Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:18](Br)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[O:20]1[C:24]2([CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>CCCCCC.C1COCC1>[C:9]1([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:27]2([OH:30])[CH2:28][CH2:29][C:24]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:25][CH2:26]2)[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccccc1Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2Cc2ccccc2)CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 42.3 %

Procedure:
26.25 ml of 2.4 molar solution of n-butyllithium in n-hexane is added dropwise with stirring at -50° to -40° C. under dry nitrogen to a solution of 10.87 g of 2-bromodiphenylmethane in 25 ml of dry THF. The mixture is stirred at -50° to -40° C. for one hour after addition is completed. A solution of 6.30 g of 1,4-dioxaspiro(4.5)decan-8-one in 20 ml of dry THF is added dropwise at -50° to -40° C. This mixture is stirred overnight (16 hours) at -70° C. to +10° C., and quenched with 50 ml of water. The organic phase is diluted with 100 ml of ether and washed three times with 50 ml portions of water. The aqueous phase and the washing water are extracted with 100 ml of CH2Cl2, which is washed twice with 50 ml portions of water. The combined organic phases are dried over Na2SO4 and evaporated to an oil. This oil is treated with ether/hexane (20 ml/50 ml) mixture to give 6.0 g (45.8%) yield of crystalline product which is recrystallized from ether/hexane (10 ml/40 ml) to provide 5.53 g (42.2% yield) of 8-[2-(phenylmethyl)phenyl]-1,4-dioxaspiro(4.5)decan-8-ol, m.p. 97°-98° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[N:15]O)[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1>CO.O1CCCC1.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[CH:12]([NH2:15])[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COCCOc1cccc2c1C(=NO)CO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cccc2c1C(N)CO2
Reaction time: 120 h
Yield: 109.9 %

Procedure:
A mixture of the above described 4-(2-methoxy-ethoxy)-benzofuran-3-one oxime (1.19 g, 5 mmol) in methanol (100 mL) and tetrahydrofuran (100 mL) with 10% palladium on carbon (1.42 g) was hydrogenated at 23° C. and atmospheric pressure for 5 days. Filtered the catalyst off, washed with tetrahydrofuran, evaporated the filtrate totally and dried in high vacuum to give the title compound as a red oil (1.15 g, 90%, ca. 90% purity, contains residual starting material); MS: m/e=193.1 (M−NH2+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.S(C)C>C1COCC1>[NH2:11][CH2:10][CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:12]
Reactant: N#CCC(O)c1cccc(Br)c1
Solvent: CSC
Solvent: C1CCOC1
Product: NCCC(O)c1cccc(Br)c1
Temperature: 0 °C

Procedure:
To a solution of nitrile 23 (22.4 g, 99 mmol) in anhydrous THF (200 mL) under nitrogen was added BH3.SMe2 (28.4 mL, 297 mmol) via addition funnel over a period of 1 h. The mixture was then refluxed for 14 h. After cooling to 0° C., the excess borane was quenched by slow addition of methanol. This was concentrated to dryness under reduced pressure. The process was repeated six times. This was followed by the dissolution of the crude product in 6N HCl and extraction with DCM. Aqueous layer was basified to pH 10 with conc. NH4OH and extracted with DCM. Combined organics were dried over Na2SO4. The solution was filtered and concentrated under reduced pressure to give 24 as clear oil. Yield (15.94 g, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.42 (bd, J=7.6 Hz, 1H), 7.22-7.34 (m, 2H), 4.69 (m, 1H), 2.67-2.74 (m, 2H), 1.65-1.77 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][OH:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].Cl.C(O[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=N)C.C(N(CC)CC)C>O>[CH3:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C@H:3]2[O:4][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:1][C@@H:2]2[CH2:15][OH:16])=[CH:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1

Procedure:
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) (about 10 g, 0.04077 moles) is reacted at about 0° C. in a reaction vessel with 2,2-dichloro-ethanimidic acid ethyl ester hydrochloride (Compound IV hydrochloride wherein R2 is dichloromethyl and R4 is ethyl) (about 8.6 g, 0.0448 moles) in 1,2-dichloromethane (about 250 mL) containing triethylamine (about 4.1 g, 0.04077 moles). Next, water (about 125 mL) is added. The resulting solids are filtered, then dried to yield (4R,5R)-2-(Dichloromethyl)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is dichloromethyl).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.B.C1COCC1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
4-Bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) was dissolved in dry THF (100 mL) and cooled to 0° C. A 1M solution of BH3.THF in THF (31.85 mL, 31.85 mmol) was slowly added. The reaction was stirred overnight, allowing it to gradually reach room temperature. K2CO3 solid (1 g) and H2O (100 mL) were added and the reaction was stirred for 30 minutes. THF was evaporated and residue extracted with EtOAc (30 mL). The organic phase was washed with 1N HCl (3×50 mL), brine (3×50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (30% EtOAc in hexanes) to give the product (2.80 g, 50%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.73 (d, J=5.8 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.1 Hz, 1.7), 7.52 (d, J=1.7 Hz, 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28]([S:31][CH2:32][CH:33]([C:37]([F:40])([F:39])[F:38])[C:34](O)=[O:35])(=[O:30])[CH3:29]>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:34](=[O:35])[CH:33]([C:37]([F:38])([F:39])[F:40])[CH2:32][S:31][C:28](=[O:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C(=O)O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 0 °C

