Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(/N=N/C(O[CH2:11][CH3:12])=O)=O.[CH2:13]([C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[N:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C[SiH](C[CH2:38][Si:39]([CH3:50])([CH3:49])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:13]([C:21]1[CH:26]=[N:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][Si:39]([CH3:49])([CH3:50])[CH2:38][Si:39]([CH3:49])([CH3:40])[CH3:38])=[CH:29][CH:28]=2)=[N:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:11][CH3:12]
Reactant: C[SiH](C)CC[Si](C)(C)CCCCCCCCO
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCCCC[Si](C)(C)C[Si](C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethylazodicarboxylate (0.087 g, 0.500 mmol) in THF (5.0 ml) was added dropwise to a stirred solution of 4-(5-octylpyrimidin-2-yl)-phenol (0.114 g, 0.40 mmol), compound 13 (0.110 g, 0.400 mmol) and triphenylphosphine (0.131 g, 0.500 mmol) in THF (10 ml). The treaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid that was recrystallized from acetonitrile.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH3:2].CN(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CN(C)C=O.O>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][N:6]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(CNc1ccncc1)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CN(C(=O)OCc1ccccc1)c1ccncc1)OCC
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 11.3 %

Procedure:
A solution of 4-pyridylaminoacetaldehyde diethyl acetal (7.0 g.) in a mixture of dried dimethylformamide (20 ml.) and dried hexamethylphosphoric triamide (7.5 ml.) was dropwise added over 5 minutes under ice-cooling and stirring to a suspension of 65.5% sodium hydride (2.0 g.) in dried dimethylformamide (3 ml.). The mixture was stirred for 10 minutes at ambient temperature, for 30 minutes at 60° C and for 15 minutes under ice-cooling. A solution of benzyl chloroformate (9.0 g.) in dried dimethylformamide (2 ml.) was dropwise added thereto under stirring and ice-cooling. The resulting mixture was stirred for 20 minutes under ice-cooling and for 15 minutes at ambient temperature. After water was dropwise added to the reaction mixture, the mixture was extracted 3 times with ethyl acetate. The extract was in turn washed twice with water and once with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residual oil was purified by column chromatography on silica gel (60 g.) using a mixture of benzene and ethyl acetate (7 : 3) as developing solvent to give oil of N-benzyloxycarbonyl-N-(4-pyridyl)aminoacetaldehyde diethyl acetal (1.3 g.).
Reaction SMILES: [C:1]([CH:3]([C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])#N.C1CC=CCC=1>[Pd].CO>[CH3:19][O:18][C:11]1[N:10]=[C:9]2[C:3]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH:1][NH:15][C:14]2=[CH:13][CH:12]=1
Reactant: COC(=O)CC(C#N)c1nc(OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1=CCC=CC1
Product: COC(=O)Cc1c[nH]c2ccc(OC)nc12
Temperature: 120 °C

Procedure:
A 2 mL microwave process vial with a stir bar was charged with crude methyl 3-cyano-3-(6-methoxy-3-nitropyridin-2-yl)propanoate (50 mg, 0.19 mmol), 10% Pd/C (5 Mol %, 20 mg, 0.01 mmol), and methanol (1.5 mL). An excess of 1,4-cyclohexadiene (91 mg, 1.13 mmol) was added and the vessel flooded with argon, capped and heated under microwave conditions at 120° C. for 5 min. The reaction was filtered through CELITE® and the solvent was evaporated in vacuo. The crude material was purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield the product as colorless oil. C11H12N2O3, Mr=220.22; 1H NMR (400 MHz, DMSO-d6) d: 3.61 (s, 3H), 3.72 (s, 2H), 3.83 (s, 3H), 6.53 (d, J=8.8 Hz, 1H), 7.38 (d, J=2.8 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 11.01 (bs, 1H); 13C NMR (100 MHz, DMSO-d6) d: 29.41 (s, —CH2—), 51.86 (s, —C(O)OCH3), 52.83 (s, —OCH3), 104.86 (s, C6′), 107.19 (s, C3′), 122.78 (s, C2′), 124.60 (s, C7a′), 126.80 (s, C7′), 141.29 (s, C3a′), 159.16 (s, C5′), 172.47 (s, >C═O); LCMS (ESI) tR: 0.69 min (>97%, UV220, ELSD), m/z: 221.2 [M+1]+.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=[O:6]>C(OCC)C>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C:5]([OH:6])([CH3:1])[CH3:4]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(O)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 93 %

