Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].[C:7]([N:11]=[N:12][C:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:9])[CH3:8].O>CO>[C:7]([N:11]=[N:12][C:13]1([NH:19][C:20]([NH:1][NH:2][C:3]([NH:5][NH:6][C:20]([NH:19][C:13]2([N:12]=[N:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[S:21])=[O:4])=[S:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: NNC(=O)NN
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC1(NC(=S)NNC(=O)NNC(=S)NC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Reaction time: 8 h

Procedure:
To a slurry of 2.25 grams (.025 moles) of carbohydrazide in 30 ml of methanol stirred by a magnetic stirrer in a 50 ml erlenmeyer flask was added 11.3 grams (.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane (from Example I). The reaction was stirred overnight, during which time complete solution was obtained. The next morning the solution was poured into 200 ml water and the product extracted with methylene chloride. The methylene chloride extract was washed with water, dried over anhydrous Na2SO4, filtered and the methylene chloride evaporated under reduced pressure to leave 11.9 grams (87.5% crude yield) of a yellow viscous liquid that slowly crystallized.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[O:23][CH2:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:25])=[C:15]([CH2:18][CH:19]4[O:23][CH2:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3CCCO3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3CCCO3)CS[C@H]12)c1csc(N)n1
Yield: 57.1 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-tetrahydrofurfurylthio-3-cephem-4-carboxylate (40 mg) was reacted with iodomethyl pivalate (38 mg), followed by purification, in the same manner as in Example 2 to give the titled compound (27 mg; 57%) as white powder.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Cl.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19]1.Cl>CO>[ClH:8].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:18]1[CH2:23][CH2:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19]1
Reactant: ClCc1ccccc1Cl
Reactant: COC(=O)C1=CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C1=CCCN(Cc2ccccc2Cl)C1
Reaction time: 24 h
Yield: 98.1 %

Procedure:
Triethylamine (2.2 g.) and 2-chlorobenzyl chloride (1.63 g.) were added to a solution of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.63 g.) in methanol (10 ml.). The solution obtained was kept for 24 hours at 20°-25° C. and then evaporated. Water (20 ml.) and 10% w/v sodium carbonate solution were then added to the residue to give a mixture of pH 10. This mixture was extracted with ether (2×20 ml.). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residual oil was dissolved in acetone to give a solution which was treated with a slight excess of ethereal hydrogen chloride. The solid which precipitated was collected by filtration and washed with acetone to give methyl 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.5 g.) m.p. 171°-175° C.
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([C:19]([OH:21])=[O:20])=[CH:7][CH:8]=2)=[O:2].[BH4-].[Na+]>O.C1COCC1>[OH:2][CH2:1][CH:3]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([C:19]([OH:21])=[O:20])=[CH:7][CH:8]=2
Reactant: O=CC1c2cc(C(=O)O)ccc2-c2ccc(C(=O)O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)C(CO)c1cc(C(=O)O)ccc1-2

