Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([CH3:29])[C:9]=3[N:10](COC)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CC1(C)[N:36]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[C@@H:35]([CH2:47]OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:34][O:33]1>O1CCOCC1.CN(C=O)C.CO>[CH2:40]([O:39][C:37]([NH:36][C@H:35]([CH2:34][OH:33])[CH2:47][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[NH:10][C:9]2[C:22]([CH3:29])=[C:23]([C:25]([O:27][CH3:28])=[O:26])[S:24][C:8]=2[C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COCn1c(-c2ccccc2O)c(C2CCCCC2)c2sc(C(=O)OC)c(C)c21
Reactant: CC1(C)OC[C@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H](CO)NC(=O)OCc3ccccc3)[nH]c2c1C
Temperature: 50 °C
Yield: 31 %

Procedure:
Methyl 6-cyclohexyl-5-(2-hydroxyphenyl)-4-(methoxymethyl)-3-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate was dissolved in dioxane (0.036M) and the same volume of 6N HCl was added. The mixture was subjected to microwave irradiation (10 min @ 130° C.). All volatiles were evaporated and the product was enriched by prep. RP-HPLC. The product-containing fractions were lyophilised to give a green glassy solid. This material was dissolved in DMF (0.16M) and benzyl (4R)-2,2-dimethyl-4-({[(4-nitrophenyl)sulfonyl]oxy}methyl)-1,3-oxazolidine-3-carboxylate (excess, prepared according to Synthesis 1996, 189 in analogy to benzyl (4R)-2,2-dimethyl-4-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-oxazolidine-3-carboxylate from benzyl (4S)-4-(hydroxymethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate and substituting tosyl chloride with 4-nitrobenzenesulfonyl chloride) was added. The suspension was heated to 50° C. overnight. All volatiles were evaporated i. vac. and the residual material was purified by prep. RP-HPLC. The product fractions were evaporated and the residual material lyophilised from MeCN/water. A beige solid was obtained, which was dissolved dry MeOH (0.2M) and 1.25M HCl in MeOH (excess) was added. The solution was left stirring at RT. After 3 h all volatiles were evaporated and the residual material was subjected to purification by chromatography (PE:EtOAc, 6:4). After evaporation of the product fractions the product was obtained as a yellow powder (31%). MS (ES+) m/z 577 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=O)[C:13]([C:25](O)=[O:26])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:28]([NH2:31])[CH2:29][NH2:30].C(Cl)Cl.O>ClCCCl>[Si:1]([O:8][CH2:9][C:10]1[N:14]2[CH2:15][C:16]3([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[NH:31][CH2:28][CH2:29][N:30]3[C:25](=[O:26])[C:13]2=[CH:12][CH:11]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: NCCN
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)n1CC(=O)c1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc2n1CC1(c3ccc(Cl)cc3)NCCN1C2=O
Yield: 42 %

Procedure:
5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (˜70% pure, 268 mg, 0.46 mmol) was stirred at reflux in 1,2-dichloroethane with ethane-1,2-diamine (938 mL) for 18 h. The resultant suspension was concentrated in vacuo to give a residue. The mixture was treated with CH2Cl2 (30 mL) and water (30 mL) to form an emulsion that was filtered through a filter system. The organic layer was then separated. The aqueous layer was extracted with further CH2Cl2 (2×30 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a waxy solid. Purification by flash column chromatography (Biotage SP4, 4 g cartridge, 0-5% MeOH gradient in CH2Cl2) gave 8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]-pyrazin-5-one as a off-white solid (85%, yield 42%). 1H NMR (400 MHz, MeOD): δ−0.11 (s, 3H), −0.04 (s, 3H), 0.79 (s, 9H), 2.79 (dt, 1H, J 12.2, 8.2 Hz), 3.32-3.37 (m, 1H), 3.51 (ddd, 1H, J 11.0, 7.9, 3.1 Hz), 3.71-3.79 (m, 1H), 4.20 (d, 1H, J 12.5 Hz), 4.44 (d, 1H, J 13.2 Hz), 4.56 (d, 1H, J 13.2 Hz), 4.76 (d, 1H, J 12.5 Hz), 6.05 (d, 1H, J 3.8 Hz), 6.77 (d, 1H, J 3.8 Hz), 7.25-7.35 (m, 4H).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([Cl:16])=[CH:8][CH:7]=2)[CH2:2]1.[CH3:17][C:18]([NH2:29])([CH3:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>>[ClH:16].[OH:1][CH:3]([CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([Cl:16])=[CH:8][CH:7]=1)[CH2:2][NH:29][C:18]([CH3:28])([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: Clc1ccc(OCC2CO2)c2ccccc12
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)c3ccccc23)cc1
Product: Cl
Yield: 43.4 %