Procedure:
MeMgBr (1.83 ml of a 3M solution in diethyl ether, 5.5 mmol) was added dropwise to a solution of 2,4-difluoroacetophenone (782 mg, 5.0 mmol) in diethyl ether (20 ml) at 0° C. The reaction was warmed to room temperature and after 1 hour was quenched and washed with water (2×20 ml), dried (MgSO4) and concentrated under reduced pressure to give the title product as colourless oil (800 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[CH:26]12[NH:37][CH:30]([CH:31]([CH2:33][C:34]([OH:36])=[O:35])[CH2:32]1)[CH2:29][O:28][CH2:27]2>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:37]2[C@H:30]3[C@H:31]([CH2:33][C:34]([OH:36])=[O:35])[CH2:32][C@@H:26]2[CH2:27][O:28][CH2:29]3)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1
Reactant: O=C(O)CC1CC2COCC1N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Product: COC(=O)C1=C(CN2[C@H]3COC[C@@H]2[C@H](CC(=O)O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Yield: 24.2 %

Procedure:
The title compound was prepared in analogy to compound 1a in Example 1 starting from methyl (4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 53a (73 mg, 0.15 mmol) and 2-(3-oxa-8-azabicyclo[3.2.1]octan-6-yl)acetic acid (121 mg, 0.7 mmol) 64c. 21 mg of the title compound was isolated by preparative HPLC as a yellow powder (yield was 16%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:28]2[O:27][CH:31]=[CH:30][CH:29]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)cc1
Reactant: OB(O)c1ccco1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccco2)cc1

Procedure:
By carrying out the operation analogously to example 3, starting from 4-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 2-furanboronic acid, the expected product is obtained and is reacted further without additional purification in order to obtain the nonacetylated xyloside.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:27][O:26]2)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:27][CH:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[OH:26])[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: Fc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(F)cc2)CN(C)CC1
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) was dissolved in 5 mL DMF and sodium hydride (250 mg, 6.24 mmol) was added portionwise at 0° C. and the mixture stirred for 10 min. 2-(4-Fluoro-phenyl)-oxirane (450 mg, 3.26 mmol) was added dropwise at same temperature and stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water. The resultant solid was filtered and washed with water (100 mL) and hexane (100 mL), and the crude product was crystallized in EtOH:hexane (5:95 ratio) to obtain 300 mg of 2-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-(4-fluoro-phenyl)-ethanol. 1H NMR (CDCl3, Free base) δ (ppm): 7.30 (m, 2H), 7.20 (d, 1H), 7.05 (m, 3H), 7.0 (d, 1H), 5.0 (t, 1H), 4.05 (d, 2H), 3.62 (d, 1H), 3.30 (d, 1H), 2.80 (m, 3H), 2.70 (m, 1H), 2.50 (s, 3H), 2.44 (s, 3H). Separation by chiral HPLC provided enantiomers 18a and 18b. Optical rotations: Compound 18a, (−)6.97 (c 0.56, Chloroform, 89.35% HPLC purity); Compound 18b, (+)13.03 (c 0.51, Chloroform, 99.51% HPLC purity).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([N:24]=[N+]=[N-])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+]=[N-].CP(C)C.O>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(N=[N+]=[N-])ncnc43)[C@@H]2O1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CN)C[C@@H](n3ccc4c(N)ncnc43)[C@@H]2O1
Reaction time: 8 h
Yield: 80.4 %