Procedure:
A small sample of 9-formyl-2,7-fluorenedicarboxylic acid (5-10 mg) was dissolved in water with a small amount of THF. An excess amount of sodium borohydride was added and allowed to react for two hours. The reaction was quenched with the careful addition of 1 M HCl until acidic. The product was extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to dryness. 1H-NMR (CD3OD): δ (ppm) 8.4 (s, 2H, Ar); 8.2 (m, 2H, Ar); 8.0 (m, 2H, Ar); 4.2 (t, 1H, CH); 4.0 (d, 2H, CH2).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][C:34]([C:38]([F:41])([F:40])[F:39])([OH:37])[CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([C@H:32]3[CH2:36][CH2:35][C@@:34]([OH:37])([C:38]([F:40])([F:41])[F:39])[CH2:33]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: OC1(C(F)(F)F)CCC(c2cccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Oc2ncccc2[C@H]2CC[C@@](O)(C(F)(F)F)C2)cc1)c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
To a vial containing cesium carbonate (1634 mg, 5.02 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (717 mg, 3.01 mmol), and 3-(2-fluoropyridin-3-yl)-1-(trifluoromethyl)cyclopentanol (500 mg, 2.006 mmol) was added NMP (13.400 ml). The mixture was heated at 200° C. for 5 h with microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with 5N NaOH before drying the organic layer over magnesium sulfate, filtering, and concentrating under reduced pressure. The resulting orange oil was purified by column chromatography (ethyl acetate/dichloromethane) to give a pale orange oil. The material was diluted with ethyl acetate and washed with water and 10 N NaOH before separating the mixture by SFC into its components, which consisted of two products identified as enantiomers by NMR. MS (ESI, pos. ion) m/z: 468.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[CH3:15][C:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([CH3:30])[NH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:15][C:16]1[C:20]([C:2]2[S:10][C:9]3[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=3[CH:3]=2)=[C:19]([CH3:30])[NH:18][N:17]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1n[nH]c(C)c1-c1cc2c(s1)C(=O)NC(C)(C)N2C
Yield: 36 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (333 mg, 1.50 mmol), sodium carbonate (265 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (2 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL), and the mixture was shaken well. The insoluble materials were filtered off. From the filtrate, the organic layer was collected, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc, then EtOAc to 90:10 EtOAc/MeOH). The obtained yellow solid was triturated with EtOAc/hexane and collected by filtration to afford the title compound (52.2 mg, 36%) as a pale yellow solid:
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=O)=O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13]
Reactant: CS(=O)(=O)OCCCC(F)(F)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)CCCI
Yield: 9.4 %

Procedure:
Sodium iodide (35.1 g, 2.15 mol) was added to a solution of 1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (20 g, 0.781 mol) in acetone (200 ml), followed by heating under reflux for 12 hours. After the reaction mixture was filtered, the filtrate was concentrated. Ethyl acetate was added to the residue, which was then filtered again. The filtrate was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-4,4,5,5,5-pentafluoropentane (21.1 g, Yield 93.4%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:9]/[CH2:10][N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[CH:9]/[CH2:10][N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CN(C/C=C(/c1ccc(Br)cc1)c1ccsc1)CC(=O)O
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1ccc(-c2ccc(/C(=C/CN(C)CC(=O)O)c3ccsc3)cc2)cc1

Procedure:
To a solution of (Z)-N-(1-(4-bromophenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine, tbutyl ester E(i) (21.14 g, 50.05 mmol) in dimethoxyethane (210 mL) was added 4-isopropylbenzeneboronic acid (16.41 g, 100.1 mmol), Pd(PPh3)4 (2.89 g, 2.50 mmol), and 2M Na2CO3 (210 mL). The vigorously stirred mixture was heated to reflux for 2 hours. The mixture was cooled, and partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. Column chromatography (2-5% acetone/hexanes) followed by a second chromatography (2-20% EtOAc/hexanes) provided (Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine, tbutyl ester F(i) (18.65 g, 81%) as a yellow oil. 1H NMR (300 MHz, CDCl3) 1.29 (d, 6H), 1.44 (s, 9H), 2.39 (s, 3H), 2.95 (hept, 1H), 3.16 (s, 2H), 3.30 (d, 2H), 6.26 (t, 1H), 6.93 (d, 1H), 7.18 (d, 1H), 7.26-7.35 (m, 5H), 7.50-7.54 (m, 4H).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:6]#[N:7].[CH2:12]([OH:14])[CH3:13].C(OCC)C>C1C=CC=CC=1>[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:6](=[NH:7])[O:14][CH2:12][CH3:13]
Reactant: Cc1ccc(C#N)cc1I
Reactant: CCO
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=N)c1ccc(C)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 189.8 %