Procedure:
Using the method of Example 5, supra, 1,2-epoxy-3-[4-chloro-(1-naphthoxy)]propane (469 mg, 2 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (120 mg, 0.67 mmol) yielded, after preparative TLC and RP-HPLC, 131 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 414 (M+, 0.5), 398 (1), 292 (100), 121 (33), 71 (43).
Reaction SMILES: [C:1]([CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])#[N:2].[ClH:10].CCCCCC.[CH3:17][OH:18]>C1(C)C=CC=CC=1>[ClH:10].[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:1](=[NH:2])[O:18][CH3:17]
Reactant: CO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=N)CC(=O)C(C)(C)C
Reaction time: 25 h
Yield: 97.5 %

Procedure:
To a suspension of cyanopinacolone (25.034 g) in anhydrous toluene (50 ml) and anhydrous methanol (8.9 ml) is added gaseous hydrogen chloride (9.9 g) with cooling and stirring at 5° to 10° C., and the whole mixture is allowed to stand at 5° to 10° C. for 25 hours. The reaction mixture is mixed with n-hexane and the precipitated hydrochloride is filtered and washed with ethyl acetate to give methyl 4,4-dimethyl-3-oxopentanimidate hydrochloride (37.746 g) as crystals melting at 104° to 104.5° C. (decomp.). Yield is 97.5%.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:30])=[C:16]([C:25](OCC)=[O:26])[C:17](=[O:24])[C:18]2([CH2:22][CH3:23])[CH3:21])=[CH:13][CH:12]=1.Cl.[C:32]([O:36][C:37](=[O:40])[CH2:38][NH2:39])([CH3:35])([CH3:34])[CH3:33]>O1CCOCC1>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:30])=[C:16]([C:25]([NH:39][CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])=[O:26])[C:17](=[O:24])[C:18]2([CH2:22][CH3:23])[CH3:21])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(CC)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC1(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 85.4 %

Procedure:
DIPEA (0.253 mL, 1.45 mmol, 1.2 eq) was added to a mixture of ethyl 7-chloro-1-ethyl-4-hydroxy-1-methyl-2-oxo-naphthalene-3-carboxylate (373 mg, 1.21 mmol) and glycine tert-butyl ester hydrochloride (0.243 g, 1.45 mmol) in dioxane (8 mL). The reaction mixture was stirred at 80° C. for 3.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow oil. The crude oil was purified by silica flash chromatography (0-75% DCM/hexane) to give the desired compound as a white solid (407 mg). MS (m/e)=338.1 (M+H-tBu)+.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:21]([N:23]([CH3:34])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:40]([O-:44])([O-])(=[O:42])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:40]([C:15]1[C:16]([C:21]([N:23]([CH3:34])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:44])=[O:42])[CH3:3]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1cccnc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.33 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.20 g of 3-ethylsulfanyl-N-methyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (Compound of Present Invention 16) and 3 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.17 g of 3-ethylsulfonyl-N-methyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 17).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH:8]1[O:12][CH2:11][CH2:10][O:9]1)([CH3:7])[CH3:6].[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O.O>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][CH2:2][N:13]=[N+:14]=[N-:15]
Reactant: CC(C)(CCCCl)C1OCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(CCCN=[N+]=[N-])C1OCCO1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of 0.74 g (3.8 mmol) of 2-(4-chloro-1,1-dimethylbutyl)-1,3-dioxolane and 0.50 g (7.7 mmol) of sodium azide in 5 mL of DMSO was heated to 100° C. with stirring. After 18 hours the solution was cooled to RT, diluted with water, and the mixture extracted with ether (3×). The combined ether extracts were washed with water (3×), dried over MgSO4, and concentrated in vacuo to afford 0.69 g (90%) of the desired compound as a light yellow liquid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]=[C:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]2.C([Li])CCC.[CH:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37]>C1COCC1>[OH:39][CH:34]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]=[C:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]2)[CH2:35][CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)CC=O
Reactant: CC(C)C1=NCCc2ccc(C=Cc3cc(I)c4cc(C#N)ccc4c3)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1cc(C=Cc2ccc3c(c2)C(C(C)C)=NCC3)cc2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of Example 8E (250 mg, 0.52 mmol) in THF (5 mL) at −90° C. was treated with 2.5M n-butyllithium in hexanes (0.210 mL, 0.525 mmol), stirred for 2 minutes, treated with isovaleraldehyde (0.056 mL, 0.63 mmol), and stirred for 30 minutes. The reaction was warmed to room temperature, quenched with water, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C>ClC(Cl)C.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)cc2nc[nH]c12
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(Br)cc2nc[nH]c12
Reaction time: 0.17 h

