Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1.C[N:28]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:28])[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1cnc(-c2ccc(F)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2ccc(F)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(4-Fluorophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 50) in place of 6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). White solid (53 mg, 75%);
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.[CH2:18]([N:21]([CH2:29][C:30](N(OC)C)=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[CH2:20].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:18]([N:21]([CH2:29][C:30]([C:17]1[S:13][N:14]=[CH:15][CH:16]=1)=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:19]=[CH2:20]
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: c1cnsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCN(CC(=O)c1ccns1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
To a −78° C. solution of diisopropylamine (9.01 mL, 64.01 mmol) in tetrahydrofuran (80 mL) is added n-butyl lithium (30.78 mL, 49.24 mmol, 1.6 M in hexanes) drop wise under nitrogen. The resulting solution is stirred at −78° C. for 20 minutes and then a solution of isothiazole (4.19 g, 49.24 mmol) in tetrahydrofuran (10 mL) is added drop wise. The resultant white slurry is stirred for 30 minutes at −78° C. A solution of tert-butyl N-allyl-N-[2-(methoxy(methyl)amino)-2-oxo-ethyl]carbamate (6.36 g, 24.62 mmol) in tetrahydrofuran (50 mL) is then added to the slurry over a 15 minutes period. The reaction is then stirred for 30 minutes at −78° C., warmed to ambient temperature and is stirred for 30 minutes. Saturated ammonium chloride (200 mL) is then added. The resulting solution is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product is purified over silica gel with a 35 minute, 5% to 100% ethyl acetate in hexanes gradient, to give the title compound (6.00 g, 21.25 mmol, 86%). ES/MS (m/e): 283.0 (M+H).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:13].[CH2:20](O)[CH2:21][OH:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:20]1[CH2:21][O:22][C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)([CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[O:13]1
Reactant: O=C(Cn1ccnc1)c1ccc2ccccc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2cc(C3(Cn4ccnc4)OCCO3)ccc2c1

Procedure:
A mixture of 5.45 g. of 1-(2-naphthoylmethyl)imidazole hydrochloride, 2.49 g. ethylene glycol and 7.6 g. p-toluenesulfonic acid monohydrate in 50 ml. of toluene is heated overnight under reflux through a Dean-Stark trap. The trap is then replaced by a separatory funnel containing 4 A molecular seives and heating is continued for a further day. After cooling, the mixture is treated with 200 ml. of ethyl acetate, neutralized by pouring into excess aqueous potassium carbonate and the organic phase separated and dried (MgSO4) to afford a solution of 1-[2,2-ethylenedioxy-2-(2-naphthyl)ethyl]imidazole. The hydrochloride salt is prepared by dropwise addition of ethereal hydrogen chloride until precipitation is complete. Filtration and recrystallization from acetone/methanol gives 3.9 g. pure hydrochloride. m.p. 269°-270° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=O)[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:3]1.C(O)C.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>O>[C:8]1([CH:6]2[C:5](=[N:25][OH:26])[CH:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:3][C:2](=[O:1])[CH2:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CC(c2ccccc2)C(=O)C(c2ccccc2)N1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2)C(=NO)C(c2ccccc2)N1
Temperature: 25 °C
Yield: 13.6 %

