Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17](=[CH2:21])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1.C(OC(C)C)(C)C>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:21][CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=1)[C:18]([OH:20])=[O:19]
Reactant: Nc1ccccc1S
Reactant: C=C(C(=O)O)c1cccc(OC)c1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: COc1cccc(C(CSc2ccccc2N)C(=O)O)c1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
7.6 ml of aminothiophenol were added to a solution of 8.9 g of the product of Step C and 130 ml of ethanol and the solution was stirred for 90 minutes at 95° C. and left to return to ambient temperature. The ethanol was eliminated under reduced pressure and 50 ml of isopropyl ether were added. Crystallization was started to obtain 7.2 of the expected product which was separated off and dried at 80° C. under reduced pressure. After chromatography of the mother liquors on silica (eluant: ethyl acetate-cyclohexane 1-1), 710 mg of pure product were obtained (Rf=0.16) which after crystallization from ether melted at 128° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[N:11]1([CH2:17][CH2:18][NH:19][C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
A 50 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.187 mL, 1.77 mmol), 2-Morpholin-4-yl-ethylamine (0.299 g, 2.30 mmol) and dioxane (9.0 mL). To the solution, diisopropyl ethyl amine (0.463 mL, 2.66 mmol) was added dropwise and allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×˜30 mL), and with brine (2×˜30 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording (2-Morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine as a yellow solid (0.315 g, 1.26 mmol, 71% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH2:38][CH:39]([CH3:41])[CH3:40])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and isobutylamine according to conditions described in general procedure C. Mp: 96-97° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.60-0.80 (m, 6 H), 1.80 (m, 1 H), 2.89 (s, 2 H), 3.26 (t, J=4.8 Hz, 4 H), 3.77 (t, J=5.2 Hz, 4 H), 6.20-6.40 (bd, 1 H), 7.03-7.07 (m, 1 H), 7.22 (s, 1 H), 7.27 (d, J=8.4 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.55-7.62 (m, 3 H), 7.81-7.83 (m, 1H), 8.00 (d, J=8.4 Hz, 1 H), 8.21 (s, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH2:29][OH:30])[C:26]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:31]([OH:34])([CH3:33])[CH3:32])=[C:27]([CH2:29][OH:30])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(O)c1ccc(Cl)nc1CO
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(C(C)(C)O)c(CO)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (105 mg, 0.34 mmol) and 2-[6-chloro-2-(hydroxymethyl)pyridin-3-yl]propan-2-ol (71 mg, 0.35 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:9][CH:10]=2)=[O:30])=[CH:32][CH:33]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Nc1ccc(-c2ncccc2Cl)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(-c3ncccc3Cl)cc2)cc1
Reaction time: 1 h

Procedure:
The product from Example 41A (17.5 mg, 0.0855 mmol), DMAP (catalytic amount), and pyridine (21 μL, 0.26 mmol) were combined in CH2Cl2 (0.5 mL) and treated with 4-tert-butylbenzoyl chloride (33 μL, 0.17 mmol). After stirring for 1 hour, the mixture was diluted with saturated NaHCO3 (1 mL) and extracted with CH2Cl2 (3×1 mL). The organic layer was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (50% diethyl ether in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3)δ 8.59 (dd, 1H), 7.91 (br s, 1H), 7.83 (d, 2H), 7.81 (dd, 1H), 7.78 (d, 4H), 7.51 (d, 2H), 7.21 (dd, 1H), 1.36 (s, 9H); MS (m/z) 365.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][C:4]=2[O:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:6]2[C:5]3[CH:9]=[CH:10][C:11]([CH2:13][N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:12][C:4]=3[O:3][C:2]([CH3:26])([CH3:1])[C:7]2=[O:8])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OC(C)(C)C(=O)N2)S(C)(=O)=O
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OC(C)(C)C(=O)N2c1ccc(F)cc1)S(C)(=O)=O
Yield: 20.1 %