Procedure:
To a suspension of crude 5-Bromo-1H-benzo[d]imidazole-7-carboxylic acid (247 mg, 0.81 mmol, 77% pure) in dichloroethane under N2 with stirring was added oxalyl chloride (0.5 mL, 5.6 equiv). Added one drop of DMF as catalyst. After 10 min, the suspension was treated with another 0.5 mL of oxalyl chloride. After 2.5 h, when effervescence ceased, added another 0.5 mL portion of oxalyl chloride and 2 drops of DMF and continued the reaction for another 1.5 h. The reaction mixture was added to 50 mL of ethanol carefully. The ethanol solution was maintained at ambient temperature for 30 min. It was then evaporated in vacuo. The residue was partitioned between EtOAc (75 mL) and satd aqueous bicarbonate (100 mL). The organic layer was washed with water (50 mL), dried (Na2SO4) and evaporated in vacuo. The crude product was coevaporated with hexane (50 mL). A suspension of the residual solid in hexane (50 mL) was filtered and washed with another 20 mL more hexane to give 200 mg. The crude product itself was used for subsequent reactions. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.53 (s, 1 H), 8.20 (s, 1 H), 7.93 (s, 1 H), 4.45 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H). 269(MH)+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[C:30]([O:34][C:35](=[O:41])[C:36]([CH3:40])([CH3:39])[CH2:37][NH2:38])([CH3:33])([CH3:32])[CH3:31]>CCO>[C:30]([O:34][C:35](=[O:41])[C:36]([CH3:40])([CH3:39])[CH2:37][NH:38][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 140 °C
Yield: 53.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.078 mmol) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (40 mg, 0.233 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (0-15% EtOAc/hexanes+2% AcOH) to give 22 mg of the title compound as a yellow oil. 1H NMR (CDCl3, 200 MHz): δ=13.2 (s, 1H), 8.35 (s, 1H), 8.28 (t, 1H, J=6.2 Hz), 8.18 (s, 1H), 7.75-7.90 (m, 2H), 7.20-7.60 (m, 8H), 5.65 (s, 2H), 3.50 (d, 2H, J=6.6 Hz), 1.47 (s, 9H), 1.21 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](O)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][C@@H:26]1[CH2:31][NH:30][CH2:29][C@@H:28]([OH:32])[CH2:27]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([N:30]3[CH2:31][C@@H:26]([CH3:25])[CH2:27][C@H:28]([OH:32])[CH2:29]3)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNC[C@@H](O)C1
Product: C[C@H]1C[C@H](O)CN(C(=O)CCN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)[C@@H](C)C2=O)C1
Product: Cl