Procedure:
7-[(3aS,4R,6R,6aR)-6-(Azidomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-4-azido-7H-pyrrolo[2,3-d]pyrimidine (3.933 g, 11.1 mmol) was dissolved in THF (20 ml) and trimethylphosphane (1M in THF) (44.3 ml, 44.3 mmol) was added at r.t. under N2 and the reaction stirred overnight. Water (4 ml) was added and the reaction was left for 15 mins. The solvents were removed in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% DCM to 20% 2M NH3 in MeOH:80% DCM as eluent to give the product as pale yellow foam (2.706 g, 81%): MS (ESI+) for C15H21N5O2 m/z 304.2 [M+H]+, 326.1 [M+Na]+; LCMS: Compound in solvent front; 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.27 (d, J=3.63 Hz, 1H), 6.63 (d, J=3.63 Hz, 1H), 5.02 (dt, J=12.14, 6.23 Hz, 1H), 4.92-4.99 (m, 1H), 4.48-4.61 (m, 1H), 2.82-2.91 (m, 1H), 2.71-2.82 (m, 1H), 2.40 (dt, J=12.65, 6.52 Hz, 1H), 2.27 (m, 1H), 2.04 (q, J=12.14 Hz, 1H), 1.56 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21](=O)[C:22](=CN(C)C)[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH:28][CH2:29][CH2:30][N:31]([C:33](OC(C)(C)C)=O)[NH2:32]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:33]5[N:31]([CH2:30][CH2:29][OH:28])[N:32]=[CH:21][C:22]=5[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C=C1C(=O)CCc2c1sc1ncnc(Nc3ccc(F)c(Cl)c3)c21
Reactant: CC(C)(C)OC(=O)N(N)CCO
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one (10.6 g, 0.026 mol) was heated to near homogeneity in dioxane (250 mL). The heat was turned off and nitrogen was bubbled through the murky solution for ˜20 min while it cooled. The reaction flask was then evacuated and filled with nitrogen three times. In a separate flask, tert-butyl 1-(2-hydroxyethyl)hydrazinecarboxylate (13.9 g, 0.079 mol) was dissolved in toluene, concentrated in vacuo to a residue, redissolved in dioxane, and sparged with nitrogen for ˜10 minutes. The solution of tert-butyl 1-(2-hydroxyethyl)hydrazinecarboxylate was evacuated and filled with nitrogen three times and then was cannulated into the flask containing the enamine. The resulting mixture became a clear red solution upon heating in an oil bath at ˜80° C. After 6 h the reaction mixture was concentrated in vacuo to half its original volume. Xylenes (250 mL) was added and the mixture was again concentrated to half the original volume. Xylenes (250 mL) was added and the mixture was concentrated to half the original volume a final time. During the solvent swap, a yellow-orange solid precipitated. The resulting slurry was submerged in an ice-bath and TFA (200 mL) was added dropwise via an addition funnel. The slurry became a brown-red solution that was allowed to stir overnight at room temperature. Two liquid phases were present the next morning. Solvent (˜200 mL) was removed in vacuo at ˜40° C. The remaining mixture (˜300 mL) was diluted with EtOAc (500 mL) and washed twice with 500 mL portions of 1.0 N NaOH. Significant emulsions formed during the final base wash, so more EtOAc (500 mL) was added with brine (100 mL) before collecting the aqueous layer. The organic layer was then washed with brine (2×300 mL). The organic layer was filtered through a small pad of silica gel (˜1″ diameter×2″) and the pad was washed with EtOAc (750 mL). The filtrate was concentrated to a total volume of ˜200 mL, resulting in the precipitation of solid. The slurry was filtered by vacuum filtration on a Buchner funnel and the resulting solid was allowed to dry overnight on the filter. An orange solid was obtained (7.25 g, 66%, >98% regioisomeric purity by 1H-NMR). 1H NMR (DMSO-d6) δ 8.56 (s, 1H), 8.38 (s, 1H), 7.88 (m, 1H), 7.66 (s, 1H), 7.61 (m, 1H), 7.40 (t, 1H), 4.93 (t, 1H), 4.16 (t, 2H), 3.73 (dt, 2H), 3.42 (t, 2H), 3.10 (t, 2H); LCMS RT=2.76 min; [M+H]+=416.4.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].C([Li])CCC.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13].[CH:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].Cl>CCCCCC.CCOCC>[OH:21][CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]([CH3:5])([CH3:1])[C:3]#[C:4][Si:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCC=O
Reactant: C#CC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCC(O)C(C)(C)C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
To a solution of 6.8 parts of 3-methyl-1-butyne in 50 parts by volume of ether, cooled to -40°, is added dropwise 46.7 parts by volume of 2.14 M n-butyl lithium in hexane. The resulting solution is allowed to warm to room temperature and is stored at that temperature for about 15-30 minutes, then cooled again to -40° and 10.8 parts of trimethylsilyl chloride is added. The temperature is allowed to rise to room temperature and the mixture is stirred for about 1 hour, at the end of which time 46.7 parts by volume of 2.14 M n-butyl lithium in hexane is added dropwise. The resulting reaction mixture is heated at the reflux temperature for about 18 hours, then is cooled to about -10° and 8.6 parts of valeraldehyde is added. The mixture is allowed to warm to room temperature, then is stirred for about 2 hours and poured into a mixture of ether and dilute hydrochloric acid. The ether layer is washed with water, dried over anhydrous sodium sulfate, stripped of solvent under reduced pressure and distilled under vacuum to afford (4(RS)-hydroxy-3,3-dimethyl-1-octynyl)trimethylsilane, characterized by an infrared absorption maximum of about 2160 reciprocal centimeters.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH:14]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(#N)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH2:14][CH2:15][N:24]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])[CH2:23][C:22]1[CH:25]=[CH:26][C:19]([C:18]([F:27])([F:28])[F:17])=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccc(C(F)(F)F)cc1
Yield: 34.6 %

