Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH:15]([OH:17])[CH2:14]2)[CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O.C(OCC)(=O)C>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:16][C:15](=[O:17])[CH2:14]2)[CH2:10][C:9]1=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(O)C1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(=O)C1
Reaction time: 14 h
Yield: 96.3 %

Procedure:
A 4.89 g (13.6 mmol) portion of 1-benzyl-4-[3-(tert-butoxycarbonylamino)-1-hydroxycyclobutan-3-yl]-2-pyrrolidone was dissolved in 100 ml of dimethyl sulfoxide to which, while cooling in an ice bath with stirring, were then added 6.24 ml (44.8 mmol) of triethylamine and 6.47 g (10.7 mmol) of sulfur trioxide-pyridine complex in that order, subsequently carrying out 14 hours of stirring at room temperature. While cooling in an ice bath with stirring, the reaction solution was mixed with water and then with ethyl acetate to effect separation of layers. The organic layer was washed with saturated brine, the aqueous layer was extracted with ethyl acetate and then the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 4.69 g (96.3%) of the title compound. Thereafter, optical resolution of Isomers F1 and F2 as enantiomers originated from the pyrrolidine 4 position asymmetric carbon atom of the thus obtained compound was carried out by HPLC under the following conditions.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:14][NH:15][CH3:16].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:15]([CH3:16])[CH3:14])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-nitrobenzoyl chloride (7.20 g, 38.8 mmol) and dimethylamine hydrochloride (3.20 g, 39.2 mmol) in 100 mL DCM is added triethyl amine (14.0 mL, 99.6 mmol) at 0° C. The cooling bath is removed and the reaction mixture is stirred overnight at RT. Then 300 mL DCM is added and the reaction mixture is washed with 50% saturated aqueous ammonium chloride, water, 50% saturated aqueous sodium hydrogen carbonate and 0.1 M aqueous NaOH. The organic phase is dried over MgSO4 and concentrated in vacuo. Yield: 5.37 g.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[C:50]([CH3:52])[N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:41][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:43]4[N:48]5[CH:49]=[C:50]([CH3:52])[N:51]=[C:47]5[CH:46]=[CH:45][CH:44]=4)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:40])[C:37]([NH2:39])=[O:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Cc1cn2c(Br)cccc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1cn2c(-c3nc(N4CCOCC4)c4sc(CN5CCN(C(C)(C)C(N)=O)CC5)cc4n3)cccc2n1
Temperature: 150 °C
Yield: 49 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-yl methyl)piperazin-1-yl]isobutyramide (150 mg, 0.21 mmol), 5-bromo-2-methyl-imidazo[1,2-a]pyridine (55 mg, 0.26 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol) and copper(I) thiophene-2-carboxylate (8 mg, 0.04 mmol) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 693 as a white solid (55 mg, 47%). LCMS (Method E): RT 4.99 min; [M+H]+ 535. 1H NMR (400 MHz, CHCl3-d): δ 8.98 (s, 1 H); 7.92-7.89 (m, 1 H); 7.68 (d, J=8.8 Hz, 1 H); 7.39 (s, 1 H); 7.27-7.23 (m, 1 H); 7.09 (d, J=5.3 Hz, 1 H); 5.22 (d, J=5.3 Hz, 1 H); 4.09-4.04 (m, 4 H); 3.94-3.87 (m, 4 H); 3.87 (s, 2 H); 2.62 (m, 8 H); 2.54 (s, 3 H); 1.29-1.23 (m, 6 H)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][C:43](O)=[O:44])[CH:37]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43](=[O:44])[CH2:42][C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=C(O)Cc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)Cc4cccnc4)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), according to the procedure in Example 29 using pyridin-3-yl-acetic acid. 1H-NMR (400 MHz, CD3OD): δ 8.80 (m, 2H), 8.54 (d, 1H), 8.10 (d, 1H), 8.06 (t, 1H), 7.98 (s, 1H), 7.18 (dd, 1H), 7.08 (d, 1H), 5.78 (m, 1H), 4.68 (m, 1H), 4.20 (m, 1H), 4.18 (s, 2H), 3.36 (m, 1H), 2.84 (m, 2H), 2.28 (m, 4H), 2.06-1.70 (m, 7H), 1.62 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C29H30N6O2, 495.2 (M+H), found 495.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccncc1
Reactant: O=C=Nc1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccncc1)Nc1c(F)cccc1F
Temperature: 110 °C
Reaction time: 4 h

