Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[NH:36][CH:35]=[CH:34]2.CC(N(C)C)=O>ClCCl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:41])[F:42])[NH:36][CH:35]=[CH:34]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1cc2cc[nH]c2cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3C(F)(F)F)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (276 mg, 2.0 mmol) and 5-hydroxy-6-trifluoromethylindole (110 mg, 0.55 mmol) and DMA (4.0 ml) were stirred at 95° C. for 1.5 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (89/10/1) to give a partially purified oil. This oil was further purified by high performance column chromatography on octadecylsilane reverse phase silica eluting with acetonitrile/water/trifluoroacetic acid (60/39.8/0.2) to give an oil which was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The dichloromethane layer was evaporated to give 6-methoxy-7-(3-piperidinopropoxy)-4(6-trifluoromethylindol-5-yloxy)quinazoline (62 mg, 25%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[O:8][C@@H:6]1[OH:7])(=[O:3])[CH3:2].[CH3:24][C:25]1([CH3:49])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]2[CH:30]=[C:29](/[C:37](/[CH3:48])=[CH:38]/[C:39]3[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=3)[CH:28]=[CH:27][C:26]1=2>N1C=CC=CC=1.CCOCC>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[O:8][CH:6]1[O:7][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39](/[CH:38]=[C:37](/[C:29]2[CH:28]=[CH:27][C:26]3[C:25]([CH3:49])([CH3:24])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]=3[CH:30]=2)\[CH3:48])=[CH:40][CH:41]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C/C(=C\c1ccc(C(=O)Cl)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)[C@H]1OC(OC(=O)c2ccc(/C=C(\C)c3ccc4c(c3)C(C)(C)CCC4(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.4 g of methyl 2,3,4-tri-O-acetyl-α-D-glucopyranuronate in 40 ml of pyridine was reacted at 0° C. with a solution of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoyl chloride in 70 ml of ether. The mixture was stirred at room temperature overnight, evaporated to dryness and the residue was chromatographed on silica gel with hexane/ethyl acetate. There was obtained methyl 2,3,4-tri-O-acetyl-1-O-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoyl]-D-glucopyranuronate as a mixture of the β- and α-anomers (ca 4:1). Melting point 149°-150° C. (from ethanol); [α]D25 =3° (c=1 in chloroform).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][N:10]=[C:11]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([O:14][CH3:15])=[O:13])=[C:4]([F:21])[CH:3]=1.[CH3:22]COC(C)=O.CO>COC(OC)N(C)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:22]=[C:17]([O:18][CH3:19])[C:16](=[O:20])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10]2)=[C:4]([F:21])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: COCC(=O)C(=NNc1cc(F)c(Br)cc1F)C(=O)OC
Agent: COC(OC)N(C)C
Solvent: CO
Product: COC(=O)c1nn(-c2cc(F)c(Br)cc2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of methyl 2-[(4-bromo-2,5-difluorophenyl)hydrazono]-4-methoxy-3-oxobutanoate (33 g, 90 mmol) in N,N-dimethylformamide dimethyl acetal (72 mL) was stirred at 110° C. for 3 h. After cooling to room temperature, the mixture was concentrated under reduce pressure. To the residue were added MeOH and silica gel The mixture was evaporated and purified by silica gel column chromatography eluting with hexane/AcOEt (1/0 to 0/1) and then AcOEt/MeOH (4/1) to give the title compound (27.9 g, 83% yield) as a brown gum: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.80 (3H, s), 3.83 (3H, s), 8.01 (1H, dd, J=8.7, 6.8 Hz), 8.15 (1H, dd, J=9.8, 6.0 Hz), 8.55 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 376 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1

