Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:31][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:24][CH:23]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 79 %

Procedure:
1.0 g (0.00532 mol) of 1-benzyl-4-hydroxypiperidine and 0.72 ml (0.00532 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.7 ml (0.00532 mol) of p-toluoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 1.3 g (80%) of 1-benzyl-piperidin-4-yl 4-methyl-benzoate was obtained as white crystals; m.p. 73°-74°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:16][C@@H:15]3[C@H:11]2[CH2:12][N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:14]3)=[CH:6][CH:5]=1)([O-])=O.O>CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:16][C@@H:15]3[C@H:11]2[CH2:12][N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:14]3)=[CH:8][CH:9]=1
Reactant: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc([N+](=O)[O-])cc3)[C@@H]2C1
Solvent: CO
Solvent: O
Product: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc(N)cc3)[C@@H]2C1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
1.21 g of 1-((1R,5S,6R)-6-(4-nitro-phenyl)-3-aza-bicyclo[3.2.0]hept-3-yl)-propan-1-one (4.44 mmol) were dissolved in 50 ml of methanol, 8.0 g of stannous dichloride SnCl2×H2O (35.46 mmol) were added, and the reaction was stirred under refluxing conditions for 2 h. The solvent was evaporated and the residue portioned between 1 N aqueous sodium hydroxide and ethyl acetate. This mixture was filtered, the two phases were separated, and the aqueous layer was extracted with ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 0.94 g of the product as a mixture of 72% para and 28% ortho substituted product which was used in the next step without further separation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[CH2:25]([OH:32])[C:26]([NH2:31])([CH2:29][OH:30])[CH2:27][OH:28]>>[OH:32][CH2:25][C:26]([NH:31][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)[CH:5]=1)([CH2:29][OH:30])[CH2:27][OH:28]
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NC(CO)(CO)CO
Product: COc1ccc(C(=O)NC(CO)(CO)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and tris(hydroxymethyl)aminomethane in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[C:11]([N:6]1[C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=4[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=3)=[CH:3][C:4]=2[O:10][CH2:9][CH2:8][CH2:7]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCCOc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(C)=O)ncc1Cl
Yield: 60.2 %

Procedure:
1-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (97 mg, 0.47 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide (167 mg, 0.494 mmol), and 10-Camphorsulfonic acid (16 mg, 0.070 mmol) in Isopropyl alcohol (4 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was neutralized with MP-carbonate (0.3 mmol) and purified on silica gel (ISCO, 2×12 g, 0-100% EtOAc:Hex) to afford 2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide as a light brown foam (144 mg, 60%). MP=196-199° C.; LCMS: 509 (M+H); 1H-NMR (DMSO): 9.50 (s, 1H), 9.21 (s, 1H), 8.99 (m, 1H), 8.20 (s, 1H), 7.49 (m, 3H), 7.34 (s, 1H), 7.16 (m, 1H), 7.06 (m, 1H), 4.55 (m, 1H), 4.34 (m, 1H), 4.01 (d, 2H, J=2.3 Hz), 3.55 (m, 1H), 3.11 (t, 1H, J=2.3 Hz), 2.62 (m, 1H), 1.95 (m, 1H), 1.72 (m, 4H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:35])[CH3:34])[C:17]([O:19]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:18])[C:13]1=[O:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:34])[CH3:35])[C:17]([OH:19])=[O:18])[C:13]1=[O:36])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Solvent: CCCCCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=C(C(=O)O)N1CC(NC(=O)COc2ccccc2)C1=O
Yield: 35 %

Procedure:
Benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-2-butenoate (100 mg) was dissolved in a mixture of 2 ml of anisole and 1 ml of trifluoroacetic acid at 0°. After 10 minutes 50 ml of hexane was added. The residue obtained by evaporating the solution in vacuo to dryness was taken up in ethyl acetate and the resulting solution was layered with water. After the pH of the aqueous layer was adjusted to 8.5, the aqueous layer was separated and layered with ethyl acetate. The pH of the aqueous layer was then adjusted to 2.5. The organic layer was separated, dried and evaporated to dryness in vacuo to provide 23 mg of the title product: nmr (CDCl3) δ 1.98 (s, 3, CH3), 2.17 (s, 3, CH3), 3.60 (m, 2, C4 --H), 4.98 (m, 1, C3 --H), 4.60 (s, 2, --OCH2CO), and 7.2 (b, 5, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[C:13](=O)(O)[O-].[Na+]>CO.O>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C([O-])O
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(F)cc1N
Yield: 80.6 %

Procedure:
A stirred solution of 2-amino-4-fluorobenzoic acid (4.86 g, 31.3 mM) in anhydrous methanol (100 mL) was saturated with anhydrous hydrogen chloride and then refluxed for 4 days. During the reflux period, the reaction mixture was periodically resaturated with hydrogen chloride. After the reflux period, the reaction mixture was cooled and concentrated to leave a whtie solid. This material was dissolved in water and the resulting solution neutralized with aqueous sodium bicarbonate and extracted with diethyl ether. The combined extracts were dried (MgSO4), filtered and concentrated to leave (4.08 g, 80.6%) of the title compound as an off white solid, mp 66°-67° C.; MS(CI): 170 (M+H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:12][P:13]([NH:19][CH:20]([CH3:22])[CH3:21])([NH:15][CH:16]([CH3:18])[CH3:17])=[S:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O>C(O)C>[CH:20]([NH:19][P:13]([CH2:12][NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([NH:15][CH:16]([CH3:18])[CH3:17])=[S:14])([CH3:21])[CH3:22]
Reactant: CCOC(=O)CN(CP(=S)(NC(C)C)NC(C)C)C(=O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)CNCP(=S)(NC(C)C)NC(C)C

