Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH:7]1[NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[C:33]([CH3:41])[CH:32]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:5])C.C(N=C=O)(C)(C)C>C1COCC1>[CH3:41][C:33]1[CH:32]=[C:31]([CH2:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([S:20]([NH:19][CH:7]3[CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][NH:9][CH2:8]3)(=[O:21])=[O:22])=[CH:24][CH:25]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: CC(C)(C)N=C=O
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CNCCC3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 114.8 %

Procedure:
To a solution of 0.2 g (0.44 mmol) of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester [WO 01/70673, Example 134] in THF (10 mL) at 0° C. was added tert-butylisocyanate (0.130 g, 0.9 mmol). The reaction mixture stirred at 25° C. for 19 h and then the THF was removed in vacuo. The resulting oil was diluted with ethyl acetate (100 mL) and the organics were washed with saturated aqueous sodium chloride (2×30 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column, eluting with an acetonitrile:water gradient, to afford 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-4-carboxylic acid as an amorphous white solid (0.23 g, 96%). MS: 556 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[N:10]#[C:11][NH2:12]>>[C:11]([NH:12][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Cl:1])=[O:8])#[N:10]
Reactant: N#CN
Reactant: O=C(Cl)c1sccc1Cl
Product: N#CNC(=O)c1sccc1Cl

Procedure:
Compounds of this invention with a linker between middle ring and Ar2 may be prepared as illustrated by the exemplary reaction in Scheme 11. Reaction of 3-chloro-thiophene-2-carbonyl chloride with cyanamide produces N-cyano-3-chloro-thiophene-2-carboxylic acid amide, followed by treating with hydroxyamine to give 3-amino-5-(3-chloro-2-thienyl)-1,2,4-oxadiazole. The amine was refluxed with 4-chlorobenzaldehyde in toluene to produce (4-chloro-benzylidene)-[5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-amine.
Reaction SMILES: [Si:1]([O:18][CH:19]([CH3:22])[C:20]#[N:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][OH:24].Cl.C([O-])(O)=O.[Na+]>CO>[Si:1]([O:18][CH:19]([CH3:22])[C:20](=[N:23][OH:24])[NH2:21])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CC(C#N)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=NO
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a flask containing 2-((tert-butyldiphenylsilyl)oxy)propanenitrile (14.6 mmol, 4.5 g) in MeOH (50 ml), NH2OH.HCl (29.1 mmol, 2 g) and NaHCO3 (43.7 mmol, 3.6 g) were added. The resulting mixture was stirred at 70° C. for overnight. The mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with H2O, dried, filtered and evaporated. Yield 4.02 g. 1H-NMR (400 MHz; DMSO-d6): δ 1.01 (s, 9H), 1.20 (d, 3H), 4.12 (q, 1H), 7.38-7.46 (m, 6H), 7.60-7.64 (m, 4H). LC-MS: [M+1]=343.12.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1.O.[OH-].[Li+].C(OC1C=CC(C(O)=O)=CC=1)CCCCCCCCCCCCCCCCC>CO>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:21])=[O:2])=[CH:9][CH:8]=1)[CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC/C=C/CCOc1ccc(C(=O)OC)cc1
Agent: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC/C=C/CCOc1ccc(C(=O)O)cc1

Procedure:
Ester 35h (600 mg, 2.07 mmol), and lithium hydroxide monohydrate (867 mg, 20.7 mmol) in 20 ml methanol were reacted according to the procedure for compound 36a. The yield was 500 mg (87%) of a white powder which was not quite pure (95%). The product was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.ClC1N=CC(N2C3N=C(N4CCOCC4)N=C(C4C=NC(N(CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=NC=4)C=3CC2)=CC=1.[C:95]([N:98]1[CH2:103][CH2:102][NH:101][CH2:100][CH2:99]1)(=[O:97])[CH3:96]>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([N:101]6[CH2:102][CH2:103][N:98]([C:95](=[O:97])[CH3:96])[CH2:99][CH2:100]6)[CH:7]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(N4CCN(C(C)=O)CC4)c3)cn2)cc1
Yield: 84.2 %