Procedure:
L-proline tert-butyl ester (5.1 g.) is dissolved in dichloromethane (40 ml.) and the solution is stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-trifluoromethylpropanoic acid (6.5 g.) in dichloromethane ( ml.). After fifteen minutes stirring in the ice bath and sixteen hours at room temperature, the precipitate formed is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to give N-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline tertbutyl ester.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1.CO>C1COCC1>[OH:5][CH2:4][C:3]1[C:2]([OH:1])=[N:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cccnc1O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cccnc1O
Temperature: 80 °C
Yield: 28.6 %

Procedure:
To a suspension of 2-Hydroxynicotinic acid (1.01 g, 7.26 mmol) in THF (2 mL) was added BH3.THF (1.0 m in THF, 18 mL, 18 mmol) and the mixture was heated to 80° C. for 18 hours. MeOH (2 mL) was added and the mixture was heated to 80° C. for an additional 2 hours before being cooled to room temperature and concentrated under reduced pressure. The resultant crude syrup was repeatedly dissolved in MeOH (5 mL) and concentrated (3×). Purification by column chromatography on silica gel (20:1—CH2Cl2:MeOH) afforded the desired alcohol (260 mg, 29%) as a white solid. 1H NMR (CD3OD) δ 4.50 (s, 2H), 6.43 (t, 1H, J=6.6 Hz), 7.34 (d, 1H, J=4.5 Hz), 7.65 (d, 1H, J=6.3 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2].[H][H]>CO.O=[Pt]=O.[Rh]>[CH:1]([O:4][C:5]([C@H:7]1[C@@H:12]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)OC(=O)c1ncccc1C(C)(C)O[SiH2]C(C)(C)C
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CO
Product: CC(C)OC(=O)[C@@H]1NCCC[C@@H]1C(C)(C)O[SiH2]C(C)(C)C

Procedure:
3-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridine-2-carboxylic acid isopropyl ester (800 mg, 2.6 mmol) was dissolved in 6 mL of methanol in a pressure hydrogenation vessel to which 100 mg of PtO2 was added (Rh on alumina may also be used). The vessel was shaken under 50 psi of hydrogen for 5 hrs. The suspension was filtered through Celite and the solution was concentrated in vacuo to provide the desired compound, cis-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidine-2-carboxylic acid isopropyl ester. MS 316 (M+1). Without further purification the product was acylated under standard conditions with 1-(4-chloro-phenyl)-cyclobutanecarbonyl chloride (itself prepared from the carboxylic acid using excess thionyl chloride at reflux for 1 hr. followed by concentration in vacuo). Water/ether extractive workup gave, after concentration of the organic layers in vacuo and chromatography on silica gel, the desired compound, cis-3-(tert-Butyl-dimethyl-silanyloxymethyl)-1-[1-(4-chloro-phenyl)-cyclobutanecarbonyl]-piperidine-2-carboxylic acid isopropyl ester (720 mg, 55% for two steps) MS 508 (M+l). The cis stereochemistry was assigned based upon a 1H NMR coupling constant of 4 Hz for the proton at C-2 of the piperidine ring.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH:34]1([NH:37][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:21])=[O:22])[CH2:36][CH2:35]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC4CC4)c3)n2)n1
Yield: 43.2 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available cyclopropylamine (0.14 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.090 g, 43%) as a white solid. MS (ISP) 510.2 [(M+H)+]; mp 150° C.
Reaction SMILES: C[Si]([C:5]1[NH:13][C:12]2[C:11](=[O:14])[NH:10][C:9]([N:15]([Si](C)(C)C)[Si](C)(C)C)=[N:8][C:7]=2[N:6]=1)(C)C.[C:24]([O:32][CH2:33][CH2:34][O:35][CH2:36]Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([O:32][CH2:33][CH2:34][O:35][CH2:36][N:6]1[CH:5]=[N:13][C:12]2[C:11](=[O:14])[NH:10][C:9]([NH2:15])=[N:8][C:7]1=2)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Si](C)(C)c1nc2nc(N([Si](C)(C)C)[Si](C)(C)C)[nH]c(=O)c2[nH]1
Reactant: O=C(OCCOCCl)c1ccccc1
Product: Nc1nc2c(ncn2COCCOC(=O)c2ccccc2)c(=O)[nH]1
Yield: 32 %