Procedure:
In a round-bottom flask were placed 15 g (50.6 mmol) of the nitro lactam 4,6-diphenyl-5-nitro-2-oxopiperidine and 85 mL of methylene chloride. Potassium tert-butoxide (5.72 g, 50.6 mmol) was added and the mixture was stirred for 15 min. To this system was added 85 mL of methanol. The mixture was stirred for 15 min and the system was cooled to -78° C. Ozone was bubbled through the reaction mixture for 4 hours, nitrogen was bubbled through the mixture, 10 mL of dimethyl sulfide was added and nitrogen was bubbled through the mixture overnight. A mixture of water and methylene chloride was added to the system and the resulting solid (8.8 g of a mixture of the nitro lactam 4,6-diphenyl-5-nitro-2-oxopiperidine and 2,5-dioxo-4,6-diphenyl-piperidine was collected by suction filtration. The filtrate was concentrated with a rotary evaporator and the residue was partitioned between methylene chloride and water. The layers were separated, and the aqueous phase was extracted with two portions of methylene chloride. The combined organic fractions were dried (sodium sulfate) and concentrated to afford 5.14 g of crude 2,5-dioxo-4,6-diphenylpiperidine which was used immediately without further purification. Under a nitrogen atmosphere in a round-bottom flask were placed 2,5-dioxo-4,6-diphenylpiperidine (5.14 g, 19 mmol) and 75 mL of ethanol. A solution of 3.96 g (57 mmol) of hydroxylamine hydrochloride and 7.74 g (95 mmol) of sodium acetate in 25 mL of water were added and the reaction mixture was stirred at room temperature. The reaction mixture was concentrated to ca. 1/2 its initial volume, and the resulting precipitate was collected by suction filtration. This precipitate (1.5 g) was washed with saturated aqueous sodium bicarbonate, water and ether to afford 722 mg of 4,6-diphenyl-5-oximino-2-oxopiperidine as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:20]=[CH:19][C:11]([N:12]([CH2:16][CH2:17]I)[CH2:13][CH2:14]I)=[CH:10][CH:9]=1.[Br:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:38])[N:28]2C(OC(C)(C)C)=O)=[CH:24][CH:23]=1>CN(C=O)C.O>[Br:21][C:22]1[CH:30]=[C:29]2[NH:28][C:27](=[O:38])[C:26]3([CH2:17][CH2:16][N:12]([C:11]4[CH:19]=[CH:20][C:8]([Cl:7])=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)Cc2ccc(Br)cc21
Reactant: Clc1ccc(N(CCI)CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cc(Br)ccc2C12CCN(c1ccc(Cl)cc1)CC2
Temperature: 70 °C
Reaction time: 48 h
Yield: 17.6 %

Procedure:
Cesium carbonate (2.09 g, 6.4 mmol) was added in portions over 5 mins to a solution of 4-chloro-N,N-bis(2-iodoethyl)aniline (preparation 14c, 0.73 g, 1.68 mmol) and tert-butyl 6-bromo-2-oxoindoline-1-carboxylate (preparation 8a, 0.50 g, 1.60 mmol) in N,N′-dimethylformamide (20 mL) was added and the mixture was stirred for 48 hours. The mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was taken up in 1,4-dioxane (15 mL) and 5M aqueous hydrochloric acid (5 mL) and the mixture was stirred and heated to 70° C. After 30 minutes, the mixture was evaporated and partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was combined with an insoluble solid which separated and the mixture was evaporated. The residue was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (0.11 g, 17%) as a pink solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:21](Cl)=[O:22].C(=O)([O-])O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[N:15]3[C:16](=[CH:17][N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[C:21]1=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc2nccn12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1Cc2cccc3ncc(n23)C1=O
Temperature: 0 °C
Yield: 45 %

Procedure:
To a solution of 989 mg (4.0 mmol) of 5-(tert-butoxycarbonylamino)methylimidazo[1,2-a]pyridine and 2200 mg (18.0 mmol) of 4-(N,N-dimethylamino)pyridine in 25 ml of chloroform was added dropwise 1.34 ml (12.0 mmol) of trichloroacetyl chloride at room temperature. The reaction mixture was heated for 5 hours under reflux. The reaction mixture was poured into ice-water. The mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. To the mixture was added 100 ml of chloroform for extraction of the desired compound. The organic layer was washed with 100 ml of a saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1) to give 492 mg of the desired compound (45.0%, pale yellow solid).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)[NH:20][CH:19]=1)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a stirred solution of (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-dibenzylamino-1H-indole (1.50 g, 2.75 mmol) in anhydrous tetrahydrofuran (30 mL) was added lithium borohydride (0.24 g, 11.0 mmol, 4.0 eq) as a solid. The resulting reaction mixture was heated at reflux for 4 hours. A saturated solution of sodium hydrogen carbonate (10 mL) was then added, and this mixture was stirred at room temperature for 30 minutes. This aqueous mixture was then extracted with ethyl acetate (3×25 mL), and the organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. Column chromatography of the residue using silica gel (approximately 50 g) and elution with ethyl acetate/hexanes [1:3] afforded the title compound (1.02 g, 70%) as a white foam: FAB LRMS (m/z, relative intensity) 530 (MH+, 87), 529 (M+, 100), 439 (10), 409 (10), 325 (32), 235 (20).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[N:15]1C2C(=CC=C3C=2N=CC=C3)C=C[CH:16]=1.C([Cu])#N>CC(N(C)C)=O>[N+:12]([C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]([C:16]#[N:15])=[N:3][CH:4]=1)([O-:14])=[O:13]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O=[N+]([O-])c1cnc(Br)c(C(F)(F)F)c1
Agent: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 67 %