Procedure:
For example, diarylamines may be produced using traditional Goldberg reactions. This method requires the derivatization of an aniline with acetic anhydride to produce an acetanilide compound. The acetanilide compound is then reacted with an arylbromide compound to produce an intermediate that must then be hydrolyzed in alcohol solution to produce the diarylamine compound. The formation of diphenylamines using the Goldberg reaction takes three reaction steps, and thus can be a lengthy process. Total cycle time for this process can be 3 to 5 days in the lab.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[Cl:11].Cl.[OH2:13]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:13])=[CH:5][C:4]=1[Cl:11]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Reactant: O
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0° C. was added dropwise DIBA1-H (1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0° C. for 1 h. 10 M HCl in water (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66° C.; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.CC(=CC)C.Cl([O-])=[O:18].[Na+].P(O)(O)([O-])=O.[Na+]>O.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:18])=[O:11])=[CH:2]1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2ncccc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c[nH]c2ncccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 86.4 %

Procedure:
2.3 g (15.7 mmol) of 1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde and 23 cm3 (217 mmol) of 2-methyl-2-butene were added to 120 cm3 of dioxane at a temperature of 20° C. and then a solution of 2.7 g (30 mmol) of sodium chlorite and 9.2 g (66.7 mmol) of monosodium phosphate in 100 cm3 of water was added. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 50 cm3 of water, filtered off, rinsed with 3 times 30 cm3 of water and then dried under a hood for 16 h. 2.2 g of 1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid were thus obtained in the form of a white powder. Mass spectrum: EI: m/z=162 M+ base peak.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[H][H].[C:23]1([CH:29]([CH3:33])[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][C:30](=[O:31])[CH:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:33])=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: CC(C(=O)Cl)c1ccccc1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)Oc1cc(=O)n(-c2ccccc2)c2ncccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 192 mg, 4.8 mmol, 1.2 eq.), and the mixture was stirred until no more hydrogen was generated, to obtain a solution. Then, 2-phenylpropionyl chloride (1.2 eq.) was added thereto, and the mixture was stirred at a room temperature for 1 hour. To the mixture was added a saturated sodium hydrogencarbonate aqueous solution, and the resulting precipitate was separated by filtration, washed with water, and dried to give 1-phenyl-4-(2-phenylpropionyloxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (1.45 g, yield 98%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.CN(C=O)C>O>[Br:14][C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cc(-c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
A mixture of 5-phenylpyrazin-2(1H)-one (0.86 g), N-bromosuccinimide (0.89 g) and DMF (16 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (0.18 g).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=1)=[O:13])[CH3:10].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.CCOCC.CCCCCC>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[C:18]=1[CH:28]([C:27]1[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=1)[OH:29])=[O:13])[CH3:10]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C(C)C)c(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
LDA (63 mL, 2M solution in THF, 126 mmol) was slowly (over 30 min) added to a solution of 2-bromo-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate A; 11.0 g, 42.1 mmol) in THF (200 mL) at −78° C. After 2 h at −78° C., a solution of 4-chlorobenzaldehyde (8.9 g, 63.2 mmol) in THF (10 mL) was slowly added and the reaction mixture was allowed to warm to −20° C. over 30 min. The reaction mixture was quenched at −20° C. with 6 ml of acetic acid, concentrated and taken up in EtOAc/water, extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The crude material was purified by chromatography (hexane/EtOAc, 60:40) to afford an orange foam. This was treated with 100 ml of 10% Et2O/hexane overnight and the resulting solid was filtered and rinsed with hexane to give the title compound as a white solid. ESI-MS: 403.1 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 0.90 (d, J=7.04 Hz, 3 H) 1.26 (t, J=7.04 Hz, 3 H) 1.45 (d, J=7.04 Hz, 3 H) 4.25 (qd, J=7.04, 3.13 Hz, 2 H) 4.69 (quin, J=7.04 Hz, 1 H) 6.73 (d, J=4.30 Hz, 1 H) 6.83 (d, J=4.30 Hz, 1 H) 7.27 (m, J=8.60 Hz, 2 H) 7.41 (m, J=8.60 Hz, 2 H); Rf=0.15 (hexane/EtOAc, 60:40)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:35][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(F)c(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(CCCBr)cc1C(F)(F)F
Yield: 73.1 %