Procedure:
Using {5-[7-(2-chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.31 mmol) obtained in Step A in Example 1-D-69 instead of {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine, and N-acetylpiperazine (59 mg, 0.46 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Example 1-D-48, amination was carried out, to obtain a crude product of 1-{4-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-piperazin-1-yl}-ethanone as a yellow solid (194 mg, 85%), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-70) as a yellow powder (71 mg, 46%).
Reaction SMILES: [OH:1][C:2]([C@@:4]1([O:57][C@@H:56]([C@@H:58]([C@@H:60]([CH2:62][OH:63])[OH:61])[OH:59])[C@H:51]([NH:52][C:53]([CH3:55])=[O:54])[C@@H:49]([OH:50])[CH2:48]1)[O:5][C@H:6]1[C@@H:43]([OH:44])[C@@H:42]([CH2:45][OH:46])[O:41][C@@H:8]([O:9][C@H:10]2[C@@H:16]([OH:17])[C@@H:15]([CH2:18][O:19][C@]3(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](NC(C)=O)[C@@H](O)C3)C(=O)O)[O:14][CH:12]([OH:13])[C@@H:11]2[NH2:40])[C@@H:7]1[OH:47])=[O:3].CC(N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)([O-])=O)(C(O)=O)C[C@@H]1O)=O.[Na+]>>[OH:3][C:2]([C@@:4]1([O:57][C@@H:56]([C@@H:58]([C@@H:60]([CH2:62][OH:63])[OH:61])[OH:59])[C@H:51]([NH:52][C:53]([CH3:55])=[O:54])[C@@H:49]([OH:50])[CH2:48]1)[O:5][C@H:6]1[C@@H:43]([OH:44])[C@@H:42]([CH2:45][OH:46])[O:41][C@@H:8]([O:9][C@H:10]2[C@@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][CH:12]([OH:13])[C@@H:11]2[NH2:40])[C@@H:7]1[OH:47])=[O:1]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](OC[C@H]2OC(O)[C@H](N)[C@@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@]4(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O4)[C@H]3O)[C@H]2O)(C(=O)O)C[C@@H]1O
Agent: CC(=O)N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Agent: [Na+]
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](O[C@H]3[C@@H](O)[C@@H](CO)OC(O)[C@@H]3N)[C@@H]2O)(C(=O)O)C[C@@H]1O

Procedure:
Synthesis of NeuAcα2-3Galβ1-3(NeuAcα2-6)GalNH2 βSEt. NeuAcα2-3Galβ1-3GalNH2 βSEt is prepared as described above and used directly or after isolation as acceptor for a α2-6-sialyltransferase (e.g. EC 2.4.99.7) reaction with a suitable glycosyl donor such as CMP-NeuAc.
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:14])(=[O:13])[CH:7]1[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1.[CH3:15]O>O>[CH3:15][O:13][C:6]([CH:7]1[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1)=[O:14]
Reactant: CO
Reactant: O=C(O)C1C=CCC=C1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C1C=CCC=C1

Procedure:
Concentrated H2SO4 (1 ml) was added to a solution of 1,4-dihydrobenzoic acid (3 g, 23.97 mmol) in freshly dried methanol (10 ml). The reaction was heated to reflux in air for 1 h, cooled, poured into H2O (25 ml) and extracted with ether (3×50 ml). The combined ether layers were washed with 5% Na[HCO3] solution (50 ml) and saturated NaCl solution (50 ml) and dried over MgSO4. The ether was removed on the rotary evaporator to leave a colourless oil which was used without further purification.
Reaction SMILES: N#N.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14](=[O:16])[CH3:15].Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:20]([CH2:19][CH2:18][NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14](=[O:16])[CH3:15])([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: CCOC(=O)CCBr
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1cc(OC)c(OC)cc1C(C)=O
Temperature: 25 °C
Yield: 35.2 %

Procedure:
Triethylamine (3.88 g, 5.34 mL, 38.44 mM) was added at once under N2 to a stirred mixture of 2'-amino-4',5'-dimethoxyacetophenone (2.5 g, 12.8 mM) and ethyl 3-bromopropionate (17.43 mL, 96.2 mM) at room temperature. Immediately the reaction mixture solified. This was heated under N2 to 140°-150° C. (bath temp.) for a period of 4 hours during which the reaction mixture had partially liquified into a red-brown, viscous slurry. After cooling to room temperature it was treated with 5% NaHCO3 solution (50 mL) and then extracted with CH2Cl2 (3×60 mL). The combined organic extracts were washed with H2O, dried (Na2SO4) and evaporated in vacuo to remove CH2Cl2 (low vacuum) and excess 3-bromopropionate (under high vacuum at 50°-60° C.). The dark oily residue was chromatographed on a column of SilicAR CC-7 (300 g, 55.5×6 cm) packed in hexane. The sample was applied to the column in CH2Cl2 (50 mL) followed by elution with hexane and then with increasing proportions of ethyl acetate/hexane, collecting 1 L fractions. Fractions 10 and 11, afforded, upon evaporation to dryness 2'-(N-2-carbethoxyethylamino)-4',5'-dimethoxyacetophenone as a waxy crystalline solid (1.33 g, 35.2%), mp 73°-75° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C:15]2=[O:2])=[CH:12][CH:13]=1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1COCCN1c1ccc(Br)cc1

