Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.7 %

Procedure:
0.200 g (0.6 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.0 mmol) of 4-nitrobenzyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:9) to obtain the product as a oil (0.29 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:20]([OH:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2)=O.CC(O)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([NH:23][C@H:19]([CH2:18][C:16]2[N:15]=[N:14][N:13]([C@H:9]3[C:10]4[C:5](=[CH:4][C:3]([CH2:1][N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:12][CH:11]=4)[CH2:6][CH2:7][CH2:8]3)[CH:17]=2)[C:20]([OH:22])=[O:21])(=[O:25])=[O:26])=[CH:32][CH:31]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn(C3CCCc4cc(C=O)ccc43)nn2)C(=O)O)cc1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(CN5CCCCC5)ccc43)nn2)C(=O)O)cc1
Reaction time: 2 h

Procedure:
(2R)-3-(1-(6-Formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)-propanoic acid (85.8 μM, 1 eq) piperidine (3 eq) and HOAc (3 eq) were heated to 40° C. for 3 d. Additional portions of piperidine (3 eq) and HOAc (3 eq) were then added. After 2 h, MP-BH4 was added and the reaction mixture was allowed to stir for 3 days. The reaction mixture was concentrated and was purified using reverse phase conditions C18 (0-100% acetonitrile/water) to afford the title compound. MS (m/z): 538.2 (m+H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccccn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cc2ccccn2)cc1
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of 2- (4-nitrobenzyl)pyridine (J. Chem. Soc., p549, 1929) (1.50 g) and 5% Pd-C (0.15 g) in ethanol (30 ml) was vigorously stirred under hydrogen atmosphere for 8 hours, and the Pd-C was filtered off. The filtrate was concentrated under reduced pressure, and the residue was separated and purified with column chromatography (ethyl acetate/hexane=1:→2:1) to give 2—(4-aminobenzyl)-pyridine (1.09 g) as yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH3:23])[CH2:5][CH:6]([O:21][CH3:22])[CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19]>C(Cl)Cl.CCOCC.[O-2].[O-2].[Mn+4]>[CH3:22][O:21][CH:6]([CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19])[CH2:5][C:4]([CH3:23])=[CH:3][CH:2]=[O:1]
Reactant: COC(C=C(C)C=CC1=C(C)CCCC1(C)C)CC(C)=CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(C=C(C)C=CC1=C(C)CCCC1(C)C)CC(C)=CC=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
1.34 g (4.2 mmol) of 1-hydroxy-5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-2,6,8-nonatriene (IV) was dissolved in 40 ml of methylene chloride, to which was then added 3.66 g (42 mmol) of manganese dioxide and the mixture was stirred at an ambient temperature for 24 hours. After the resulting mixture was diluted with an ether, it was dried over anhydrous magnesium sulfate and filtered, followed by evaporation of the solvent to obtain 5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-nona-2,6,8-trienal (V) as a mixture of E and Z isomers in a yield of 91%.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[C:4]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)N1CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
A solution of 2.0 g of diketene in 10 ml of dry benzene was added dropwise at 10°-15° C. to a solution of 3.84 g of 3-phenylindoline in 35 ml of dry benzene. The solution was then stirred at room temperature for 90 minutes and the volatile components were removed in vacuo. The residue was recrystallized from ether to give 4.2 g of N-acetoacetyl-3-phenylindoline. A further recrystallization from ethanol gave a purer product having a melting point of 88°-9° C.
Reaction SMILES: N1CCCCC1.C([O:10][C:11]1[C:16]([CH3:17])=[C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:21]=3[CH:22]=2)[O:14][C:13](=[O:29])[C:12]=1[CH3:30])(=O)C.[S:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].[OH-].[Na+]>C1COCC1>[CH3:30][C:12]1[C:13](=[O:29])[O:14][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([CH:27]=[C:35]4[C:34](=[O:36])[NH:33][C:32](=[O:37])[S:31]4)=[CH:23][C:21]=3[CH:22]=2)=[C:16]([CH3:17])[C:11]=1[OH:10]
Reactant: CC(=O)Oc1c(C)c(-c2cc3cc(C=O)ccc3o2)oc(=O)c1C
Reactant: O=C1CSC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1c(-c2cc3cc(C=C4SC(=O)NC4=O)ccc3o2)oc(=O)c(C)c1O
Reaction time: 1 h

Procedure:
Piperidine (100 mg) was added to a solution of 4-acetyloxy-3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-2H-pyran-2-one (374 mg) and 1,3-thiazolidine-2,4-dione (135 mg) in THF (50 ml), and the mixture was subjected to heated reflux for 4 hours. After cooling, a 15% sodium hydroxide aqueous solution (10 ml) was added to the reaction solution, and then after stirring for one hour it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH=5/1) to obtain 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: Brc1cccc(Br)n1
Product: Brc1cccc(OCc2ccccc2)n1
Yield: 76 %

