue. The mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, and 1N aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml) and di-tert-butyl carbonate (437 mg) were added. The mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1→4/1) to give the title compound (64 mg, 12%).
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([NH:17][CH:18]=[C:19]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[N:28][C:27]=2Cl)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13]1)=[O:11]>O>[CH3:8][O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:26](=[CH:31][CH:30]=[CH:29][N:28]=3)[C:25](=[O:33])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18]2)[CH2:13]1)=[O:11]
Reactant: CCOC(=O)C(=CNC1CCN(C(=O)OC)C1)C(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(C2CCN(C(=O)OC)C2)c2ncccc2c1=O
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
45 mg of sodium hydride (abt. 60% oil suspension 1.13 mmol) was added to 5 ml of a tetrahydrofuran solution of 411 mg of the compound obtained in Example 1 (1.08 mmol) under an argon atmosphere at 0° C. and the solution was stirred at the same temperature for 5 minutes. It was further stirred at room temperature for 30 minutes, then water (15 ml) was added and extraction was performed with ethyl acetate (30 ml). Next, the organic layer was washed with saturated saline (10 ml), then dried over anhydrous sodium sulfate, then the solvent was distilled off under vacuum. The precipitated crystal was washed with diethyl ether and the crystal was obtained by filtration to obtain 314 mg (84%) of the above-identified compound as a colorless crystal.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:33])[C:14]=2[C:18](=[O:32])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[Cl:33][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:34])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[C:23]([F:31])[CH:22]=1)=[O:32]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(C(=O)NCc3ccc(C(F)(F)F)c(F)c3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](CO)n1ccc2c(C(=O)NCc3ccc(C(F)(F)F)c(F)c3)c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(6-chloro-5-(3-fluoro-4-(trifluoromethyl)benzylcarbamoyl)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (120 mg, 0.00022 mol), potassium carbonate (100 mg, 0.0007 mol) and methanol (7 mL, 0.2 mol). The reaction was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][N:20]1[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[CH:21]1>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:19][N:20]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[CH:21]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2cccc(Cl)n2)cc1
Reactant: ClCn1cnc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(Oc2ccc(OCn3cnc(Cl)c3Cl)cc2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
At room temperature (about 20° C.), 4.9 g of 4-(6-chloro-2-pyridinyloxy)-phenol in 40 ml of anhydrous dimethylformamide is dripped into 0.6 g of 100% strength sodium hydride in 20 ml of anhydrous dimethylformamide. The mixture is subsequently stirred for 30 minutes at 50° C., and then 4.2 g of 1-chloromethyl-4,5-dichloroimidazole in 20 ml of anhydrous dimethylformamide is dripped in at room temperature. This mixture is stirred for 2 hours at 60° C. and overnight at room temperature. It is then stirred into 200 ml of ice water and the solution is extracted three times with methyl tert-butyl ether. The organic phase is washed with 5% strength sodium hydroxide solution and water, and dried, and the solvent is evaporated off under reduced pressure. The crude product obtained is recrystallized from toluene. There is obtained 6.6 g of 1-[4-(6-chloro-2-pyridinyloxy)-phenoxymethyl]-4,5-dichloroimidazole: m.p.: 94°-98° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[CH:27][CH:26]=1)=[O:4].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:6]2[N:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:23])[CH3:24])=[CH:17][CH:16]=3)[C:8]3[C:13]([C:5]=2[C:3]([OH:2])=[O:4])=[CH:12][C:11]([O:14][C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[CH:41]=2)=[CH:10][CH:9]=3)=[CH:30][CH:29]=1)([OH:33])=[O:32]
Reactant: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(O)ccc3n2-c2ccc(OC(C)C)cc2)cc1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)Oc1ccc(-n2c(-c3ccc(C(=O)O)cc3)c(C(=O)O)c3cc(Oc4cccc(Cl)c4)ccc32)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-hydroxy-1-(4-isopropoxyphenyl)-2-(4-methoxycarbonylphenyl)indole-3-carboxylic acid methyl ester (150 mg, 0.32 mmol, see step (b) Example 43) and 3-chloro-phenylboronic acid (100 mg, 0.64 mmol. Yield 97 mg (54%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(Cl)(Cl)Cl>CN(C)C=O.[Cu]>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(I)cc1OC