Procedure:
4-Aminopyridine (100 mg, 1.06 mmol) and 2,6-difluorophenyl isocyanate (181.3 mg, 1.17 mmol) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[N:21]1([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:7])=[CH:4][CH:3]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CCNCC2)cc1
Yield: 202.4 %

Procedure:
A solution of 4-fluoro-N-quinolin-3-yl-benzamide (2.0 g, 3.76 mmol) and piperazine (6.2 g, 72 mmol) in methylsulfoxide (30 mL) was heated 100° C. for 1.5 days, to give the product 2.53 g (100%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:41])([F:40])[C:8]1[CH:9]=[C:10]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][C@H:14]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:12].C(N(CC)CC)C>ClCCl>[F:41][C:7]([F:6])([F:40])[C:8]1[CH:9]=[C:10]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][C@H:14]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A solution of methanesulfonyl chloride (1.1 g) in dichloromethane (4 ml) was added to a stirred solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(1H-indol-3-ylmethyl)piperazine (4.99 g) and triethylamine (1.1 g) in dichloromethane (50 ml) at ice-bath temperature over a 20-minute period. After being stirred at the same temperature for 1 hour, the reaction mixture was diluted with dichloromethane (50 ml) and then washed with water and aqueous sodium bicarbonate solution. The dichloromethane layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane-methanol (30:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (4.31 g) as a powder.
Reaction SMILES: [N:1]1([CH:6]([C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:17][C:18]([F:23])([F:22])[C:19](O)=O.[OH-].[NH4+]>>[N:1]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:19]([C:18]([F:23])([F:22])[F:17])=[N:16][C:11]=3[CH:10]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(c1ccc(N)c(N)c1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Product: CCC(c1ccc2[nH]c(C(F)(F)F)nc2c1)n1ccnc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
A mixture of 6.1 parts of 4-[1-(1H-imidazol-1-yl)propyl]-1,2-benzenediamine and 90 parts of trifluoroacetic acid was stirred for 15 minutes at 80° C. The reaction mixture was poured into crushed ice and treated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:10:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane (4 parts-17.5 parts). The product was filtered off and dried, yielding 1.8 parts (22%) of 5-[1-(1H-imidazol-1-yl)propyl]-2-(trifluoromethyl)-1H-benzimidazole; mp. 173.2° C. (compound 83).
Reaction SMILES: CCOCC.Br[CH2:7][C:8](=O)[CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].[CH:22]([NH2:24])=[S:23]>CCO>[S:23]1[CH:7]=[C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[N:24]=[CH:22]1
Reactant: NC=S
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Solvent: CCO
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1Cc1cscn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ether (7.5 mL) was added to the above solution of 2-(3-bromo-2-oxopropyl)-1H-isoindole-1,3(2H)-dione and cooled to 0° C. in an ice/NaCl salt bath. Then thioformamide (European Journal of Medicinal Chemistry, 2004, 39, 867-872.) (1.20 g) in EtOH (8 mL) was added, and the reaction was stirred overnight. The solvents were evaporated and the reaction mixture was purified by RP-HPLC to provide 2-(1,3-thiazol-4-ylmethyl)-1H-isoindole-1,3(2H)-dione as a white solid. LCMS: (M+H)+=245.1.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10](=[O:19])[N:11]=[C:12]3[CH:17]=[C:16](C)[CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[Br:32]Br.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:32][CH:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:19]
Reactant: BrBr
Reactant: Cc1ccc2c(-c3ccccc3)ccc(=O)nc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Nc2ccccc2C(c2ccccc2)CC1Br
Temperature: -70 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a 200 mL three neck round-bottomed flask equipped with a nitrogen inlet and septum were added 5.48 grams (21.8 mmol) 5-phenyl-8-methyl-2-oxobenzazepine, 100 mL dichloromethane, and 4.55 grams (21.8 mmol) phosphorus pentachloride. After dissolution, 1.85 mL (22.9 mmol) pyridine was added, and the solution cooled to -70° C. To the stirring solution (some precipitate appeared at this temperature, but did not affect the reaction) was added a solution of 1.12 mL (21.8 mmol) bromine in 10 mL methylene chloride dropwise over 20 minutes. The reaction was then allowed to warm quickly (10 minutes) to 0° C., and 50 mL of saturated aqueous sodium bisulfite solution was added. The reaction was then diluted with methylene chloride and allowed to stand under sodium bisulfite solution with periodic shaking for 2 hours, until the organic phase no longer exhibited a reddish color. The organic phase was then dried over sodium sulfate and evaporated. The residue was suspended in methylene chloride and filtered, and the solid dissolved to afford 3.39 grams (47%) of product as a white solid. The filtrate was adsorbed onto silica gel and chromatographed using 7:3 hexane/ethyl acetate as eluant to afford additional product as a white solid, 1.38 g, total 5.14 (71%).
Reaction SMILES: Cl[C:2]1[N:11]2[N:12]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([Cl:20])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:21][NH2:22]>O1CCCC1>[Cl:20][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([NH:22][CH3:21])[N:11]3[N:12]=[C:13]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:10]3[C:9]=2[CH:8]=1
Reactant: CN
Reactant: Clc1ccc2nc(Cl)n3nc(-c4ccco4)nc3c2c1
Solvent: C1CCOC1
Product: CNc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12