Procedure:
Tert-butyl [(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-methyl](methylsulfonyl)carbamate (compound obtained in Reference Example 48(2), 200 mg) and 4-fluorophenylboronic acid (146 mg) were treated in the same manner as described in Reference Example 1(2) to give tert-butyl {[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methyl}(methylsulfonyl)carbamate (50 mg) as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:12]([O:14]C)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[Li+]>C1COCC1.O.Cl>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C1(CCCCC(C)C)CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCCCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
To a solution of methyl 1-(5-methyl-hexyl)cyclopentanecarboxylate (110 mg, 0.4 mmol) in 21 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (26 mg, 0.6 mmol) in 5.0 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 60 mg (71%) of the desired product. MS [M+H]+213.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]([F:13])([F:12])/[C:7](=[N:10]/[OH:11])/[S:8][CH3:9]>>[F:5][C:6]([F:13])([F:12])/[C:7](=[N:10]/[O:11][C:3](=[O:4])[NH:2][CH3:1])/[S:8][CH3:9]
Reactant: CN=C=O
Reactant: CS/C(=N\O)C(F)(F)F
Product: CNC(=O)O/N=C(\SC)C(F)(F)F
Yield: 95.6 %

Procedure:
A mixture of 17.12 g (0.3 mol) of methyl isocyanate and 47.74 g (0.3 mol) of S-methyl (Z)-2,2,2-trifluoro-N-(hydroxy)thioacetimidate was sealed in a glass tube and heated at 100° in a steam bath for 17 hours. The contents of the tube were distilled at reduced pressure to give 62.02 g (96%) of S-methyl (Z)-2,2,2-trifluoro-N-(methylcarbamoyloxy)thioacetimidate as a colorless, viscous liquid: bp 96° (0.6 mm); nD25 1.4638; ir (neat) 5.73μ (C=O); 19F NMR (CFCl3) δ -64.6 ppm (q, J=1.2 Hz); 1H NMR (CFCl3) δ 2.63 ppm (q, J=1.2 Hz, 3), 2.88 ppm (d, J=4.5 Hz, 3H) and 6.47 ppm (NH).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH2:12]([O:19][C@@H:20]1[CH2:23][C@H:22]([NH2:24])[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CC#N>[CH2:12]([O:19][C@@H:20]1[CH2:23][C@H:22]([NH:24][C:2]2[C:3]([NH2:9])=[CH:4][CH:5]=[C:6]([F:8])[CH:7]=2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1C[C@@H](OCc2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(F)cc1N[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.92 mL, 8.36 mmol) in CH3CN (60 mL) were added cis-3-benzyloxycyclobutylamine (1.48 g, 8.36 mmol) and DIPEA (1.46 mL, 8.36 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo to afford the title compound as yellow oil (3.2 g, quantitative). To a solution of the product thus obtained (1.6 g, 5.03 mmol) in MeOH (20 mL) was added Iron powder (1.13 g, 20.12 mmol), NH4Cl (1.56 g, 30.18 mmol) and H2O (8 mL) and the reaction mixture stirred at 90° C. for 2 h under a nitrogen atmosphere. The resulting dark green mixture was filtered through a pad of Celite® and the filtrate concentrated in vacuo giving a dark brown solid. The crude material was partitioned between EtOAc (50 mL) and water (30 mL). Aqueous layer extracted with EtOAc (2×30 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to afford the title compound as a dark brown gum (1.13 g, 78%). 1H NMR (CDCl3, 300 MHz): δ 7.25-7.30 (5H, m), 6.6 (1H, dd, J=14.0, 2.8 Hz), 6.35-6.26 (1H, m), 6.26-6.18 (1H, m), 4.43 (2H, s), 3.95-3.83 (1H, m), 3.50-3.37 (1H, m), 2.90-2.78 (2H, m), 1.92-1.79 (2H, m). NMR: 328138. LCMS (Method B): RT 2.87 min [M+H]+ 287.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]([O:17]C)=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:2]=[N-:3].O.[OH-].[Li+].Cl>CO.O>[N:1]([CH2:4][C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]([OH:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:2]=[N-:3]
Reactant: COC(=O)c1c(CN=[N+]=[N-])c(-c2ccccc2)nc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Yield: 78.9 %

