Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:16][C:17]1[C:18]([CH3:30])=[N:19][C:20]2[C:25]([N:26]=1)=[C:24]([C:27](=O)[CH3:28])[CH:23]=[CH:22][CH:21]=2>C(Cl)Cl>[Si:1]([O:8][C:27]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[N:26]=[C:17]([F:16])[C:18]([CH3:30])=[N:19]2)=[CH2:28])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(F)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
TBSOTf (2.92 mL, 12.73 mmol) was added (dropwise, over 3 min) to a mixture 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (2.00 g, 9.79 mmol) and TEA (2.05 mL, 14.7 mmol) in DCM (100 mL) at 0° C., and the resulting solution was stirred at 0° C. for 30 min. The mixture was diluted with DCM (50 mL), washed with saturated aq. NaHCO3 (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide 5-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-fluoro-2-methylquinoxaline (3.451 g) as an orange-brown oil. This oil was taken up in THF (100 mL) and cooled to 0° C., water (2.82 mL, 157 mmol) and NBS (1.743 g, 9.79 mmol) were sequentially added, and the resulting solution was stirred at 0° C. for 2 min. The mixture was diluted with Et2O (100 mL) and sequentially washed with water (80 mL), saturated aq. NaHCO3 (80 mL), water (80 mL), and brine (80 mL). The resulting solution was dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-20% EtOAc/hexanes) provided 2-bromo-1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (2.77 g, 9.78 mmol, 100% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (1H, d, J=5.3 Hz), 8.25 (1H, d, J=4.3 Hz), 7.82 (1H, t, J=7.8 Hz), 5.02 (2H, s), 2.80 (3H, d, J=1.4 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −69.34 (1F, s). m/z (ESI, +ve) 283.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cccc(Br)c1F
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(Br)c1F
Temperature: -78 °C

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (0.150 g, 0.739 mmol) in THF (3.21 mL) cooled to −78° C. was added phenylmagnesium bromide (0.887 mL, 0.887 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr and then allowed to warm to room temperature slowly over 3 hr. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2 and the layers were separated. The aqueous phase was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound as a colorless residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: BrCCCOc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (3-bromopropoxy)benzene (1.3 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 3:1) and crystallized from dichloromethane-hexane to provide 0.7 g of alpha-oxo-4-[[(3-phenoxy) propyl]oxy]benzeneacetic acid methyl ester, mp 61°-62° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Li]CCCC.[CH3:21][O:22][CH2:23][O:24][C:25]1[C:26]([C:39](=O)[CH2:40][CH3:41])=[CH:27][C:28]2[C:29]([CH3:38])([CH3:37])[CH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[C:33]=2[CH:34]=1>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])/[C:6](/[F:7])=[C:39](\[C:26]1[C:25]([O:24][CH2:23][O:22][CH3:21])=[CH:34][C:33]2[C:32]([CH3:36])([CH3:35])[CH2:31][CH2:30][C:29]([CH3:37])([CH3:38])[C:28]=2[CH:27]=1)/[CH2:40][CH3:41])[CH3:1]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCC(=O)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure B and using triethyl 2-fluoro-2-phosphonoacetate (5.6 mL, 27.6 mmol), THF (50 mL), n-BuLi (17.3 mL, 1.6 M in hexane, 27.6 mmol), and 1-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one (Intermediate 14, 2.8 g, 9.2 mmol) in THF (10 mL), followed by flash column chromatography on silica gel (3% EtOAc-hexane), the title compound was obtained as a mixture containing minimal 2-Z isomer (3.3 g). The mixture was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[N:3]=1.[F-:25].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[N:3]=1
Reactant: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(Cl)c2cc1F
Reactant: [F-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(F)c2cc1F
Temperature: 140 °C
Yield: 78.8 %

Procedure:
To a solution of 1-chloro-7-fluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinoline (1 g, 2.89 mmol) in DMSO (6 mL), was added CsF (0.879 g, 5.78 mmol) and the mixture was heated to 140° C. for 4 hrs. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using 50% DCM/Hexanes. The product fractions were collected and the solvent removed under vacuum to give 1,7-difluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinoline (750 mg, 79% yield). MS: MS m/z 330.1 (M++1).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](OC)=[O:15]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:15])[N:11]=1
Reactant: NC(=S)NC1CC2CCC1C2
Reactant: COC(=O)C(Br)c1ccccc1
Product: O=C1N=C(NC2CC3CCC2C3)SC1c1ccccc1