Procedure:
1.41 g (6.20 mmol) of benzyltriethylammonium chloride and 0.98 g (6.20 mmol) of potassium permanganate are added to a solution of 500 mg (2.07 mmol) of 4-(4-bromophenyl)morpholine (Example 15A) in 10 ml of dichloromethane. After 5 h under reflux, the contents of the flask are concentrated in vacuo, and the residue is purified by preparative HPLC. The concentrated product is dried under high vacuum. 217 mg (35.7% of theory) of the title compound are obtained.
Reaction SMILES: [OH-].[K+].OC[C:5]12[CH2:12][O:11][C:8]([CH3:13])([O:9][CH2:10]1)[O:7][CH2:6]2.[CH3:14][O:15]CBr>CS(C)=O.O>[CH3:14][O:15][C:5]12[CH2:6][O:7][C:8]([CH3:13])([O:9][CH2:10]1)[O:11][CH2:12]2
Reactant: CC12OCC(CO)(CO1)CO2
Reactant: COCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC12COC(C)(OC1)OC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Powdered potassium hydroxide (16.2 g, 0.290 mol) is suspended in 100 mL of dimethyl sulfoxide and the mixture is stirred at 25° C. for 5 min. Then 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2.2.21octane (10.0 g, 0.062 mol) is added followed by bromomethyl methyl ether (9.3 g, 6.1 mL, 0.074 mol). The reaction mixture is stirred for 30 min and then diluted with water (1 L) and extracted with dichloromethane several times. The combined organic layers are washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 4-(methoxy)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane. This crude material is dissolved in methanol (100 mL) and stirred with pyridinium p-toluenesulfonate (1.6 g, 6.200 mmol) in water (100 mL) for 30 min. The pH of the solution is adjusted to 7 with solid sodium bicarbonate and the solvents are removed under reduced pressure. The resulting solids are triturated with methanol and the methanol solution is evaporated to give 2-(methoxymethoxy)-1,1,1-tris(hydroxymethyl)ethane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[O:23][C:22]([C:24](OC)=[O:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:35][C:12]1[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][N:14]([S:16]([C:19]2[O:23][C:22]([CH2:24][OH:25])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[C:13]=1[C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(CO)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of methyl 5-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}-2-furoate (825 mg) in tetrahydrofuran (8 mL) was added dropwise a 1.5 mol/L solution (5.38 mL) of diisobutylaluminum hydride in toluene under ice-cooling and the mixture was stirred for 1 hr. Hydrochloric acid was added to the reaction mixture and the mixture was further stirred for 1 hr and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:2) to give the title compound as a colorless oil (yield 565 mg, 53%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:15]2[CH:14]=[C:13]([NH:16]C(OC(C)(C)C)=O)[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.Cl.CC(OC)(C)C>C(#N)C>[OH:1][CH2:2][CH:3]1[C:15]2[CH:14]=[C:13]([NH2:16])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(CO)c1ccccc1-2
Agent: Cl
Solvent: CC#N
Solvent: COC(C)(C)C
Product: Nc1ccc2c(c1)C(CO)c1ccccc1-2
Temperature: 25 °C
Yield: 99 %