Procedure:
Hydrogen chloride gas was bubbled over a period of 35 minutes into a stirred solution of 3-iodo-4-methylbenzonitrile (preparation 51a, 2.00 g, 8.2 mmol) and ethanol (0.70 mL, 12.3 mmol) in benzene at 0° C. The mixture was stirred for 30 minutes at room temperature and then the mixture was placed in the refrigerator and left overnight. Diethyl ether (200 mL) was then added and a white solid precipitated. After leaving the mixture a further night in the refrigerator the precipitate was filtered. Dichloromethane and saturated aqueous potassium carbonate solution were added to the solid with stirring. The organic layer was dried (MgSO4) and evaporated to give the title compound (4.50 g, 80%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:29])[C:27]=1[NH2:28])[C:22]([OH:24])=[O:23]>CC(N(C)C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[C:4]1[NH:18][C:19]2[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:25]=[C:26]([CH3:29])[C:27]=2[N:28]=1
Reactant: Cc1cc(C(=O)O)cc(N)c1N
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Solvent: CC(=O)N(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3c(C)cc(C(=O)O)cc3[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To mixture of 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (144 mg, 0.4 mmol) and 3,4-diamino-5-methyl-benzoic acid (82 mg, 0.5 mol) was added DMA (0.8 mL) and the resulting solution was stirred at 0° C. for 0.5 h, and at the room temperature for 2.5 h. After it was heated open to the air at 110° C. for 15 h, the reaction mixture was concentrated under reduced pressure and the residual crude was used for the next step reaction without purification. ESI-MS m/z 376.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.[C-:11]#[N:12].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Clc1cc(Br)ccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 122.9 %

Procedure:
To a magnetically stirring solution of 4-bromo-1-bromomethyl-2-chloro-benzene (3.59 g, 12.67 mmol) from step 2 above and tetrabutylammonium bromide (0.41 g, 1.27 mmol) in CH2Cl2/H2O 1:1 (60.0 mL), was added a solution of KCN (2.48 g, 38.01 mmol) in H2O (30 mL). The resulting orange mixture was stirred at room temperature for 3 hours. The layers of the resulting reaction mixture were separated and the organic layer was washed with NaHCO3 sat solution (3×50 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (30% EtOAc in Hexanes) to yield the intermediate as a clear oil (3.59 g, 100%). 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 2H), 7.37-7.60 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>CCO>[CH3:36][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Oc4ccccc4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(Oc3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Yield: 97 %

Procedure:
The crude 2-methyl-2-(4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester (0.316 g, 0.614 mmol) was combined with 5 N NaOH (0.61 mL, 3.05 mmol) in absolute EtOH (20 mL) and heated to reflux for 3 h. The reaction mixture was cooled, filtered through hyflo, and the solvent removed in vacuo from the filtrate. The residue was acidified with 1 N HCl (3.2 mL) and then extracted with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to give 0.282 g of crude 2-methyl-2-(4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid. Approximately ⅓ of this material was purified by LCMS to afford 0.014 g of analytically pure 2-methyl-2-(4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid: 1H NMR (500 MHz, CDCl3) δ 7.90 (d, 2H, J=8.80 Hz), 7.36-7.32 (m, 2H), 7.18-7.12 (m, 1H), 7.03-6.99 (m, 3H), 6.88-6.86 (m, 2H), 6.79-6.77 (m, 3H), 4.16 (t, 2H, J=6.84 Hz), 2.94 (t, 2H, J=6.84 Hz), 2.34 (s, 3H), 1.44 (s, 6H). HRMS (ES+) m/z exact mass calcd for C28H28NO6 474.1917, found 474.1929.
Reaction SMILES: CC([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([O:12][C:13]([CH3:15])=O)[C@H:9]([O:16]C(C)=O)[C@@H:8]([O:20]C(C)=O)[C@@H:7]1[O:24][C@@H:25]1[O:30][C@H:29]([CH2:31][O:32]C(C)=O)[C@@H:28]([O:36]C(C)=O)[C@H:27]([O:40]C(C)=O)[C@H:26]1[O:44]C(C)=O)=O.[CH2:48](O)C=C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[O-].[Na+]>C(Cl)Cl.O>[C@@H:25]1([O:24][C@@H:7]2[C@@H:6]([CH2:5][OH:4])[O:11][CH:10]([O:12][CH2:13][CH:15]=[CH2:48])[C@H:9]([OH:16])[C@H:8]2[OH:20])[O:30][C@H:29]([CH2:31][OH:32])[C@@H:28]([OH:36])[C@H:27]([OH:40])[C@H:26]1[OH:44]
Reactant: C=CCO
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCOC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
α-D-cellobiose octaacetate (48.59 g, 71.6 mmol) was dissolved in methylene chloride (600 mL), and allyl alcohol (29 ml, 0.43 mol) and trimethylsilyl trifluoromethanesulfonate (16 mL, 86.0 mmol) were added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 1.5 hours. Water (200 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (200 mL). The extract was washed with a saturated aqueous NaCl solution (100 mL) and after it was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (300 mL) and sodium methoxide (28 mL, 0.14 mol) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 2 hours. Dowex 50w×8 was added to the reaction mixture until the reaction mixture became neutral and after it was filtered, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 8:2:1, V/V) to obtain the desired title compound (24.8 g, yield: 91%) as a pale yellow amorphous substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[N:7][CH:8]=1.[Cu][C:11]#[N:12].C(Cl)(Cl)Cl>N1C=CC=CC=1.[OH-].[NH4+].[Cl-].[NH4+]>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[CH:6]=[N:7][CH:8]=1
Reactant: N#C[Cu]
Reactant: OCc1cncc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cncc(CO)c1
Temperature: 165 °C
Reaction time: 2 h
Yield: 357.5 %