Procedure:
A solution of 1.0 g (4.44 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.32 ml (2.22 mmol) para-trifluoromethylbenzylamine in 25 ml acetonitrile was stirred for 16 h at 80° C. Concentration in vacuo and flash chromatography (gradient: 0-10% MeOH in EtOAc) afforded 480 mg (31%) of the title compound as a light brown oil. MS m/e (%): 626 (M+H+, 100).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[Br-].[CH2:29]([Zn+])[CH2:30][CH3:31]>C1COCC1.[Cu]I>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC[Zn+]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: [Cu]I
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OCC)c1OC
Temperature: 160 °C

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.1 g), palladium chloride dppf adduct with DCM (0.01 g), copper (I) iodide (0.003 g) and n-propyl zinc bromide (0.5M solution in THF, 0.96 ml) in THF (0.5 ml) was stirred and heated in the microwave at 160° C. for 10 minutes. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-propylbenzoate (0.034 g) as a clear gum.
Reaction SMILES: [C:1]([S:4]C)(C)=O.O(CC)[K].C1(O)C=CC=CC=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]=[C:30]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:31])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C@H:29]([S:4][CH3:1])[C@H:30]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:31])=[O:23])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(=C[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CSC(C)=O
Agent: CCO[K]
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CS[C@H]([C@@H](C)C(=O)OCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of AcSMe (24.4 g, 0.27 mol) in THF (580 ml) cooled in an ice-bath was added KOEt (22.8 g, 0.27 mol). After stirring for 3.5 h at room temperature, phenol (11.9 ml, 0.14 mol) and a solution of (2S)-2-(2-benzyloxycarbonyl-propenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (15.6 g, 0.045 mol) in THF (50 ml) were successively added to the mixture. After 45 min, the mixture was quenched with saturated NH4Cl aqueous solution and concentrated in vacuo. The residue was diluted with EtOAc (600 ml), and washed with 1N NaOH aqueous solution (300 ml×3) and saturated brine (200 ml). The organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc=9/1) to give (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester which was contaminated with PhOH. The collected fraction which included (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was washed with 5N NaOH aqueous solution (300 ml) and H2O (300 ml) to remove phenol, and dried over anhydrous MgSO4. The organic layer was concentrated in vacuo to obtain (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (12.5 g, 70%).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[O:5][CH3:6].[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br.O>CN(C)C=O>[CH3:1][O:2][N:3]([CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([Br:10])[CH:12]=1)[C:4](=[O:7])[O:5][CH3:6]
Reactant: CONC(=O)OC
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(Cc1cccc(Br)c1)OC
Reaction time: 3 h
Yield: 455 %