Procedure:
2,6-Dibromopyridine was condensed with benzyl alcohol by Ullmann reaction to obtain 2-benzyloxy-6-bromopyridine (yield 76%). This was further condensed with m-cresol by Ullmann reaction to obtain 2-benzyloxy-6-(3-methylphenoxy)-pyridine (yield 83%), which was then subjected to catalytic reduction in the presence of a catalyst, 5% palladium-carbon, to obtain 6-(3-methylphenoxy)-2-pyridone (yield 96%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[CH3:12][CH:13]1[CH2:15][N@@:14]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CN(CCN(C)C)C>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:14][C@H:13]([CH2:15][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH3:12])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)[N@]2CC2C)cc1
Agent: CN(C)CCN(C)C
Agent: Cc1ccc(S(=O)(=O)[N@@]2CC2C)cc1
Agent: [Li]CCCC
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)CC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(Trimethylsilyl)acetylene (5.8 mL, 41.65 mmol) was dissolved in 15 mL dry TMEDA and cooled to 0° C. n-BuLi (12.50 mL, 31.24 mmol) was added dropwise via an addition funnel and the resulting mixture was stirred for 20 min at RT. The solution was recooled to 0 ° C. and cannulated to a 0° C. solution of (S)-2-methyl-1-(4-methylbenzenesulfonyl)aziridine (2.2 g, 10.4 mmol) in 15 mL TMEDA . The resulting solution was stirred for 20 h at RT. The reaction mixture was cooled to 0° C. and quenched with sat. NH4Cl and the organic solvent removed. The residue was partitioned between EtOAc and H2O. The organic layer was washed with sat. NaHCO3, brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 (90% hexanes: 10% acetone) to afford the title compound. MS (m/z): 310.2 (M+H) (Calc'd for C15H23NO2SSi: 309.5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([NH2:28])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:36][CH:37]1[CH2:40][CH:39]([S:41](Cl)(=[O:43])=[O:42])[CH2:38]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([NH:28][S:41]([CH:39]3[CH2:40][CH:37]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:38]3)(=[O:43])=[O:42])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)C1CC(OCc2ccccc2)C1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Yield: 49.3 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Intermediate (I-5d), 8-Amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (I-5c: 350 mg, 0.7 mmol) in pyridine (3 mL) was reacted with 3-benzyloxy-cyclobutanesulfonyl chloride (273 mg, 1.05 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 250 mg of the product (45.3% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[F-:23].[Cs+].CS(C)=O>CCOC(C)=O>[F:23][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)Oc1ccc(-c2cc(-n3cccn3)cc(Cl)n2)cc1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2cc(-n3cccn3)cc(F)n2)cc1
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a 2 dram vial equipped with a stir bar and charged with 2-chloro-6-(4-isopropoxyphenyl)-4-(1H-pyrazol-1-yl)pyridine (41 mg, 0.13 mmol) was added CsF (199 mg, 1.31 mmol), then DMSO (0.7 mL). The vial was placed in a 140° C. heating block with vigorous stirring for 18 hours. The reaction mixture was transfered to a separatory funnel and was diluted with EtOAc (50 mL). The organic solution was washed twice with brine:water (25 mL:25 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford 2-fluoro-6-(4-isopropoxyphenyl)-4-(1H-pyrazol-1-yl)pyridine as a yellow solid (25 mg, 63%). 1H-NMR (500 MHz, CDCl3) δ 8.07 (dd, J=2.6, 0.4 Hz, 1H), 8.03-7.99 (m, 2H), 7.95 (t, J=1.4 Hz, 1H), 7.81 (d, J=1.4 Hz, 1H), 7.09 (t, J=1.6 Hz, 1H), 7.01-6.97 (m, 2H), 6.57 (dd, J=2.7, 1.7 Hz, 1H), 4.65 (spt, J=6.1 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H); MS: MS m/z 298.2 (M++1).
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].N[C:7]1[C:8]([Cl:18])=[C:9]([Cl:17])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.[ClH:19]>O>[Cl:19][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[Cl:18]
Reactant: Cl
Reactant: Nc1cc(C(F)(F)F)cc(Cl)c1Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 55 %