Procedure:
N-trifluoroacetyl-N-[bis(isopropylamino)phosphinothioylmethyl]glycine, ethyl ester (2 g, 5.1 mm), was dissolved in ethanol. The solution was stirred and sodium tetrahydrido boron (194 mg, 5.1 mm) was added portionwise over a ten minute period. The solution was stirred for an additional 30 minutes. The solvent was removed by evaporation under vacuum and the residue was washed with water. The water was saturated with sodium chloride and the aqueous layer and insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel employing ether as an eluant to yield N-[bis(isopropylamino)phosphinothioylmethyl]glycine, ethyl ester, as a white solid, m.p. 63° C. and having the following analysis: Calculated: C, 42.17; H, 8.90; N, 13.40; P, 9.90; S, 10.20. Found: C, 41.98; H, 8.10; N, 13.22; P, 9.39; S, 9.74.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1>C(O)CCC.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>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=4)[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Sc4ccc(Cl)cc4)cc23)CC1
Temperature: 110 °C
Yield: 50.6 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), p-chloro-thiophenol (188 mg, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in nBuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-pentane:ethyl acetate 9.5:0.5→8:2) to give 300 mg of the title compound as colourless oil (yield 50%). 1H NMR (CDCl3) δ 8.05-8.15 (m, 2H), 7.60-7.70 (m, 2H), 7.40-7.50 (m, 2H), 7.15-7.30 (m, 3H), 3.45-3.55 (m, 4H), 3.10-3.15 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.[C:20]([O:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH2:38][O:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33]Br)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]1([C:20]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=2[CH2:38][O:39][C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[CH2:33][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:9]([CH3:19])=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:13]=3[CH3:14])[CH:5]=[CH:6][CH:7]=2)=[O:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(C)c(-c2cccc(O)c2)c(C)c1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(C)c(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)c(C)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 4.49 g (17.5 mmol) of methyl 3′-hydroxy-2,6-dimethylbiphenyl-4-carboxylate with 8.46 g (19 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 2.54 g (18 mmol) of potassium carbonate, the desired product is obtained in the form of a yellow oil (m=7.4 g; Y=69%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:16]1([C:2]2[C:3]3[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]c2ncnc(-c3ccccc3)c12
Temperature: 125 °C

Procedure:
Ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (50.0 mg, 0.222 mmol), phenyl boronic acid (32.4 mg, 0.266 mmol) and potassium carbonate (0.332 mL, 0.665 mmol) were added to tetrahydrofuran (1.5 mL) in a microwave vial. The solution was purged with nitrogen for 5 minutes and PdCl2(dppf)-CH2Cl2 (18 mg, 0.022 mmol) was then added. The reaction was sealed and heated at 125° C. by microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of desired product was carried out by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Pure fractions were pooled and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate and EtOAc were added to the residue. The organic layer was separated and the aqueous layer was then extracted with EtOAc (×3). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the product as a solid. LRMS (ESI) calc'd for C15H14ClN3O2 [M+H]+: 268, found 268. 1H NMR (600 MHz, DMSO-D6) δ 13.01 (s, 1H), 8.91 (s, 1H), 8.30 (s, 1H), 7.63 (m, 2H), 7.49 (m, 3H), 3.82 (q, 2H, J=7.04 Hz), 0.78 (t, 3H, J=7.04 Hz).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]3C3CCCCO3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26].CCOC(C)=O>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22][CH3:23])[NH:13]3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1C1CCCCO1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2c(N)nc(OCCC3CC3)nc2[nH]1

Procedure:
2-[(2-Cyclopropylethyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (845 mg) was dissolved in MeOH (10 mL) and TFA (1 mL) was added. The reaction was stirred over a weekend and was evaporated to dryness under reduced pressure to give a brown solid. EtOAc was added and the solid was filtered off and washed with more EtOAc (15 mL EtOAc used in total). The solid was then washed with Et2O (5 mL) and air-dried under suction to give the title compound as an off-white solid (937 mg).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:23]([OH:24])[C@H:22]([O:25][C@@H:26]2[O:55][C@@H:54]([CH3:56])[C@@H:45]([O:46]CC3C=CC=CC=3)[C@@H:36]([O:37]CC3C=CC=CC=3)[C@@H:27]2[O:28]CC2C=CC=CC=2)[C@@H:21]([CH2:57][OH:58])[O:20][C@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([NH:4][C@@H:5]1[C@@H:23]([OH:24])[C@H:22]([O:25][C@@H:26]2[O:55][C@@H:54]([CH3:56])[C@@H:45]([OH:46])[C@@H:36]([OH:37])[C@@H:27]2[OH:28])[C@@H:21]([CH2:57][OH:58])[O:20][C@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@H](O)[C@H]1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H]1NC(C)=O
Reaction time: 24 h
Yield: 85 %