Procedure:
The crude 2-bromo-5-nitro-3-(trifluoromethyl)pyridine 21 is dissolved in dimethylacetamide (DMA) and phenanthroline (0.2 equivalents) is added. The mixture is heated to 160° C. and CuCN (2 equivalents) is added. The mixture is stirred for 40 minutes. Chromatography is performed to produce the 5-nitro-3-(trifluoromethyl)pyridine-2-carbonitrile 22 in a yield of 67%.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][NH:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:26]=O>C(O)=O>[CH3:26][N:18]1[CH2:19][C:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([NH:15][S:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=2)(=[O:14])=[O:13])[CH2:17]1
Reactant: C=O
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CNC2)cc1
Solvent: O=CO
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CN(C)C2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Ethyl 2-(3-(4-pentylphenylsulfonamido)azetidin-3-yl)acetate (35 mg, 0.095 mmol) was dissolved into formic acid (2 mL). The solution was treated with formaldehyde (16 mg of 36% solution, 0.19 mmol). The mixture was stirred at 110° C. for 2 h. Solvent was removed under vacuum. The residue was added CH2Cl2(10 mL) and washed with saturated sodium bicarbonate (3×5 mL) and H2O (10 mL) dried over MgSO4 and concentrated. The residue was loaded onto a silica gel column and eluted with EtOAc/hexane (30% to 50%) to obtain the title compound as a white powder (20 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, 2H, J=7.6 Hz), 7.30 (d, 2H, J=7.6 Hz), 4.03 (q, 2H, J=7.2 Hz), 3.36 (d, 2H, J=7.2 Hz), 3.23 (d, 2H, J=7.2 Hz), 2.95 (s, 2H), 2.68 (t, 2H, J=7.6 Hz), 2.30 (s, 3H), 1.67-1.60 (m, 2H), 1.33 (br, 4H), 1.19 (t, 3H, J=7.2 Hz), 0.92 (m, 3H); MS ESI 383.2 [M+H]+, calcd for [C19H30N2O4S+H]+383.20.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.[I-].[Na+].I>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:24][C:23]4[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 130 °C
Yield: 42.6 %

Procedure:
4-Chloro-7-(3-chloro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine (100 mg, 0.35 mmol) was dissolved in acetonitrile (2 mL). To the mixture was added 4-flouroaniline (0.067 mL, 0.71 mmol), sodium iodide (80 mg, 0.53 mmol) and HI (47%, 0.2 mL). The mixture was heated in a sealed tube at 130° C. for 10 minutes in a Personal Chemistry Microwave (Smith Creator). The solvent was removed under vacuum and the resulting orange residue dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography over silica gel using a 0-100% ethyl acetate-hexane gradient to give the product as an off white solid (53 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[NH:11][C:10]([CH:21]([CH3:23])[CH3:22])=[C:9]2[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.O.N(OC)=O.[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:10]([CH:21]([CH3:22])[CH3:23])[N:11]=[C:12]([CH:18]([CH3:19])[CH3:20])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)OC)C1c1ccc(F)cc1
Agent: CON=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Temperature: 20 °C
Yield: 94.9 %

Procedure:
In a 4 1 glass reactor, 750 g 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl)-1,4-dihydropyridine were mixed with 2250 g water and 245 g of acetic acid. Thereafter 7 mols of methyl nitrite were introduced at 58 to 60° C. After cooling to 20° C. 363 g of 45% by weight strength aqueous sodium hydroxide were added to result in an increase of the pH up to 9. The resulting suspension was filtered and the product that has been filtered off was washed twice with in each case 800 ml of water and then dried at 50 to 60° C. under reduced pressure. 708 g of 4-(4-fluoropheny) -2,6-diisopropyl-3,5-di(methoxy-carbonyl)-pyridine were isolated, which corresponds to a yield of 95% of theory.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]#N)[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].C([Al+]CC(C)C)C(C)C.C[OH:59].[H-]>C1C=CC=CC=1.O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=[O:59])[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C#N)c1)OCCCCCCCCCCCCCCCC
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C=O)c1)OCCCCCCCCCCCCCCCC
Yield: 40 %