Procedure:
A stirred mixture of 5-hydroxymethyl-3-bromopyridine (8.50 g, 45.2 mmol) and copper (I) cyanide (10.1 g, 11.3 mmol) in pyridine (50 mL) was heated in a sealed pressure reaction vessel at 165° C. for 20 hours. After cooling to 23° C., the mixture was diluted with concentrated ammonium hydroxide (15 mL) and saturated aqueous ammonium chloride (60 mL), after stirring for 2 hours, the mixture was treated with chloroform (50 mL) and allowed to set for 72 hours. The aqueous layer was then extracted with chloroform. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 2 inch column, 4:1 EtOAc:hexane as eluant) followed by crystallization from diethyl ether to afford 5-hydroxymethyl-3-pyridinecarbonitrile (5.42 g, 40.4 mmol, 89% yield): Rf 0.49 (EtOAc); 1H NMR (CDCl3, 200 MHz)δ8.80 (m, 2H), 8.03 (s, 1H), 4.83 (s, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:4][Si:9]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:12])[CH3:11]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
2-Bromoethanol (3.44 g, 27.53 mmol), t-butyldimethylchlorosilane (4.23 g, 28.07 mmol), and imidazole (3.97 g, 58.31 mmol) was dissolved in dimethylformamide (20 ml) and the solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and then with saturated brine, and dried over magnesium sulfate. Insoluble solids were removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain t-butyldimethylsilyl 2-bromoethyl ether (6.05 g) as crude product. The crude product (1.83 g), 2-phenylimidazole (1.11 g, 7.70 mmol), and potassium carbonate (1.50 g, 10.9 mmol) was added in dimethylformamide (10 ml), and the mixture was heated at 80° C. for 10 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and then with saturated brine, and dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as pale yellow oil (1.16 g, yield: 50%).
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)C1C=CC=CC=1)C.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH:4][C:27](=[O:28])[O:29][CH:30]([CH3:32])[CH3:31]
Reactant: CCOc1ccc(N)c(F)c1OCC
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(NC(=O)OC(C)C)c(F)c1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
2-Fluoro-3,4-diethoxyaniline (0.17 g) and N,N-diethylaniline (0.13 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.11 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(2-fluoro-3,4-diethoxyphenyl)carbamate (Compound No. 1) (0.23 g) in a yield of 94.4%. M.P., 79°-81° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].Cl.[F:18][CH:19]1[CH2:22][NH:21][CH2:20]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH:19]([F:18])[CH2:20]2)=[O:8])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)c1
Reactant: FC1CNC1
Agent: Cl
Product: O=C(c1ccc(Br)c(OCC(F)(F)F)c1)N1CC(F)C1

Procedure:
Starting with 4-bromo-3-(2,2,2-trifluoroethoxy)benzoic acid and 3-fluoroazetidine hydrochloride, Int06.04 was prepared analogously to the procedure for the preparation of Int02.06.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[S:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)(=[O:35])(=[O:34])[NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:41][CH2:40][C:39]3[CH:38]=[CH:37][C:36]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:43][CH:42]=3)=[O:23])=[CH:17][C:9]1=2
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: NS(=O)(=O)c1ccc(CNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10 to give the title compound. LCMS: In/z=615.9 (M+H+); retention time=0.77 minutes.