Procedure:
To a solution of methyl 3-(azidomethyl)-2-phenylquinoline-4-carboxylate (2b) (1781 mg, 5.0 mmol) in methanol (50 mL) was added the solution of lithium hydroxide monohydrate (674 mg, 28.1 mmol) in 25 mL water. The reaction mixture was stirred at reflux for 4 h and the residue was acidified with 1N HCl to pH 2. The volume of reaction mixture was reduced under reduced pressure. The resulting aqueous phase was extracted with ethyl acetate (150 mL). The organic phase was separated and washed with brine (20 ml) and dried over sodium sulfate and then concentrated in vacuo. Crystallization from ethyl acetate/hexane to afford the title compound (1200 mg, 66%) as an off white solid. MS APCI, m/z=305 (M+1). LCMS: 1.09 min.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:19]C)[CH:11]=2)=[O:8])=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([OH:19])[CH:11]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2)ccc1C(=O)O
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)c(O)c1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of 4-[(biphenyl-4-carbonyl)amino]-2-methoxy benzoic acid (2.78 g; 8 mmol) in CHCl3 (175 mL) was cooled until it became cloudy (approx. 40° C.) and BBr3 (1.5 mL; 16 mmol) was added over 2 minutes. The mixture was allowed to warm slightly with stirring for 2 hours after which time another 1.5 mL BBr3 (16 mmol) was added and the reaction mixture was left to warm to room temperature overnight. The resulting slurry was added brine (50 mL) and the organic solvent was removed in vacuo. The resulting solid was Isolated by filtration, washed with H2O, air dried, refluxed in 99% EtOH (100 mL), cooled and filtered to yield 2.2 g (82%) of a white solid. Mp. 266° C. (decomposes).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)=O.C(OP([CH2:59][C:60]#[N:61])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[C:37]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:39][C:34]([C:32]([C:31]2[CH:46]=[CH:47][C:48]([O:49][CH3:50])=[C:29]([O:28][CH3:27])[CH:30]=2)=[CH:59][C:60]#[N:61])=[CH:35][CH:36]=1
Reactant: COc1ccc(C(=O)c2ccc(-c3ccccc3)cc2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc(-c3ccccc3)cc2)cc1OC

Procedure:
3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4'-phenylbenzophenone (2.33 g, 7.32 mmol), diethylcyanomethylphosphonate (1.5 mL, 8.1 mmol) and lithium hexamethyldisilazide (8.1 mL, 8.1 mmol, 1M) with a reaction time of 22 hours. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 1.76 g (70%) of a mixture of the E and Z isomers as a white solid: mp 132.0-134° C.; 1H NMR (CDCl3) δ 7.70-7.39 (m, 18H), 7.10-6.80 (m, 6H), 5.69 (s, 1H), 5.68 (s, 1H), 3.95 (s, 6H), 3.93 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H); 13C NMR (CDCl3) δ 162.2, 151.1, 148.8, 148.6, 143.0, 142.6, 140.0, 137.9, 135.9, 131.4, 130.1, 129.3, 129.1, 128.8, 128.8, 127.9, 127.1, 127.0, 126.0, 126.9, 123.1, 122.2, 118.3, 118.2, 112.6, 111.1, 110.7, 93.2, 92.9, 56.0, 55.9, 55.8; Anal. Calcd for C23H19NO2. Theoretical: C, 80.92; H, 5.61; N, 4.10. Found: C, 80.55; H, 5.80; N, 3.95.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[C:7]1(=[O:13])[O:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:13])=[O:12]
Reactant: O=C1CCCCO1
Reactant: Sc1cccs1
Product: O=C(O)CCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with δ-valerolactone to obtain 5-(2-thienylsulfanyl) valeric acid represented by Chemical Formula [4].
Reaction SMILES: [C:1]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1.O>CCOCC>[OH:8][C@@H:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2)C1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.9 %