Agent: [Cu]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(C(=O)OC)c(OC)c2)cc1OC
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a mechanically stirred suspension of 90 g of copper powder in 450 mL of dimethylformamide was added 90 g of methyl 4-iodo-2-methoxybenzoate (which was prepared as in Example 1). The resulting mixture was heated at reflux for 6 days and then cooled to room temperature and diluted into 1500 mL of chloroform. The mixture was filtered and the copper was washed with 2×150 mL of chloroform. The residual copper was suspended in 2 liters of water and extracted with 6×150 mL of chloroform. All the organic fractions were combined, dried and concentrated to approximately 250 mL. The concentrate was cooled to 0° C. and the precipitate filtered to give 33 g of 3,3'-dimethoxy-4,4'-bis(methoxycarbonyl)biphenyl as a pale yellow powder. Deprotection of the dimethoxy compound was accomplished with boron trichloride according to step 5 of Example 1 to yield 3,3'-dihydroxy-4,4'-bis(methoxycarbonyl)biphenyl. The structure was confirmed by NMR.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:26]5[CH:31]=[CH:30][C:29]([S:32][CH:33]6[CH2:35][CH2:34]6)=[CH:28][CH:27]=5)[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[O:37]1CO1>ClCCl.CC(C)=O>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:26]5[CH:27]=[CH:28][C:29]([S:32]([CH:33]6[CH2:35][CH2:34]6)=[O:37])=[CH:30][CH:31]=5)[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: C1OO1
Reactant: CC(C)CNc1nc(-c2ccc(SC3CC3)cc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)CNc1nc(-c2ccc(S(=O)C3CC3)cc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
A solution of 50 mg (100 μmol) N-cyclopropyl-4-{6-[4-(cyclopropylsulfanyl)phenyl]-8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide in 5.0 mL dichloromethane was cooled to −30° C. and 1.16 mL of a 0.15 molar dioxirane solution in acetone were added. After 15 minutes of stirring the mixture was warmed to 23° C., the solvent removed and the residue was purified by chromatography to give 33.3 mg (59%) of the title compound. 1H-NMR (CDCl3): δ=0.67 (2H), 0.86-1.05 (5H), 1.06 (3H), 1.07 (3H), 1.25 (1H), 2.09 (1H), 2.28 (1H), 2.95 (1H), 3.56 (2H), 6.36 (1H), 6.54 (1H), 7.60 (1H), 7.63 (2H), 7.70 (2H), 7.94 (2H), 7.96 (1H), 8.02 (2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](N)=[O:20])=[CH:14][CH:13]=1)=[O:11].S(=O)(=O)(O)[OH:23].N([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:20])=[O:23])=[CH:14][CH:13]=1)=[O:11]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
10.7 g of 4-(2,3-dichlorophenylcarbamoyl)phenylacetamide was dispersed in 100 ml of acetic acid, and 17.5 ml of sulfuric acid was added. Then, a solution obtained by dissolving 3.2 g of sodium nitrite in 17.5 ml of water, was dropwise added to bring the reaction temperature to a level of 20° C.±5° C. Thereafter, the mixture was stirred at room temperature for two hours, and then poured into 400 ml of ice water. The resulting crystals are collected by filtration, thoroughly washed with water and then dried to obtain 9.8 g of desired 4-(2,3-dichlorophenylcarbamoyl) phenyl acetic acid. The yield was 91.3%, and the melting point of this compound was from 184° to 185.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:44])[CH:43]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:10]=[C:9]2[NH:34]C(=O)C(F)(F)F.C(N(CC)CC)C>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:44])[CH:43]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[N:10]=[C:9]2[NH2:34]
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cc3cc(F)cc(F)c3)cc12)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cc3cc(F)cc(F)c3)cc12

Procedure:
N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide (450 mg, 0.75 mmol) was dissolved in methanol (6 mL) and triethylamine (1.5 mL) and the solution was refluxed for 3 hours. The solvents were removed under reduced pressure and the residue was purified by flash chromatography (eluant: DCM). Title compound was isolated as white foam (300 mg, yield 80%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:17]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[S:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)(=[O:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
Prepared as in example 5-27 from dibenzylamine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 380.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 4.52 (s, 4H), 7.10 (m, 4H), 7.25 (m, 6H), 8.00 (d, 2H, J=8.4 Hz), 8.15 (d, 2H J=8.4 Hz), 13.5(s, broad, 1H).