Procedure:
Synthesis was performed from N-bicyclo[2.2.1]hept-2-ylthiourea and methyl alpha-bromophenylacetate according to Method C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Product: Cc1ccccc1-c1cc(N2CCC(N3CCCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 47.6 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (58.2 mg, 48%).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([OH:11])C.[OH-].[K+].Cl>O>[OH:11][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: CCO
Reactant: O=C1CCCCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCO
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a solution of 12.0 g of 6-hexanolactone in ml of ethanol was added a solution of 11.7 g of potassium hydroxide in 20 ml of water under ice-cooling and the reaction mixture was stirred for 2.5 hours at 40° C. After reaction, the reaction mixture was adjusted to pH 9 by adding 1N-HCl solution and washed with ethyl acetate (twice). The aqueous layer was concentrated under reduced pressure and the residue was adjusted to pH 1 by adding 1N-HCl solution and extracted by ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 11.5 g of 6-hydroxyhexanoic acid. A mixture of 1 g of -hydroxyhexanoic acid obtained above, 0.72 mg of sodium bicarbonate in 20 ml of water was stirred for 15 minutes. After reaction, the solvent was removed and the resulting residue was washed with acetonitrile to give 1.24 g of sodium 6-hydroxyhexanoic acid. Then, 276 mg of this compound was dissolved in 2.7 ml of dimethylformamide and to this solution was added 161 mg of methoxymethyl chloride and the reaction mixture was stirred for 1.5 hours at room temperature. After adding 10 ml of ethyl acetate to the reaction mixture, the organic layer was washed with saline, saturated sodium bicarbonate aqueous solution and saline respectively and dried over magnesium sulfate. The solvent was removed to give 190 mg (59%) of methoxymethyl 6-hydroxyhexanoate [Compound (15)].
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:20])[C:14]1=[O:28])([O-])=O.Cl[Sn]Cl>CCO>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:20])[C:14]1=[O:28]
Reactant: O=C(Nc1ccncc1)c1cccn(C2CCc3c2cccc3[N+](=O)[O-])c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a mixture of 1-(4-nitro-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (3.5 g, 1.0 eq) in EtOH (125 mL) was added SnCl2*2H2O (5.0 eq) in portions, the mixture was stirred at 70° C. overnight. At the end of reaction, the mixture was concentrated and ethyl acetate was added. The organic layer was washed with NaHCO3 aqueous for three times. The combined organic layer was washed with brine and dried over MgSO4, filtered and evaporated to give the crude product, which was purified by HPLC to afford 1-(4-amino-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (3 g, 93%). MS (ESI) 347.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ12.44 (s, 1H), 8.49 (d, J=3.0 Hz, 2H), 8.46 (d, J=4.2 Hz, 1H), 7.72 (d, J=3.0 Hz, 2H), 7.57 (d, J=4.2 Hz, 1H), 6.96 (t, J=4.5 Hz, 1H), 6.57-6.61 (m, 2H), 6.45 (t, J=4.2 Hz, 1H), 6.31 (d, J=4.2 Hz, 1H), 5.19 (s, 2H), 2.85-2.90 (m, 1H), 2.65-2.75 (m, 2H), 2.00-2.05 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([CH:12]=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[SH:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(OCC)C>CN(C)C=O.ClCCl>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:7]=[C:2]2[S:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][C:3]2=[N:4][CH:5]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ncc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1cc2ncc(C(F)(F)F)cc2s1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
3-Chloro-5-(trifluoromethyl)-2-pyridinecarbaldehyde (Chemical Abstracts number 175277-50-6, purchase from Maybridge), potassium carbonate (4.95 g), and ethyl mercaptoacetate (2.52 g) were combined in N,N-dimethylformamide (25 mL) at 25° C. and stirred for 18 hours. The mixture was then heated at 50° C. for 6 hours, allowed to cool to room temperature, poured into a mixture of diethyl ether (80 mL) and dichloromethane (25 mL), and washed with aqueous sodium carbonate. The organic phase was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered to remove solids. The filtrate was concentrated and the residue purified by flash chromatography (dichloromethane) to provide the title compound. MS (DCI/NH3) m/z 276.0 (M+H)+.
Reaction SMILES: [ClH:1].[S:2]1[CH2:6][CH:5]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH:10]2[CH3:23])[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH3:28]OC1C(N2CCNC(C)C2)=NC=CC=1>>[ClH:1].[S:2]1[CH2:6][CH:5]([CH:7]([CH3:28])[CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH:10]2[CH3:23])[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2
Reactant: COc1cccnc1N1CCN(CCC2CSc3ccccc32)C(C)C1
Reactant: COc1cccnc1N1CCNC(C)C1
Agent: Cl
Product: COc1cccnc1N1CCN(CC(C)C2CSc3ccccc32)C(C)C1

Procedure:
The title compound was prepared (48%, mp 167°-170° C.) in a manner analogous to the preparation of 1-[2-(2,3-dihydrobenzo[b]thien-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 6) by the reaction of 2,3-dihydro-3-benzo[b]-thienepropanol tosylate with 1-(3-methoxy-2-pyridinyl)-3-methylpiperazine.
Reaction SMILES: C([O:8][NH:9][C:10]([CH:12]([CH:16]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=1)[CH2:17][CH2:18][CH2:19][CH:20]1[C:24](=[O:25])[NH:23][C:22](=[O:26])[NH:21]1)[CH:13]([CH3:15])[CH3:14])=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10]([CH:12]([CH:16]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=1)[CH2:17][CH2:18][CH2:19][CH:20]1[C:24](=[O:25])[NH:23][C:22](=[O:26])[NH:21]1)[CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)C(C(=O)NOCc1ccccc1)C(CCCC1NC(=O)NC1=O)c1ccc(C(N)=O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(C(=O)NO)C(CCCC1NC(=O)NC1=O)c1ccc(C(N)=O)cc1
Yield: 41 %