Procedure:
To a solution of 1.45 g of 5,9-dichloro-2(2-furyl)[1,2,4]triazolo[1,5-c]quinazoline in dry tetrahydrofuran (150 cc) at 50° is added gaseous methylamine over 40 minutes. The mixture is concentrated to dryness, triturated with water and filtered to afford a white solid. This is recrystallized by dissolution in hot toluene and, after several minutes of heating to remove water by azeotropic distillation, addition of cyclohexane during cooling. Pure 9-Chloro-2-(2-furyl)-5-methylamino[1,2,4]triazolo[1,5-c]quinazoline, mp 166°-168°, is thus obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3]1.[Li]CCCC.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](Cl)=[O:25])=[CH:16]1>C1COCC1.CCCCCC>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([O:9][CH2:8][CH2:7][CH:6]2[CH2:5][CH2:4][CH2:3][N:2]2[CH3:1])=[O:25])=[CH:16]1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: CN1CCCC1CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCCC1CCOC(=O)c1c[nH]c2ccccc12
Reaction time: 0.5 h

Procedure:
To a dry THF solution (30 ml) of 2-(1-methyl-2-pyrrolidine)ethanol at -10° to 5° C. was dropwise added a 1.5M hexane solution of n-BuLi (16.0 ml, 24.0 mmol) over a period of 10 min. Stirring was continued for 30 min. To a mixture was then dropwise added at -5° to 5° C. a dry THF solution (20 ml) of indole-3-carboxylic acid chloride (4.20 g, 24.0 mmol) over a period of 45 min. The cooling bath was removed. After stirring overnight at room temperature, a reaction solution was poured onto a cold diluted hydrochloric acid, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.91 g of the title compound as a yellow viscous material. A foamy solid;
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[O:21][CH3:22])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[S:23]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)([O-:26])(=[O:25])=[O:24].[CH3:34][C:35]1[S:36][C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[N+:39]=1[CH3:40].N1CCCCC1.CCOCC>CO>[S:23]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)([O-:26])(=[O:25])=[O:24].[C@@H:2]1([O:1][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:34][C:35]3[S:36][C:37]4[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=4[N+:39]=3[CH3:40])=[CH:15][C:14]=2[O:21][CH3:22])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: Cc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCOCC
Product: COc1cc(C=Cc2sc3ccccc3[n+]2C)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
4-Formyl-3-methoxyphenyl β-D-galactopyranoside (1c)(3.14 g, 0.01 mol) was dissolved in hot methanol (20 ml) and 2,3-dimethylbenzothiazolium tosylate (3.35 g, 0.01 mol) was added followed by a drop of piperidine. The mixture was heated under reflux for 2 h, during which time it become strongly coloured. The reaction mixture was then cooled and ether (200 ml) was added to precipitate the product as an orange solid, which was well washed with methanol to give (26c){4.8 g, 80%, m.p. 147°-149° C., [α]D -10.4`0 (c 1, DMSO)}. (Found: C, 55.66; H, 5.28; N, 2.11. C30H34O11NS2Calc: C, 55.54; N, 5.28; N, 2.16.)
Reaction SMILES: [Na].[CH3:2][C:3]([C:6]1[C:11]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:9]=[C:8]([CH3:23])[N:7]=1)([CH3:5])[CH3:4].[N:24](OCCC(C)C)=[O:25].[Cl-].[NH4+]>N.O1CCCC1>[CH3:5][C:3]([C:6]1[C:11]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:9]=[C:8]([CH:23]=[N:24][OH:25])[N:7]=1)([CH3:2])[CH3:4]
Reactant: CC(C)CCON=O
Reactant: COCCOCOc1c(C(C)(C)C)nc(C)nc1C(C)(C)C
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)nc(C=NO)nc1C(C)(C)C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