Procedure:
Compound 69-2 (3.05 g) was dissolved in methylene chloride (46 ml), triphenylphosphine (4.00 g) and N-bromosuccinimide (2.69 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.86 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:37][CH2:36][C:35]2[C:34]3[CH:33]=[C:32]([Cl:38])[C:31]([Cl:39])=[CH:30][C:29]=3[N:28]([CH2:40][C:41](O)=[O:42])[C:27]=2[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[NH:1]([C:41](=[O:42])[CH2:40][N:28]1[C:29]2[CH:30]=[C:31]([Cl:39])[C:32]([Cl:38])=[CH:33][C:34]=2[C:35]2[CH2:36][CH2:37][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][CH2:26][C:27]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Reactant: Nc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3cc(Cl)c(Cl)cc23)CC1
Reaction time: 18 h
Yield: 51.2 %

Procedure:
DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over-Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (98:2) to give 0.12 g of impure product. Then, crystallization from EtOAc/heptane gave 91 mg (39%) of a white solid: mp 172.5° C.; IR (diffuse reflectance) 3288, 1699, 1661, 1602, 1550, 1498, 1472, 1442, 1421, 1367, 1309, 1298, 1268, 1252, 1162 cm−1; MS (CI) m/z 488 (M+H+), 390, 388, 354, 153, 152, 136, 95, 93, 52, 51; Anal. Calcd for C25H27Cl2N3O3: C, 61.48; H, 5.57; N, 8.60; found: C, 61.49; H, 5.67; N 8.51.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](F)=[O:6].[CH3:14][OH:15]>C(N(CC)CC)C>[Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([O:15][CH3:14])=[O:6]
Reactant: CO
Reactant: O=C(F)c1cc(F)c(F)c(Br)c1F
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(F)c(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
772 g of 3-bromo-2,4,5-trifluoro-benzoyl fluoride are added dropwise to 1460 ml of methanol and 340 g of triethylamin, while cooling with ice. The mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated in vacuo and the resulting residue is taken up in water and methylene chloride. The water is extracted with methylene chloride once more. The organic phase is dried with Na2CO3 and concentrated in vacuo. The resulting residue is distilled in vacuo.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=1[O:48][CH3:49])C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[CH3:49][O:48][C:41]1[CH:42]=[C:43]([O:46][CH3:47])[CH:44]=[CH:45][C:40]=1[C@@H:10]1[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]1[OH:8]
Reactant: COc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
To a solution of 1-deoxy-2,3,4,6-tetra-O-benzyl-1-(2,4-dimethoxyphenyl)-β-D-glucopyranose (1.1 g) in methanol (10 mL) and tetrahydrofuran (5 mL) was added 10% palladium-carbon powder (0.50 g), and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.47 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[F:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[F:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:31][CH2:30]1
Reactant: FCCN1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: OCCCN1CCN(CCF)CC1
Temperature: 85 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
3-Bromopropan-1-ol (581 mg, 4.18 mmol) and potassium carbonate (2.88 g, 20.9 mmol) were added to a solution of 1-(2-fluoroethyl)-piperazine diTFA salt (1.5 g, 4.18 mmol) in acetonitrile (11 ml). The reaction mixture was stirred at 85° C. for 4 hours and then loaded directly onto a column and eluted with a mixture of methanol in methylene chloride (7/93) to give 3-[4-(2-fluoroethyl)piperazin-1-yl]propan-1-ol (721 mg, 91%).
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:11]([O:13]N1C2C=CC=CC=2N=N1)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:11](=[O:13])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(C(=O)On1nnc2ccccc21)=C1SCS1
Product: CCOC(=O)C(C(=O)Nc1ccccn1)=C1SCS1
Yield: 51 %

Procedure:
Following the procedure of Example 27, the titled compound (51%) was prepared from ethyl 2-(1,3-dithietan-2-ylidene)-2-[(1-benzotriazolyl)oxycarbonyl]acetate and 2-aminopyridine.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=O)(C)(C)C.[OH:33][NH:34]C(C1C(COC(=O)C)CCCCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]=[CH:15][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:8]1[C:6](=[O:5])[NH:34][OH:33])[CH3:21]
Reactant: CCOC(=O)C=CC1CCCCN(S(=O)(=O)c2ccc(OC)cc2)C1C(=O)OC(C)(C)C
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)NO)cc1
Product: CCOC(=O)C=CC1CCCCN(S(=O)(=O)c2ccc(OC)cc2)C1C(=O)NO