Procedure:
The compound obtained in step g above (25g) (150 mg, 0.312 mmol) and 10% Pd/C (20 mg) were stirred in MeOH (10 mL) at room temperature for 15 h under H2 atmosphere, the mixture was filtered through celite, washed with MeOH several times and then concentrated. The residue was purified by silica gel column chromatography which gave the title compound as a white solid (50 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:32][O:33][C:34]1[N:39]=[N:38][C:37]([NH2:40])=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:14](=[O:16])[N:40]([C:37]3[N:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: COc1ccc(N)nn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(-c3ccc(OC)nn3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a solution (80 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (1 g) in methylene chloride were added triphosgene (0.7 g) and triethylamine (1.19 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 6-methoxypyridazin-3-amine (2 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (50 mL), sodium methoxide (3 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.45 g, 27%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:61](O)=[O:62])[CH2:56][CH2:57][C:58](=[O:60])[NH2:59])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[C:44]([NH:54][C@H:55]([C:61]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:62])[CH2:56][CH2:57][C:58](=[O:60])[NH2:59])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-glutamine.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41](OS(C(F)(F)F)(=O)=O)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[C:42]([Cl:45])=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c1
Product: CCOC(=O)Cc1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (4-chloro-3-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)OCC[O:11]2)=[CH:6][CH:5]=1.CCCCCCC.CCOCC>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:11])[CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2(CCCOCCc3ccccc3)OCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCCC
Product: COc1ccc(C(=O)CCCOCCc2ccccc2)cc1
Yield: 77.6 %

Procedure:
This compound was synthesized as described under 5.c) with 0.8 ml of HCl (1N) and 0.65 g (1.9 mmol) of 2-(4-methoxyphenyl)-2-[3-(2-phenylethoxy)propyl]-1,3-dioxolane obtained under a) in 50 ml of THF. Column chromatography (SiO2, heptane/ether 4:1) gave 0.44 g (78%) of white crystals.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:17]O.O>ClCCl.C[Re](=O)(=O)=O>[O:1]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][N+:14]([O-:17])=[CH:15][CH:16]=1)[Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccncc1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
4-[2-(tert-Butyldimethylsiloxy)ethyl]pyridine (0.222 g, 1.00 mmol) obtained in Step 1 was dissolved in dichloromethane (2.00 mL), then methyltrioxorhenium (VII) (0.001 g, 0.005 mmol) and 30% aqueous hydrogen peroxide (1.00 mL) were added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction was confirmed by thin-layer chromatography, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 4-[2-(tert-butyldimethylsiloxy)ethyl]pyridine-N-oxide (0.153 g, yield 64%).
Reaction SMILES: CN.C[CH2:4][N:5](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:36]([O:43][C:44]1[CH:45]=[C:46]2[C:52]([C:53]([OH:55])=O)=[C:51]([C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=3)[O:50][C:47]2=[CH:48][N:49]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:43][C:44]1[CH:45]=[C:46]2[C:52]([C:53]([NH:5][CH3:4])=[O:55])=[C:51]([C:56]3[CH:57]=[CH:58][C:59]([F:62])=[CH:60][CH:61]=3)[O:50][C:47]2=[CH:48][N:49]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2cnc(OCc3ccccc3)cc12
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cnc(OCc3ccccc3)cc12
Yield: 38.9 %

Procedure:
Methanamine (3.1 mL, 6.2 mmol, 2M in THF) was added to a stirring solution of DIEA (646 μL, 3.70 mmol), HATU (563 mg, 1.48 mmol), 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3-carboxylic acid (448 mg, 1.23 mmol) in DMF (12 mL) at room temperature. The mixture concentrated then diluted with EtOAc and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give 5-(benzyloxy)-2-(4-fluorophenyl)-N-methylfuro[2,3-c]pyridine-3-carboxamide (180 mg, 39% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1H, s), 8.37-8.45 (1 H, m), 7.98-8.08 (2H, m), 7.29-7.50 (7H, m), 7.06 (1H, s), 5.42 (2H, s), 2.83 (3 H, d, J=4.52 Hz). LC-MS retention time: 2.00 min; m/z (MH+): 377. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[C:9]=1[C:29](OCC)=[O:30]>>[OH:7][C:8]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[C:9]=1[C:29]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:30]
Reactant: Nc1nccs1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(-c2cccs2)c(-c2ccccc2)c1O
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc(-c2cccs2)c(-c2ccccc2)c1O
Yield: 73.9 %

Procedure:
Using the procedure of Example 5, 10 g of amino thiazol and 6.9 g of the product of Step D were reacted to obtain 5.8 g of the expected product which was crystallized from acetonitrile melting at 260°-262° C.