Procedure:
A solution of sodium nitrate (39 g.) in water (85 ml.) is added over 1 hour to a solution of 5-amino-3,4-dichloro-α,α,α-trifluorotoluene (117.5 g., 0.51 mol) in 1700 ml. concentrated hydrochloric acid at -6° C. and the solution stirred for 1 hour then filtered. The filtrate is added to a solution of cuprous chloride (76.5 g.) in concentrated hydrochloric acid (500 ml.) over 5 minutes at 0° to 8° C. and gradually heated to 80° C. over 80 minutes. The reaction mixture is cooled to 35° C. and extracted with hexane (2×300 ml.). The extract is washed with water, 2% sodium hydroxide solution, dried and distilled to give 3,4,5-trichloro-α,α,α-trifluorotoluene (70 g., 55%) b.p. 82°-86° C./10 mm, 95% pure.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH:14]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A solution of tert-butyl 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynylcarbamate (300 mg, 0.78 mmol) in CH2Cl2 (10 mL) was treated with TFA (2 mL) and stirred at rt for 45 min. The mixture was concentrated under vacuum and the residue was partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was separated and washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (180 mg, 80%) as a red oil. 1H NMR (DMSO-d6) δ 8.65 (s, 1H), 8.47 (d, 1H, J=5.6 Hz), 8.43 (dd, 1H, J=10.7, 2.5 Hz), 8.17 (d, 1H, J=8.6 Hz), 7.54 (t, 1H, J=8.6 Hz), 7.04 (d, 1H, J=5.6 Hz), 3.49 (s, 2H); MS(ESI+): m/z 288.17 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:6][S:5][C:4]([NH:7][C:8](=[O:10])[CH3:9])=[N:3]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[S:5][CH:6]=1
Reactant: CC(=O)NC1=NC(=O)CS1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1nc(Cl)cs1
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-(4-oxo-4,5-dihydro-thiazol-2-yl)-acetamide (Step 129.2) (14.8 g, 94 mmol) and POCl3 (175 mL, 20 eq) is heated to 105° C., stirred for 15 min, allowed to cool and concentrated. The residue is poured onto ice-H2O and extracted with EtOAc (2×100 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×100 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 99:1) to afford 13.9 g of the title compound as a white solid: ESI-MS: 177.0 [M+H]+; tR=2.74 min (System 1); TLC: Rf=0.66 (DCM/MeOH, 9:1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:28][N:29]([CH3:40])[C:30](=[O:39])[CH2:31][CH:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(O)(=O)C>[CH2:15]([N:22]1[CH2:27][CH2:26][N:25]([CH:35]2[CH2:36][CH2:37][CH:32]([CH2:31][C:30]([N:29]([CH3:28])[CH3:40])=[O:39])[CH2:33][CH2:34]2)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CN(C)C(=O)CC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C(=O)CC1CCC(N2CCN(Cc3ccccc3)CC2)CC1

Procedure:
Sodium triacetoxyborohydride (1.5 g) is added to a mixture of 1-benzylpiperazine (714 μl), N,N-dimethyl-2-(4-oxocyclohexyl)acetamide (820 mg) and acetic acid (680 μl) in THF (50 ml). The mixture is stirred over night. An aqueous solution of potassium carbonate (20%) is added and the mixture stirred for 30 min. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with satd. aqueous NH4Cl (2×), dried (Na2SO4) and filtered, and the solvent is removed under reduced pressure. The crude product is purified using reverse phase HPLC (Varian C18 Microsorb) eluting with a gradient of 10-100% acetonitrile in water containing 0.2% trifluoroacetic acid to give 2-(4-(4-benzylpiperazin-1-yl)cyclohexyl)-N,N-dimethylacetamide (800 mg). m/z(+) 344 (M+H+). The 2-(pyrrolidin-1-yl)ethanamine and the tert-butyl 4-oxopiperidine-1-carboxylate used to synthesize 34 were purchased from Aldrich. The tert-butyl 3-oxocyclohexylcarbamate used to synthesize 50 was purchased from AB Chem. The 1-benzyl-1,4-diazepane used to synthesize 52 was purchased from Lancaster.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](O)([CH3:11])[CH3:10].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([CH3:11])=[CH2:10]
Reactant: CC(C)(O)c1c(F)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C)c1c(F)cccc1Cl
Yield: 67.5 %

Procedure:
A mixture of 2-(2-chloro-6-fluorophenyl)propan-2-ol (19.0 g), concentrated sulphuric acid and water was heated at reflux for 2 hours. It was cooled and extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with hexane to give 2-(2-chloro-6-fluorophenyl)-propene (11.6 g) as a dear oil, NMR (CDCl3) 1.95(s,3H) 4.95(s,1H), 5.85(s,1H), 6.85-7.0(m,1H), 7.05-7.2(m,2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COC(CCC([O:15][C:16]1[C:17]([CH3:33])=[C:18]([CH3:32])[C:19]2[O:23][CH:22]([CH2:24][CH2:25][C:26](OC)=[O:27])[S:21][C:20]=2[C:30]=1[CH3:31])=O)=O.C(OCC)(=O)C.Cl>O1CCCC1>[OH:15][C:16]1[C:17]([CH3:33])=[C:18]([CH3:32])[C:19]2[O:23][CH:22]([CH2:24][CH2:25][CH2:26][OH:27])[S:21][C:20]=2[C:30]=1[CH3:31]
Reactant: COC(=O)CCC(=O)Oc1c(C)c(C)c2c(c1C)SC(CCC(=O)OC)O2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Temperature: 0 °C