Procedure:
A solution of (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (10.3 g, 35.64 mmol) anhydrous toluene (120 mL) was cooled to −78° C. and (R)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 17.8 mL, 17.8 mmol, 0.5 equiv) was added slowly. After 5 min, catecholborane (11.4 mL, 107 mmol, 3 equiv) was added slowly. The reaction mixture was then transferred into the freezer (˜14.2° C.) and left overnight. LC-MS (16 min) showed 9:1 ratio of the R to S isomer. The mixture was cooled to 0° C. and water was added dropwise to quench the reaction. The reaction mixture was diluted with ether, washed with 5% aq NaOH (2×150 mL), water (150 mL), 5% aq HCl (100 mL), brine (100 mL), and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120 g silica gel column eluted with a 4-35% EtOAc in hexanes gradient. The purified product was recrystallized from an ether hexanes mixture to afford (R)-tert-butyl 3-((R)-hydroxy(phenyl)methyl)piperidine-1-carboxylate (4.45 g, 43%) as white solid with the ratio of R/S isomers 23.5:1. LC-MS (3 min) tR=1.70 min; LC-MS (3 min) tR=10.62 min, m/z 314 (M+Na). 1H NMR (CDCl3) δ 7.28 (m, 5H), 4.46 (d, 1H), 3.87 (d, 1H), 3.89-3.51 (br s, free exchange 1H), 3.00 (m, 2H), 2.68 (t, 1H), 2.52 (t, 1H), 1.94 (m, 1H), 1.76 (m, 1H), 1.65 (m, 1H), 1.42-1.20 (m, 10H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O.C1(C)C=CC=CC=1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=1)=[O:19])[CH3:26]
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)CC(C(=O)c1ccc(OC)cc1)c1ccccc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A suspension of NaH (12.8 mmol, 512 mg) in DMSO (23 mL) was added 4′-methoxy-2-phenylacetophenone (12.8 mmol, 2.89 g) in 10 ml toluene dropwise under argon. After 30 minutes of stirring, ethyl bromoacetate (1.4 mL, 1 eq.) in 10 mL of toluene was added and the mixture was stirred at rt overnight. The reaction was quenched by addition of 2N HCl (4 mL), and then 60 mL of water. The mixture was extracted with CH2Cl2 (3×30 mL), dried over MgSO4 and concentrated under vacuum overnight to afforded 4.0 g (99%) of 4-(4-methoxy-phenyl)-4-oxo-3-phenyl-butyric acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[CH2:21](Br)C#C.CO.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:21])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Product: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
3.50 g (11.81 mmol) of (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid tert-butyl ester (example 4A]) and 1.97 ml (17.71 mmol) of propargyl bromide were dissolved in 60 ml of acetonitrile and 3 ml of MeOH and treated with 6.62 g (14.17 mmol) Cs2CO3. After vigorous stirring for 3 h at ambient temperature and filtration, the solvent was evaporated and the residue redissolved in EtOAc. The organic phase was washed with aqueous 1N NaOH (two times) and aqueous 10% NaCl. After extraction of the water phases with EtOAc (two times), the organic phase was dried (Na2SO4) and evaporated to give 3.48 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]([N:9]([CH3:25])[C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH2:28]([NH:31][CH3:32])[CH:29]=[CH2:30]>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7](=[O:8])[N:9]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:31]([CH2:28][CH:29]=[CH2:30])[CH3:32])[CH2:12][CH2:11]2)[CH3:25])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Reactant: C=CCNC
Solvent: CO
Product: C=CCN(C)CCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
A solution of 219 mg (0.524 mmol) of trans-Methanesulfonic acid 4-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-butyl ester and 0.48 ml of N-allyl methyl-amine in 1 ml of MeOH was stirred over night at RT, and for 2 h under reflux. After concentration of the reaction-mixture in vacuo, the crude product was purified by chromatography over silica gel with EtOAc/H2O/AcOH/Aceton (6:2:1:1) to give 165 mg (80%) of clean trans-{4-[4-(Allyl-methyl-amino)-butyl]-cyclohexyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 393 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11]([C:33]2[CH:32]=[CH:31][N:30]=[C:29]([F:28])[CH:34]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccnc(F)c2)nc1Cl

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-fluoro-4-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=37%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:11][O:12][NH:13][CH3:14].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:13]([O:12][CH3:11])[CH3:14])=[O:6]
Reactant: O=C(Cl)CCC(F)(F)F
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCC(F)(F)F
Temperature: 0 °C
Yield: 270.9 %

Procedure:
4,4,4-Trifluorobutyric acid chloride (6.4 g from above) in CH2Cl2 (80 ml) was treated with O,N-dimethylhydroxylamine hydrochloride (60.0 mmol, 5.85 g). The mixture was cooled to 0° C., then treated with pyridine (160.0 mmol, 12.9 ml), then allowed to warm to room temperature overnight. The mixture was diluted with CH2Cl2 (200 ml), then washed with brine(2×50 ml). Solvent was removed from the volatile product by simple distillation at atmospheric pressure to provide 20 g of 4,4,4-trifluoro-N-methoxy-N-methyl butyramide, which may be used without further purification. 1H NMR (CDCl3) δ3.70 (3H, s), 3.19 (3H, s), 2.78-2.65 (2H, m), 2.57-2.40 (2H, m).