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and 1.1 eq. (3S,5S)-5-methyl-piperidin-3-ol; hydrochloride (intermediate 4) gave the titled compound in 84% yield as off-white solid. MS: 471.3 (MH+, 2Cl).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].[C:4](=[O:7])([O-])O.[Na+].CS(C)=O.[Si]([O:20][CH:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[C:39](=[O:40])[C:38]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]5[C:49]([C:54]#[N:55])=[CH:50][CH:51]=[CH:52][CH:53]=5)=[CH:44][CH:43]=4)=[C:37]([CH2:56][CH2:57][CH3:58])[N:36]=[C:35]3[CH2:59][F:60])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[F:60][CH2:59][C:35]1[N:34]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH:24]3[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]3)=[CH:29][CH:30]=2)[C:39](=[O:40])[C:38]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[C:54]3[NH:55][C:4](=[O:7])[O:2][N:3]=3)=[CH:46][CH:47]=2)=[C:37]([CH2:56][CH2:57][CH3:58])[N:36]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(CF)n(-c2ccc(OC3CCC(O[Si](C)(C)C(C)(C)C)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CF)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 6.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogen carbonate (0.23 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-{[1-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy]phenyl}-2-(fluoromethyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.18 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL). N,N′-carbonyldiimidazole (0.07 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (1 mL), tetrabutylammonium fluoride tetrahydrofuran solution (1 mol/L, 0.1 mL) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated from the reaction mixture under reduced pressure. The residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.01 g, 6%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH3:13])=[CH:5][CH:4]=1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:11]1[O:12][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[C:9]([CH3:13])[N:10]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCc1ccc(-c2ocnc2C)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(-c2oc(Cl)nc2C)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
A solution of Example 33A (0.94 g, 4.8 mmol) in THF (20 mL) was cooled to −78° C., then treated slowly with LiHMDS (1M in THF, 6.3 mL, 6.3 mmol). The reaction was stirred at −78° C. for 20 min and then treated all at once with solid hexachloroethane (2.31 g, 9.75 mmol). The flask was removed from the cold bath, and the reaction mixture was allowed to stir overnight at room temperature. After this time, it was poured into water and extracted with Et2O. The combined Et2O extracts were concentrated in vacuo, and the residue was chromatographed on silica gel (Analogix® SF25-60 column; 100% hexane for 10 minutes, then 0% to 15% EtOAc/hexanes over 10 minutes) to afford 0.673 g (61%) of the title compound as a bright yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.17 (d, J=3.6, 1H), 6.93 (dt, J=3.7, 1.0 1H), 2.86 (qd, J=7.6, 1.0 2H), 2.27 (s, 3H), 1.26 (t, J=7.5, 3H). MS (DCI+) m/z 228 (M+H).
Reaction SMILES: [C:1]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[CH2:27][SH:28])([O:3][CH2:4][CH3:5])=[O:2].S(C1(O)C=CC=CC1C(O)=O)(O)(=O)=O.[CH3:43][O:44][C:45](OC)([CH3:47])[CH3:46]>>[C:1]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[CH2:27][S:28][C:45]([O:44][CH3:43])([CH3:47])[CH3:46])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: COC(C)(C)OC
Agent: O=C(O)C1C=CC=CC1(O)S(=O)(=O)O
Product: CCOC(=O)C1=C(C)NC(CSC(C)(C)OC)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 g of 3,5-dicarboethoxy-6-methyl-2-(mercaptome-thyl) -4-(m-nitrophenyl)-1,4-dihydropyridine (4,92 mmol.) and 20 mg of 2-sulphosalicylic acid bihydrate (0,049 mmol.) are dissolved in 20 ml of 2,2-dimethoxypropane. The solution is stirred for 2 hours at room temperature, then the solvent is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with a NaHCO3 solution (5%, 2×10 ml) and water (3×20 ml), dried on Na2SO4 and evaporated at reduced pressure. 1.8 g of 3,5-dicarboethoxy-6-methyl-2-[2-methoxyprop-2-yl-thiomethyl]-4-(m-nitrophenyl)-1,4-dihydropyridine (thick yellow oil) are obtained.
Reaction SMILES: [N:1]([C@H:4]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][OH:6])=[N+:2]=[N-:3].N1C=CC=CC=1.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[S:32]([O:6][CH2:5][C@H:4]([N:1]=[N+:2]=[N-:3])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:33])=[O:31]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO)N=[N+]=[N-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-azido-3-(hexadecyloxy)propan-1-ol (1 eq) and pyridine (4 eq) in DCM (0.1 M) at 0° C., was added Tf2O (2 eq). The reaction was stirred at 0° C. for 1 hour and quenched by H2O. The aqueous phase was extracted with DCM. The combined organic phases were washed with H2O, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give (R)-2-azido-3-(hexadecyloxy)propyl trifluoromethanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1OC)[C:5]#[N:6].B.C1C[O:16][CH2:15]C1.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][O:16][CH3:15]
Reactant: C1CCOC1
Reactant: COc1ccc(C#N)cc1Br
Agent: B
Solvent: CO
Product: CONCc1cccc(Br)c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A stirring solution of 3-bromo-4-methoxy-benzonitrile (1.00 g, 4.7 mmol) in THF (30 ml) was treated drop-wise with borane-THF (14.2 ml, 1M solution in THF, 14.2 mmol). The mixture was heated at reflux, under argon for 5 h. To the cooled reaction mixture was cautiously added MeOH (20 ml). The volatiles were removed in vacuo and the residue was treated with 2N HCl (20 ml). After heating at reflux for 0.45 h and cooling to room temperature the mixture was basified by addition of solid K2CO3. The basic solution was extracted with diethyl ether (2×). The organic phase was dried (MgSO4) and the solvent removed in vacuo to afford the title compound as a colourless oil (64%).