Procedure:
A mixture of guanine (2.0 g), ammonium sulfate (1.5 g), and hexamethyldisilazane (126 g) was heated at reflux under nitrogen overnight. Excess hexamethyldisilazane was removed by distillation at reduced pressure. Dry benzene (10 ml) was added to the residual oil and any remaining ammonium sulfate removed by filtration. To this solution was added triethylamine (4 ml) and a solution of 2-benzoyloxyethoxymethyl chloride (2.8 g) in dry benzene (15 ml) and the mixture heated at reflux under nitrogen overnight. The solvent was evaporated in a rotary evaporator at reduced pressure and the residue dissolved in 95% ethanol. The solution was warmed on a steam bath for 1/2 hour to effect hydrolysis of the silyl groups. The ethanol was then evaporated and the residual solid thoroughly washed with water, filtered and dried. Recrystallization from methanol and then from water (residual guanine was insoluble in the hot solvents and was removed by filtration) afforded 9-(2-benzoyloxyethoxymethyl)guanine (0.58 g., 14% of theoretical), m.p. 222°-226° C. A later condensation of the tris-(trimethylsilyl) guanine with a 60% excess of 2-benzoyloxyethoxymethyl chloride gave a 32% yield of 9-(2-benzoyloxyethoxymethyl)guanine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH2:12][CH2:11][Br:10]
Reactant: BrCCBr
Reactant: Oc1c(Br)cccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1c(Br)cccc1Br

Procedure:
A mixture of 2,6-dibromophenol (10.2 g, 40 mmol), 1,2-dibromoethane (7.6 g, 40 mmol) and NaOH (1.76 g, 44 mmol) in water was heated at reflux overnight under stirring. The mixture was cooled, extracted with diethyl ether (2×100 mL), the extract washed with aqueous NaOH, brine, dried (MgSO4) and concentrated to give the product as a pale yellow oil. Yield: 10.0 g (70%). 1H NMR (400 MHz, CDCl3) δ 3.73 (t, 2H), 4.31 (t, 2H), 6.88 (t, 1H), 7.50 (d, 2H). *Previously reported in Tetrahedron Lett. 1998, 39, 2219-2222.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:24]([CH3:26])[CH3:25])C(OCC[Si](C)(C)C)=O)[C@H:10]([CH2:27][N:28]([CH:38]2[CH2:40][CH2:39]2)[C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:24]([CH3:25])[CH3:26])[C@H:10]([CH2:27][N:28]([CH:38]2[CH2:39][CH2:40]2)[C:29](=[O:37])[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)Cc1ccccc1)C1CC1)C(=O)OCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)Cc1ccccc1)C1CC1
Reaction time: 8 h

Procedure:
To a solution of (3R,4S)-3-[(cyclopropyl-phenylacetyl-amino)-methyl]-4-{[isopropyl-(2-trimethylsilanyl-ethoxycarbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (2.55 g, 4.44 mmol) in CH3CN (30 mL) is added tetrabutylammonium fluoride trihydrate (4.34 g, 13.33 mmol) under a nitrogen atmosphere. The reaction mixture is stirred overnight at reflux. The solvent is removed under vacuum and Water and CH2Cl2 are added, the layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH/NH4OH 98:2:1) to give the title product. TLC, Rf (CH2Cl2/MeOH/NH4OH 98:2:1)=0.11. MS (LC-MS): 430.2 [M+H]+; tR (HPLC, C18 column, 20-100% CH3CN/H2O/16 min, 100% CH3CN/1.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.90 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Product: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 4 h