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][O:19][C:20](=[O:22])[CH3:21])=O)=CC=1)([O-])=O.C(O)(=O)C.[H][H]>C(O)C.[C].[Pd]>[C:20]([OH:22])(=[O:19])[CH3:21].[C:20]([O:19][CH2:18][C@@H:13]1[CH2:14][C@@H:15]([OH:17])[CH2:16][NH:12]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-acetoxymethyl-4-hydroxypyrrolidine (1.55 g) in ethanol (23 ml), 10% palladium-carbon (233 mg) and acetic acid (330 mg) were added. The mixture was stirred at room temperature for 2 hours under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated to remove the solvent. The residue was combined with water, washed with dichloromethane and concentrated to give (2S,4R)-2-acetoxymethyl-4-hydroxypyrrolidine acetate.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O>CC(C)=O.O>[C:11]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
294 g (2.51 mol) of L-valine was dissolved into 786 g of ion-exchange water, 358 g (2.42 mol) of an aqueous solution of 27% sodium hydroxide and 363 g of acetone. With stirring the solution, 533 g (2.43 mol) of lauroyl chloride and 358 g (2.47 mol) of an aqueous solution of 27% sodium hydroxide were simultaneously added dropwise thereto so that pH=12±0.2 and the temperature is kept at 19 to 20° C. After completion of the addition, the solution was stirred at 20° C. for 60 minutes. Then, it was heated up to 40° C., and 171 g of 75% sulfuric acid was added thereto in order to adjust pH=1.5. The layers of the oily substance and water phase that separated at 60° C. were split, and 1950 g of warm water of 60° C. was added to the oily substance. After the mixture was cooled down to 20° C., the precipitated solid substance was filtered out and washed with water. Then, the substance was vacuum-dried at 50° C. to obtain 710 g of N-lauroyl-L-valine (2.37 mol, yield 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39]C(=O)C)=[CH:35][CH:34]=1.[OH-].[K+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.9 g 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-acetoxy-benzyl)-benzene in 150 mL methanol is added 25 mL 4 M aqueous potassium hydroxide solution. The solution is stirred at room temperature for 1 h and then adjusted to pH 5 with 4 M hydrochloric acid. Most of the methanol is evaporated and the remaining solution is extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent is removed in vacuo.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[Br:14][C:15]1[CH:24]=[CH:23][C:18]2[C:19](=O)[CH2:20][O:21][C:17]=2[CH:16]=1>C1COCC1>[Br:14][C:15]1[CH:24]=[CH:23][C:18]2[C:19]([CH2:5][C:3]#[N:4])=[CH:20][O:21][C:17]=2[CH:16]=1
Reactant: O=C1COc2cc(Br)ccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1coc2cc(Br)ccc12
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.7 g, 0.0173 mol) was washed with hexanes then suspended in THF (8 mL). Diethyl cyanomethylphosphonate (3.07 g, 0.0173 mol) was added dropwise and stirred 10 minutes to give clear yellow solution. A solution of 11-5 (3.38 g, 0.0158 mol) in THF (20 mL) was added dropwise, the solution stirred for 0.5 hour, then heated to reflux for 0.5 hour. A solution of 6N HCL (3.4 mL) was added and the THF was removed under vacuum. The concentrated solution was diluted with Et2O and washed with 4×30 mL 6N HCl, the ether layer was dried (MgSO4), filtered and evaporated. The residue was chromatographed (20% EtOAc/Hexanes) to give 11-6 as an orange solid.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH:13]3[NH:17][C:16](=[O:18])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.CI.[C:21]([O-])(O)=O.[Na+]>C1COCC1>[CH3:21][N:17]1[CH:13]([CH:10]2[CH2:9][CH2:8][C:7]3([O:3][CH2:4][CH2:5][O:6]3)[CH2:12][CH2:11]2)[CH2:14][CH2:15][C:16]1=[O:18]
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)N1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CCC1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (27 mg, 1.07 mmol, 95%) in THF under argon was added 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one (135 mg, 0.60 mmol, prepared in the Example 12 Step E). After stirring 1 hour at room temperature, Methyl iodide (0.07 mL, 1.12 mmol) was added dropwise and the reaction stirred at room temperature overnight. The reaction mixture was poured onto saturated NaHCO3 and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ethyl acetate/DCM).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:10]>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10]
Reactant: O=C(Cl)Oc1ccc(Cl)c(Cl)c1
Reactant: COP(OC)OC
Product: COP(=O)(OC)C(=O)Oc1ccc(Cl)c(Cl)c1

Procedure:
From 10.3 g (85 mmole) of trimethylphosphite and 13.5 g (60 mmole) of 3,4-dichlorophenyl chloroformate (100°, 2 hours). Yield 11.4 g (64%) B.p.0.04 164° C. nD20 1.5271. Solidifies to colourless crystals m.p. 58°-9° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17]O)[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][Br:1])[CH:11]=1
Reactant: OCc1cc(Br)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1CBr
Temperature: 5 °C
Reaction time: 1 h

Procedure:
4.0 g N-bromosuccinimide are slowly added to a solution of 5.0 g 1-bromo-4-chloro-3-hydroxymethyl-benzene and 5.9 g triphenylphosphine in 50 ml of tetrahydrofuran cooled to 5° C. After 1 h stirring at ambient temperature the precipitate is filtered off and the solvent is eliminated in vacuo. The residue is purified on silica gel (cyclohexane/ethyl acetate 50:1).