Procedure:
A solution of 1,2-di-O-(n-hexadecyl)-3-O-(3-cyanobenzyl)-glycerol (5.0 g., 7.6 mmoles) and diisobutylaluminum hydride (1.17 g., 8.2 mmoles) in benzene (25 ml.) was stirred for 16 hours at ambient temperature. The reaction mixture was treated with methanol (4.22 ml.) and water (2.5 ml.) and stirred to decompose unreacted hydride, and then filtered and extracted with benzene (3×25 ml.). The combined benzene extract was dried (Na2SO4), filtered and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene) [2.0 g., 40% yield, oil, ir (CHCl3) 1700 cm-1, n.m.r. (CDCl3) δ10.1 (s, 1, --ArCHO)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccc(Sc2ccc(Br)cc2)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(Cl)cc3)cc2)c1C
Yield: 35.9 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(4-chlorophenylsulfanyl)-benzene (0.24 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(4-chloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.089 g, 34%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)=[CH:18][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1([O-])O[O:37]1.O.O.O.O.[Na+].CO>C(O)(=O)C.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:35])[CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)=[CH:20][CH:21]=1)=[O:37])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(NC(=O)Cn2ccc3cc(F)ccc32)cc1)C(=O)O
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CS(=O)Cc1ccc(NC(=O)Cn2ccc3cc(F)ccc32)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To a stirred solution of (2R)-2-tert-butoxycarbonylamino-3-{4-[2-(5-fluoro-indol-1-yl)-acetylamino]-benzylsulfanyl}-propionic acid (460 mg, 0.917 mmol) in acetic acid (20 mL) was added sodium perborate tetrahydrate (148 mg, 0.963 mmol). This solution was stirred at 40° C. until complete (TLC: 20% methanol in dichloromethane), then cooled to room temperature, diluted with ethyl acetate (100 mL), washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2; 10-20% methanol in dichloromethane as eluent) yielded the titled compound as a 1:1 mixture of diastereomers as an off-white solid. Rf 0.09 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 7.32 (2H, d, J=9 Hz, Ar—H), 7.44-7.34 (2H, m, Ar—H), 7.31-7.19 (3H, m, Ar—H), 6.94 (1H, td, J=9, 2.5 Hz, 6.43 (1H, d, J=3 Hz, Ar—H), 5.07 (2H, s, NCH2CO), 4.23-3.80 (3H, m, PhCH2S and CHN), 2.87 (2H, m, CH2CHN), 1.37 and 1.35 (both 4.5H, s, CMe3 diastereomers); ESI-LCMS e/z calculated for C25H28FN3O6S 517.168, found 518 (M+H)+, 540 (M+Na)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[OH-].[K+].S(O[CH:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:22])(C1C=CC(C)=CC=1)(=O)=O.O>O1CCOCC1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:22]
Reactant: OCCOCCO
Reactant: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(COCc1ccccc1)OCCOCCO
Temperature: 63 °C
Reaction time: 13.5 h
Yield: 36.7 %

Procedure:
HO(CH2)2O(CH2)2OH (21.2 g), potassium hydroxide (11.2 g) and dioxane (100 ml) were charged into a four necked flask and heated to an internal temperature of 63° C. to dissolve potassium hydroxide. A solution obtained by dissolving 32.0 g of TsOCH(CH3)CH2OCH2Ph obtained in Example 2-1 in dioxane (50 ml), was dropwise added over a period of 30 minutes, and while maintaining the internal temperature within a range of from 60 to 100° C., stirring was continued for 13.5 hours. The mixture was left to cool, then added to water (200 ml) and extracted three times with dichloromethane (50 ml). The organic layer was washed with water (20 ml). It was dried over magnesium sulfate, filtered and then concentrated by an evaporator to obtain a crude product (52 g). it was purified by silica gel chromatography to obtain 9.32 g of the above-identified compound.