Procedure:
13.0 g 9-Hydroxymethyl-2-(Boc-amino)fluorene was dissolved in 110 ml acetonitrile and stirred under reflux. 42 ml 2 N HCl (2.0 equiv, 84 mmol) was added drop-wise. The reaction mixture was stirred under reflux for 45 min. The reaction mixture was cooled to room temperature and the reaction was monitored by TLC [Rf=0.1 PE-MTBE (1:2)]. The solvent was partially eliminated by rotary evaporation and the residue was dissolved in 70 ml 2 N HCl. The solution was carefully washed with 2×50 ml MTBE. The aqueous phase was adjusted to pH 9 by Na2CO3 and extracted with 2×70 ml EtOAc. The organic phase was washed with 50 ml brine and dried over Na2SO4. The solvent was eliminated by rotary evaporation. The product was used without further purification. The structural identity was verified by NMR (8.76 g, 99% yield).
Reaction SMILES: [C:1]([C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].CO>C1COCC1.C(Cl)Cl.O>[NH2:2][CH2:1][C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1
Reactant: N#Cc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
A solution of (S)-5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (5.0 g, 0.017 mol), prepared as in Example 19, in 75 mL of THF was stirred under argon in an ice bath and a solution of LAH in THF (1.0 M, 34.3 mL, 34.3 mmol) was added dropwise over 10 minutes. The mixture was cooled to 0° C., stirred for 30 minutes, allowed to warm to room temperature, and let stand for 1.5 hours. The mixture was cooled to 0° C. and then a sufficient amount of saturated sodium potassium tartrate solution was added such that the mixture could by freely stirred. An additional 30 mL of saturated sodium potassium tartrate solution and 200 mL of 10% methanol in methylene chloride were added, the mixture was stirred for 15 minutes, and then 100-150 mL of water was added. The organic layer was separated and the aqueous phase was extracted twice with 10% methanol in methylene chloride (2×125 mL). The combined extracts were washed with 75 mL of water, dried over magnesium sulfate, and concentrated by evaporation to a residue (5.2 g). Purification by column chromatography on silica gel (elution: 5% methanol/methylene chloride) gave (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (2.92 g, 10.0 mmol).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
±D-xylose: ±D-glucose: +
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:6][C@@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:8]([O:10]C)=[O:9])[CH2:4][CH3:5].O1CCCC1.CO.O>C(O)(=O)C>[CH2:3]([O:6][C@@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:8]([OH:10])=[O:9])[CH2:4][CH3:5]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCCC)C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCCC)C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
51 mg (1.28 mmol) of sodium hydroxide are added to a solution of 200 mg (0.42 mmol) of methyl (S)-2-propyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate in 2 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirred overnight at ambient temperature. The reaction is halted by the addition of 2 ml of water and 0.5 ml of acetic acid, and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (dichloromethane/methanol 90/10). 147 mg of 2-(S)-propyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of an oil. Yield=76%.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][NH:43][CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])[C:38]2=[N:49][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:54][CH2:53][C:16]([CH3:55])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:52])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:51])=[CH:28][C:29]=2[C:30]2[CH:50]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][NH:43][CH2:44][C:45]([OH:48])([CH3:46])[CH3:47])[C:38]2=[N:49][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:55])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:52])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:51])=[CH:28][C:29]=2[C:30]2[CH:50]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:53][CH2:54]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CNCC(C)(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1CNCC(C)(C)O)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 89 %

Procedure:
Prepared in 89.0% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-{[(2-hydroxy-2-methylpropyl)amino]methyl}-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.18-8.11 (m, 2H), 7.98-7.93 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.33 (d, J=7.3 Hz, 1H), 7.25-7.12 (m, 3H), 5.71 (br. s., 1H), 4.62 (br. s., 1H), 4.14-4.02 (m, 2H), 3.92-3.81 (m, 1H), 3.74 (br. s., 1H), 3.56-3.41 (m, 6H), 2.64 (d, J=10.6 Hz, 1H), 2.39 (s, 3H), 1.93 (d, J=12.8 Hz, 1H), 1.81 (d, J=13.2 Hz, 4H), 1.74-1.72 (m, 1H), 1.63 (br. s., 4H), 1.19 (s, 3H), 1.11 (s, 9H), 1.08 (d, J=4.4 Hz, 9H); LCMS (ESI, M+1): 745.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:18]2[C:22]([Br:23])=[CH:21][N:20]([CH3:24])[N:19]=2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:23][C:22]1[C:18]([C:14]2[CH:13]=[C:12]([NH:11][C:6]([C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:7])[CH:17]=[CH:16][CH:15]=2)=[N:19][N:20]([CH3:24])[CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3ccc(Cl)cc3)c2)n1
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To 4-chlorobenzoyl chloride (15 mg, 0.08 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (21 mg, 0.08 mmol) and triethylamine (12 μL, 0.08 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (23 mg, 72%), m.p. 184.4-184.8° C. (EtOAc/hexane).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:15]O>Cl>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH2:3][C:4]([O:6][CH3:15])=[O:5]
Reactant: CO
Reactant: COc1cccc(C(N)CC(=O)O)c1
Agent: Cl
Product: COC(=O)CC(N)c1cccc(OC)c1

Procedure:
A solution of β-amino-3-methoxy-benzenepropanoic acid (WO 0041469) (9.38 g, 52 mmol) in concentrated hydrochloric acid (10 ml) and methanol (115 ml), was heated under reflux for 7 hours, then cooled. The reaction was evaporated under reduced pressure, and the residue partitioned between ethyl acetate (300 ml) and 1N sodium hydroxide solution (300 ml). The layers were separated, and the organic phase evaporated under reduced pressure to afford the title compound as a colourless oil, 8.8 g.