Procedure:
2.52 g of methyl N-methoxycarbamate in N,N-dimethylformamide (30 ml) was stirred together with 1.15 g of 60% sodium hydride at room temperature for 30 minutes. 1.00 g of 3-bromobenzyl bromide was added dropwise at room temperature, and the resulting solution was stirred for 3 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 4.99 g of methyl N-methoxy-N-(3-bromobenzyl)carbamate as a transparent viscous liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].C(N([CH2:27][CH3:28])CC)C.[C:29]1(C)[C:30]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:32]=C[CH:34]=1>ClCCl.O>[C:1]([O:5][C:6]([NH:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH2:9][CH2:10][O:11][S:35]([C:30]1[CH:31]=[CH:32][C:27]([CH3:28])=[CH:34][CH:29]=1)(=[O:37])=[O:36])=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2 g (6.75 mmol) [3-Hydroxy-1-(3-nitro-phenyl)-propyl]-carbamic acid tert-butyl ester were dissolved in 10 ml dichloromethane and 1.4 ml (20.1 mmol) triethylamine. Under ice-cooling, 1.54 g (8.10 mmol) toluene sulfonic acid chloride in 5 ml dichloromethane were added and the mixture was stirred 30 min at 0° C. and 18 h at room temperature. The reaction mixture was diluted with 10 ml water and 30 ml dichloromethane, the organic layer was separated and washed with water, dried over Na2SO4 and evaporated to dryness. The crude product was used without further purification. 3.05 g, Rt.=3.35 min (method C), LCMS: 351 (M-boc+H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[OH-:19].[NH4+]>O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:1][C:8](=[O:19])[NH:9]1
Reactant: O=Cc1ccccc1Cl
Reactant: N#CCc1ccccc1
Reactant: [OH-]
Agent: [NH4+]
Solvent: O
Product: O=C1Cc2ccccc2C(c2ccccc2Cl)N1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 47 %

Procedure:
This material was prepared in a similar manner to that described in Acta Chimica Academiae Scientiarum Hungaricae 1969, 60(1-2), 177. Thus a mixture of benzyl cyanide (40 g, 342 mmol) and polyphosphoric acid (200 g) was heated and stirred at 80° C. for 45 minutes. 2-Chlorobenzaldehyde (24 g, 171 mmol) was added with very vigorous stirring over 25 minutes. The mixture was heated to 135° C. for 31/2 h, cooled to 100° C. and poured into water (450 ml). 0.88 Ammonium hydroxide (600 ml) was added and the mixture left overnight. The precipitate was filtered off and refluxed in 5% sodium hydroxide (500 ml). The mixture was filtered hot after 2 h and the solid (30 g) chromatographed (SiO2, 200 g) using chloroform as eluent. This gave a solid that was crystallised (ethanol) to give 1-(2-chlorophenyl)-1,4-dihyroisoquinol-3-one (20.5 g, 47%) m.p. 180°-2° C.