Procedure:
10 g of lithium aluminum hydride were suspended in 500 ml of dried tetrahydrofuran, and then a solution of 32.0 g of methyl 3-[5-(3-methoxycarbonylpropionyloxy)-4,6,7-trimethyl-1,3-benzoxathiole-2-yl]propionate (prepared as described in Example 31) in 160 ml of tetrahydrofuran was added dropwise with stirring and ice-cooling and under a nitrogen stream to the suspension. After the dropwise addition, the reaction mixture was stirred for 1 hour at room temperature and then refluxed for 4 hours. The reaction mixture was then cooled with ice-water, after which a mixture of 10 g of ethyl acetate and 50 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 1 hour at room temperature, after which aqueous tetrahydrofuran was added dropwise. The reaction mixture was then poured into ice-water. The pH of the mixture was adjusted to an acid value by the addition of a 10% w/v aqueuous solution of hydrochloric acid, and the precipitating product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography and the title compound, melting at 116.5°-117° C., was obtained from the fraction eluted with a 9:1 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([OH:15])[C:9]=1[C:16](=[O:18])[CH3:17].[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C@@H:26]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[O:25][C@@H:24]1Br)(=[O:21])[CH3:20].Cl>C(Cl)(Cl)Cl.[Cl-].C([N+](CCCC)(CCCC)CC1C=CC=CC=1)CCC.O>[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C@@H:26]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[O:25][C@H:24]1[O:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([OH:15])[C:9]=1[C:16](=[O:18])[CH3:17])(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)c1c(O)cc(C)cc1O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cc(C)cc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 27 h
Yield: 80.2 %

Procedure:
Potassium carbonate (414 g) is suspended in chloroform (1.3 l), and thereto is added dropwise water (29 ml) gradually. To the mixture are added tributylbenzylammonium chloride (37 g), 2',6'-dihydroxy-4'-methylacetophenone (100 g), and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (419 g), and the mixture is stirred at room temperature for 27 hours. To the mixture is added water (21 ml), and the mixture is stirred for further 2.5 hours. The mixture is neutralized with 18% hydrochloric acid (about 500 ml) under ice-cooling. To the mixture are added 18% hydrochloric acid (about 200 ml) and water (500 ml), and the chloroform layer is separated, washed with water and a saturated aqueous sodium chloride solution, dried, and concentrated. To the residue is added methanol (400 ml), and the mixture is concentrated under reduced pressure to about a half volume thereof. To the resultant is added methanol (2 l), and the mixture is heated a little, and stirred under ice-cooling for 30 minutes. The precipitates are collected by filtration, and dried under reduced pressure to give 2'-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylacetophenone (239.75 g). The physicochemical properties of the compound are the same as those of the compound obtained in Reference Example 2.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:16][OH:17].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[OH:17][CH2:16][CH2:15][CH:14]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH2:12][N:11]([CH3:10])[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCCC(CCO)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC(CCO)c1ccccc1)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
N,N-Diisopropylethylamine (0.352 mL, 261 mg, 2.02 mmol) and 5-(methylamino)-3-phenylpentan-1-ol (300 mg, 1.68 mmol) from Example 180, Step B, were dissolved in 4.0 mL of dichloromethane. The solution was cooled to 0° C., benzoyl chloride (0.205 mL, 248 mg, 1.77 mmol) was added dropwise, and the mixture was stirred for an additional 30 min. The mixture was then partitioned between 15 mL of dichloromethane and 15 mL of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with 2×15 mL of dichloromethane. The combined organic extracts were washed with 20 mL of brine, dried over sodium sulfate, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 10% ethyl acetate in dichloromethane, to give 467 mg of the title compound. 1NMR (400 MHz, CD3OD) was complicated by the presence of a mixture of rotamers: δ 7.45-7.06 (m, 9H), 6.97 (d, 1H, J=8 Hz), 3.53-3.23 (m, 2H), 3.17-3.00 (m, 2H), 3.02 and 2.85 (two singlets, 3H), 2.88-2.78 and 2.57-2.49 (two multiplets, 1H), 2.07-1.64 (m, 4H). Mass spectrum (ESI): m/z=298 (M+1).