Procedure:
3-(2-Hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-azepan-3-yl)-acrylic acid ethyl ester was synthesized from 3-(2-Ethoxycarbonyl-vinyl)-1-(4-methoxybenzene sulfonyl)-azepane-2-carboxylic acid tert-butyl ester in the same manner as the procedures used for the preparation of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-azepan-3-ylmethyl ester: MS (M+H)+ =427.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][CH2:11][CH2:12][S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CC(O)=O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:10][CH2:11][CH2:12][S:13][C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:8]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCCCCBr
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCCCBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Bromohexanoyl chloride (46 μl, 0.31 mmol) was dissolved in 0.2 ml CH2Cl2 and added to a solution of H2N—CH2—CH2-STrt (100 mg, 0.28 mmol), DIEA (97 μl, 0.56 mmol) in CH2Cl2 (0.8 ml). The mixture was stirred for 2 h at RT. The reaction mixture was acidified with AcOH (50 μl) and the solvent was removed in vacuo. The residue was purified on silica gel (heptane/EtOAc=1:1) to obtain Br—(CH2)5—CONH—(CH2)2-STrt.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[Cl:6][C:7]1[CH:8]=[C:9](O)[CH:10]=[C:11]([C:13]([N:15]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:12]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([N:15]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:10]=[C:9]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[CH:8]=1
Reactant: C=CCN(C(=O)c1cc(O)cc(Cl)c1)C1CCCC1
Reactant: OCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCCO)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of tetrahydrofuran (100 mL), 1,3-propanediol (1.6 mL, 30 mmol) and phenol 16 (4.3 g, 15 mmol) at 0° C. was added diethyl azodicarboxylate (DEAD, 3.6 mL, 23 mmol) dropwise over 10 min. The solution was warmed to ambient temperature and stirred for 16 h, prior to concentration in vacuo. The oil was partially purified by chromatography on silica gel to provide alcohol 17 (3.9 g) contaminated with Mitsunobu by-products. This material was used directly in subsequent experiments. 1H NMR (300 MHz, CDCl3) δ 6.93 (s, 2H), 6.8 (s, 1H), 5.9 (bs, 1H), 5.18 (d, 2H), 4.4-3.8 (m, 7H), 2.05 (m, 2H), 1.4-1.9 (m, 10H). Mass spectrum (CI) calcd. for C18 H24NO3Cl: 338 (M+H). Found: 338.
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.O.O[N:12]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>CN(C=O)C>[Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH2:12])=[O:9])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1coc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1coc(Br)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
A solution of 5-bromo-furan-3-carboxylic acid (0.364 g, 1.92 mmol), 3-hydroxybenzotriazole hydrate (0.28 g, 2.11 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.40 g, 2.11 mmol) in DMF (11 mL) is stirred at room temperature for 2 hours. The reaction mixture is then cooled to 0° C. and aq. NH3 (0.22 mL) is added. The mixture is stirred at room temperature for an additional 5 hours, then the solvent is removed in vacuo and the residue dissolved in EtOAc, washed with 1N NaOH, and 1N HCl. The organic layers are combined, dried over MgSO4 and concentrated to afford the title compound (0.288 g, 79%). HPLC (254 nm): Rt 2.17 min (85.3%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1.[C:29]1([NH2:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7](=[N:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6][CH2:5]1)[CH3:3]
Reactant: CC(C)N1CCC(=O)CC1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(=Nc2ccccc2)CC1

Procedure:
To a stirred and refluxing mixture of 48 parts of 1-(1-methylethyl)-4-piperidinone, 1 part of 4-methylbenzenesulfonic acid and 540 parts of methylbenzene is added dropwise a solution of 30 parts of benzenamine in 90 parts of methylbenzene. Upon completion, the whole is stirred and refluxed for 3 hours with water-separator. The reaction mixture is evaporated, yielding 72 parts of N-[1-(1-methylethyl)-4-piperidinylidene]benzenamine as a residue.