Sodium metal (0.28 g, 12.6 mmoles) is dissolved in 50 mL of freshly distilled ammonia at reflux under argon. The reaction mixture is stirred at reflux until the solution turns light gray. 4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)-methoxy]-2-methyl-pyrimidine (3.0 g, 9.7 mmoles) is dissolved in 20 mL of tetrahydrofuran and added to the reaction. After 10 minutes, isoamyl nitrite (2.3 g, 19.3 mmoles) is added, and the reaction mixture is stirred at reflux for 2 hours. It is quenched by the addition of ammonium chloride (1.0 g, 18.7 mmoles) and the ammonia is allowed to evaporate at room temperature. The remaining oil is partitioned between 50 mL of ethyl acetate and 50 mL of water. The organic layer is washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate, and the solvent is evaporated. The crude product is adsorbed onto a silica gel plug which is eluted with 300 mL of 5% ether in chloroform, followed by 300 mL of ether. Evaporation of the ether eluant gives 4,6-bis (1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine-carboxaldehyde oxime (0.7 g, 21%) , mp 90°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10]
Reactant: Clc1cccc(I)c1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
1,2-Dichloro-3-iodobenzene (4.95 g, 18.1 mmol), trimethylsilylacetylene (2 g, 20 mmol), bis(triphenylphosphine)palladium(II)chloride (245 mg, 0.35 mmol), and copper(I)iodide (45 mg, 0.24 mmol) were combined in triethylamine (120 mL) and heated at reflux for 45 minutes. The mixture was allowed to cool to room temperature and was then partitioned between diethyl ether and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was taken directly on to the next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=1[NH2:28].[C:34]([O:38][C:39]([N:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C>C(#N)C>[Br:25][C:26]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=1[NH:28][C:45]([CH:43]1[CH2:44][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:42]1)=[O:46]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Nc1cc(Cl)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Cl)ccc2Br)C1
Reaction time: 8 h
Yield: 74 %

Procedure:
HATU (980 mg, 2.58 mmol) was added to a mixture of 2-bromo-5-chloroaniline (352 mg, 1.7 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (402 mg, 2 mmol) in Acetonitrile (8 mL) at room temperature followed by DIPEA (0.74 mL, 4.26 mmol). After stifling overnight, reaction mixture was concentrated under reduced pressure and resulting residue was purified via silica gel column chromatography (0-50% ethyl acetate/hexanes) to yield tert-butyl 3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate 7.56 (490 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C15H19BrClN2O3: 389.02; found: 389.57.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:7]2[C:6]([F:9])=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]=2[F:1])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Temperature: 25 °C
Yield: 105 %

Procedure:
A mixture of 3,4,5-trifluoronitrobenzene (20.0 g, 113 mmol, commercially available from AsymChem of Durham, N.C.), dry DMF (100 ml), 4-fluorophenol (13.9 g, 124 mmol), and Cs2CO3 (56 g, 172 mmol) was stirred under N2 at 60-70° C. for 1-2 hrs. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc (2×). The EtOAc extractions were washed with sat'd NaCl (1×), dried over Na2SO4, and concentrated in vacuo to give 4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (32.0 g, 105%) which was used in the next step without further purification. 1H NMR (DMSO-d6): δ7.15 (m, 2H), 7.22 (m, 2H), 8.31 (d, 2H, J=7.6 Hz).