Procedure:
In this example, 6.05 g of 4-benzyloxyphenylacetic acid obtained as in Example 1, is dissolved in 125 ml of thionyl chloride, and boiled for 4 hours. Excess thionyl chloride is distilled off under reduced pressure, and the residue is dried, whereby 4-benzyloxyphenylacetic acid chloride is obtained. The thus obtained product is then dissolved in 25 ml of anhydrous benzene, and the resulting solution is added dropwise to 8.3 g of triethyl phosphite in a nitrogen gas stream with stirring under ice cooling.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=2[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:41]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:41])[C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:21])[CH3:22])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C:12]=2[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)Nc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)N(C)c1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
To a stirred solution of ethyl 3-{3-[(4-bromophenyl)carbamoyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (100 mg, 0.18 mmol) in DMF (2 mL) is added NaH (60% dispersion in mineral oil, 7.7 mg, 0.19 mmol) at 0° C. The suspension is stirred for 10 minutes then iodomethane (12.0 μl 0.19 mmol) is introduced and the reaction mixture is stirred overnight. The mixture is quenched with water, extracted with EtOAc, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 40% EtOAc in hexanes) gives ethyl 3-{3-[(4-bromophenyl)(methyl)carbamoyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (75 mg, 73%) that is dissolved in THF (8 mL), MeOH (1 mL), and water (1 mL) and treated with 10M aqueous NaOH (0.1 mL). The mixture is stirred for 16 h then concentrated and acidified with HOAc. The resulting solid is filtered, washed with water, collected, and dried to give the title compound (50 mg, 70%).
Reaction SMILES: [Br:1]([OH:4])(=[O:3])=[O:2].[NH2:5][CH2:6][CH2:7][C@H:8](O)[CH2:9]O.C(O)(=O)C.[Br:16](O)(=O)=O>C(O)C>[Br:1]([O:4][C@@H:8]([CH2:7][CH2:6][NH2:5])[CH2:9][Br:16])(=[O:3])=[O:2]
Reactant: [O-][Br+2]([O-])O
Reactant: NCC[C@H](O)CO
Solvent: CCO
Solvent: CC(=O)O
Product: NCC[C@@H](CBr)O[Br+2]([O-])[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-Amino-(S)-1,2-butandiol bromate 6 (0.537 mol, 100 g) and an acetic acid solution (185 g) with 33% bromic acid dissolved therein were added to a 500□ round-bottom flask and the mixture was agitated at 40° C. for 2 hours. After the preparation of an intermediate was confirmed by Thin Layer Chromatography (TLC), anhydrous ethanol (285 g) was added thereto. The reaction mixture was agitated under reflux for 3 hours to complete the reaction and then concentrated under reduced pressure to completely remove the solvent, thereby obtaining 115 g of crude 4-amino-1-bromo-(S)-2-butanol bromate 7.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.[CH3:21][OH:22].O>C1(C)C=CC=CC=1>[OH:2][CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:22][CH3:21])[C:5]=2[CH2:4][O:3]1
Reactant: O=C1OCc2ccccc21
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1COC2O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The phthalide (346 mg) prepared in reference example 33 was dissolved in toluene (20 ml). The solution was cooled to -78° C. A 1.76N solution of diisobutylaluminum hydride (DIBAL) in toluene (1.43 ml) was added dropwise to the cooled solution. The mixture was stirred for 30 min. at -78° C. Methanol (0.2 ml) was added to the reaction solution to decompose the excess DIBAL. Water was added to the reaction solution. A temperature of the solution was up to room temperature. The solution was stirred for 30 min. at room temperature. The reaction solution was dried over anhydrous sodium sulfate, washed with ethyl acetate and evaporated to give the residue contained the title compound having the following physical data. The residue was used in next reaction without purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>S(Cl)(Cl)=O.C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][C:16]([C:10](=[O:12])[CH2:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCc1ccccc1
Reactant: N#Cc1cccc(CC(=O)O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Temperature: 0 °C
Yield: 20.4 %

Procedure:
First, 3-cyanophenylacetic acid (3 g, 0.019 mol) is heated under reflux in thionyl chloride (50 ml) for 90 minutes. The excess thionyl chloride is then removed by distillation and the residual acid chloride added in one portion to a solution. 1-phenylpentane (2.76 g, 0,019 moles) in methylene chloride (10 ml). Anhydrous aluminum chloride (2.98 g) is added in small portions over 10 minutes. The reaction mixture is then heated under reflux for 1 hour, cooled and poured into a mixture of ice water (250 ml) and concentrated hydrochloric acid (50 ml). The mixture is extracted with ether (2×100 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on silica (hexane: ethyl acetate at 90:10 ) to yield 3-(4-pentylphenacyl) benzonitrile (1.13 g, m.p. 73° C.). This nitrile is heated under reflux in a mixture of 75% sulfuric acid (8 g) and acetic acid (8 g) for 90 minutes. The reaction mixture is then diluted with water (100 ml) and extracted with ether (2×75 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane to provide 3-(4-pentylphenacyl)benzoic acid (0.97 g), m.p. 109°-111° C., which was identified by IR and NMR spectroscopy.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10]1)=[O:8])([CH3:3])[CH3:2].[CH3:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](O)=[C:32]([F:37])[CH:31]=1)=[O:29]>>[F:37][C:32]1[CH:31]=[C:30]([C:28](=[O:29])[CH3:27])[CH:35]=[CH:34][C:33]=1[O:14][CH:11]1[CH2:12][CH2:13][N:9]([C:7](=[O:8])[C:6]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])[CH2:10]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: CC(=O)c1ccc(O)c(F)c1
Product: CC(=O)c1ccc(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)C2)c(F)c1
Yield: 62 %

Procedure:
Prepared in analogy to Example 3(c) from rac-methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl ester (Example 14(a)) and 3-fluoro-4-hydroxyacetophenone. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 62%). MS (m/e): 464.0 (M+H+, 100%).