Procedure:
The syrupy product was used directly for the preparation of 8-methoxycarbonyloctyl 2-acetamido-4-O-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)-2-deoxy-β-D-glucopyranoside. The crude disaccharide (3.78 g) was dissolved in 50 ml of dry methanol, and 5 ml of 0.2 N sodium methoxide in methanol was added. After 24 h at room temperature, the solution was deionized using the acid resin. Solvent removal left an oil which was dissolved in dichloromethane (100 ml). The solution was washed with water and dried over magnesium sulfate prior to evaporation to a residue (1.01 g, 85% yield) from the fully blocked disaccharide. Purification was by recrystallization from ethyl acetate-hexane, mp 145°-146°, [α]D25 -33.6° (c 1.2, chloroform).
Reaction SMILES: [CH:1]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:24]=[CH:25][C:11]=34)[CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][O:3][CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.[N:45]([C:48]1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4COCC3COC4)N=2)=CC=1)=[C:46]=[O:47]>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH:5]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([NH:20][C:46]([NH:45][CH3:48])=[O:47])=[CH:21][CH:22]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:29])([F:28])[F:30])[N:24]=[CH:25][C:11]=34)[CH:1]([CH2:2][O:3][CH2:4]1)[CH2:8][O:7][CH2:6]2
Reactant: Nc1ccc(-c2nc(N3C4COCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: O=C=Nc1ccc(-c2nc(N3C4COCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(-c2nc(N3C4COCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
A solution of 4-(4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (47 mg, 0.11 mmol) in dichloromethane (2 mL) was treated triethylamine (140 μL), followed by triphosgene (25 mg, 0.08 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1.1 mL)—was added to the 9-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-(4-(4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea. MS (ES+): 478.3 (M+H)+
Reaction SMILES: [N:1]#[N:2].C(OC([NH:13][C@@H:14]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:24])[CH3:23])=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:1]#[N:2].[NH2:13][C@@H:14]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccc2ccccc2c1)NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@@H](N)Cc1ccc2ccccc2c1)C(N)=O
Yield: 98.8 %

Procedure:
A solution of 0.725 g of N2 -[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-(2-naphthyl)butyl]-N1 -tert.butyl-L-prolinamide was dissolved in 25 ml of ethanol and hydrogenated at room temperature and under atmospheric pressure over 0.5 g of 10% palladium-on-carbon for 20 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.54 g of N2 -[3(S)-amino-2(R)-hydroxy-L-(2-naphthyl)butyl]-N1 -tert.butyl-L-prolinamide as a white foam which was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][S:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([Cl:33])[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[CH:17][C:11]=2[N:10]=1)(C)(C)C.[Li+].[OH-]>CO.O>[Cl:33][C:15]1[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[CH:17][C:11]2[N:10]=[C:9]([S:8][CH2:7][C:6]([OH:34])=[O:5])[NH:13][C:12]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(C#Cc3ccc(Oc4ccccc4)cc3)c(Cl)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CSc1nc2cc(C#Cc3ccc(Oc4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of compound 33-1 (29.0 mg, 0.059 mmol) in MeOH (6 mL) was added to 5% aqueous LiOH (3 mL) and the mixture was stirred at rt for 20 h. The mixture was then diluted with water (2 mL), evaporated to ½ of the initial volume and acidified with 5% aqueous HCl. The solution was extracted with EtOAc (3 mL then 1 mL, twice). The organic layers were combined, washed with water (three times, 1 mL) and evaporated to dryness in vacuo. The resulting oily residue was dissolved in DMSO (1.0 mL), filtered and purified by reverse-phase HPLC to give the title compound as off-white solid. LR-MS (API-ES): calculated for C23H15ClN2O3S 434.1, observed m/e 435.0 (M+H)+ (Rt 2.96 min).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]=[C:12]1[CH2:21][OH:22].C(N(CC)CC)C.Cl>ClCCl>[O:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]=[C:12]1[CH:21]=[O:22]
Reactant: OCC1=COc2ccccc2O1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1=COc2ccccc2O1
Reaction time: 0.08 h

Procedure:
A solution of 1.2 ml (14 mmol) of oxalyl chloride in 30 ml of anhydrous dichloromethane is cooled to −60° C. under an inert atmosphere; 2 ml (28 mmol) of anhydrous dimethyl sulphoxide are then added to the medium. After 5 minutes of stirring, 1.53 g (9.33 mmol) of the alcohol obtained in Step A in 15 ml of dichloromethane are slowly added to the solution. 15 minutes later, 6.5 ml (47 mmol) of triethylamine are added to the medium. After returning to ambient temperature, the solution is acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with dichloromethane. The organic phases, dried over magnesium sulphate and then filtered, are concentrated in vacuo. The title aldehyde is obtained pure in the form of a white solid after passage over a silica column (eluant:AcOEt/PE:10/90).