Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:18]([Zn]CC)[CH3:19]>>[CH2:18]([C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:19]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: CC[Zn]CC
Product: CCc1cc(C(=O)OC)cnc1OCC(F)(F)F
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (610 mg, a white solid) from methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (1.0 g, 3.2 mmol, Step-1) and diethylzinc (6.4 mL, 6.4 mmol, 1M solution in n-hexane) instead of dimethylzinc by the similar manner in Step-3 of Amine-27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccc1C

Procedure:
From 3-methoxy-4-methylbenzoic acid, HATU and N-ethyldiisopropylamine in THP, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+23.0° (c=1.03, CHCl3), ES-MS m/e (%): 415 (M+H+, 100).
Reaction SMILES: [P:1]([O-:6])([O:4]C)[O:2]C.O.[CH2:8]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:9][CH2:10][CH3:11]>CO>[CH3:8][P:1](=[O:6])([O-:4])[O-:2].[CH2:8]([O:12][CH2:13][CH2:14][CH2:15][NH3+:16])[CH2:9][CH2:10][CH3:11].[CH2:8]([O:12][CH2:13][CH2:14][CH2:15][NH3+:16])[CH2:9][CH2:10][CH3:11]
Reactant: COP([O-])OC
Reactant: CCCCOCCCN
Solvent: O
Solvent: CO
Product: CCCCOCCC[NH3+]
Product: CP(=O)([O-])[O-]
Yield: 89.4 %

Procedure:
A mixture of 11 g. (0.1 moles) of dimethyl phosphite, 20 ml. of water and 20 ml. of methanol is reacted with a mixture of 13.12 g. (0.1 moles) of 3-butyloxypropyl amine and 30 ml. of methanol as described in Example 1. 22.6 g. of 3-butyloxypropyl-ammoniummethyl phosphonate are obtained. Yield: 89.4%. nD30 =1.4420
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]([CH3:14])[CH3:13].[C:15](O)(=O)C.[S:19]([O:24]C)([O:22][CH3:23])(=[O:21])=[O:20]>C1COCC1>[CH3:23][O:22][S:19]([O-:24])(=[O:21])=[O:20].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N+:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(C)Cc1c[nH]c2ccc(Br)cc12
Reactant: CC(=O)O
Reactant: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COS(=O)(=O)[O-]
Product: C[N+](C)(C)Cc1c[nH]c2ccc(Br)cc12
Yield: 391.7 %

Procedure:
According to the procedure of C. Huebner et al., J. Am. Chem. Soc., 75, 5887 (1953), a solution of 5-bromo-3-(dimethylaminomethyl)indole (28.3 g, 0.11 mol) and acetic acid (1.60 mL, 0.028 mol) in dry THF (154 mL) was added dropwise over a 1/2 hour period to a solution of dimethyl sulfate (52.04 mL, 0.55 mol) and acetic acid (1.60 mL, 0.028 mol) in dry THF (62 mL), keeping the temperature between 10°-15° C. The reaction was cooled in an ice bath for 1 hour, filtered, washed thoroughly with ether, and air dried for 1 hour to yield 41.6 g (100%) of product as a white solid. This was used immediately in the next step.
Reaction SMILES: ClC[N:3]1[CH:7]=[C:6]([CH3:8])[O:5][CH:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:15][C:16]1[CH:39]=[CH:38][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:22]2)=[CH:18][CH:17]=1.[C:40](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:6]1[O:5][C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:3][C:7]=1[CH2:40][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:23]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:22]2)=[CH:38][CH:39]=1
Reactant: CC1=CN(CCl)C(c2ccccc2)O1
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
A mixture of 3-chloromethyl-5-methyl-2-phenyloxazole (324 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (657 mg, yield: 90%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]1([N:69]([CH2:71][CH:72]2[CH2:77][CH2:76][CH2:75][CH2:74][NH:73]2)[CH3:70])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:73]1[CH2:74][CH2:75][CH2:76][CH2:77][CH:72]1[CH2:71][N:69]([CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[CH3:70])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(CC1CCCCN1)C1CCCCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN(C)C3CCCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-cyclohexyl-N-methyl-piperidin-2-ylmethyl-amine in DMSO at ambient temperature.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:2]2.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.Cl>CO.CC(C)=O>[ClH:17].[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@H:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:2]2
Reactant: O=C(NC1CN2CCC1CC2)c1cccc(Cl)c1
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc(Cl)c1

Procedure:
N-(3-Quinuclidinyl)-3-chlorobenzamide (52.5 g) dissolved in methanol is added to a solution of D-tartaric acid (29.7 g) in methanol. The precipitate obtained is collected by filtration and treated twice with methanol under reflux. The salt thus purified (20 g) is decomposed with aqueous sodium hydroxide solution and the product extracted with chloroform. After the organic phase has been dried and evaporated, the base obtained is treated in acetone with ethanolic hydrogen chloride solution. The hydrochloride which precipitates is collected by filtration and recrystallized in ethanol. 9.4 g of optically pure (S)-(-)-N-(3-quinuclidinyl)-3-chlorobenzamide hydrochloride are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1([OH:18])[CH2:17][NH:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:16]2[CH2:17][C:14]([OH:18])([CH3:13])[CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1(O)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(O)CN(C2CN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.21 g, 1.23 mmol), 3-methylazetidin-3-ol (0.13 g, 1.48 mmol) and 4 Å molecular sieves (1.2 g) in DCE (5 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.52 g, 2.47 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the solution was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, 0:100 to 100:0) to give 3-Hydroxy-3-methyl-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester as a colourless oil (0.09 g, 30%). 1H NMR (300 MHz, CDCl3): δ 3.93 (dd, J=9.2, 7.2 Hz, 2 H), 3.82-3.70 (m, 2 H), 3.50-3.40 (m, 1 H), 3.32 (d, J=8.1 Hz, 2 H), 3.21 (d, J=8.1 Hz, 2 H), 1.51 (s, 3 H), 1.43 (s, 9 H).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]([CH2:10]O)[C:7]([O-:9])=[O:8].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1C=CC=C[CH:39]=1>>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:5]2[CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[N:1]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:10][CH:6]2[C:7]([O:9][CH3:39])=[O:8])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)[O-])cc1
Product: COC(=O)C1CN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 0.50 g (1.26 mmol) of 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 5 ml of pyridine cooled to 0° C. was added 0.284 g (2.59 mmol) of tosyl chloride. The mixture was stirred at 0° C. for 2 hours and then concentrated to remove the solvent. To the residue was added 8 ml of anhydrous ethanol and the mixture refluxed for 2 days. The mixture was concentrated to dryness and ethyl acetate added. The mixture was washed with H2O, 2 N citric acid, brine and dried with Na2SO4. The filtrate was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness to give 0.60 g of a foam. Anal. for C25H26N2O7S2 : Calc'd: C,56.6; H,4.9; N,5.3; S,12.1; Found: C,56.2; H,5.2; N,5.2; S,11.4; Mass spectrum (ES) 531.6 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12].[H][H]>CO.[Pt].CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:13][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCN
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOCC
Solvent: CO
Product: CCCNCc1ccc(Br)cc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To 4-bromobenzaldehyde (100 g, 0.54 mol) and n-propylamine (36.3 g, 0.60 mol) in methanol (100 mL) was added 5% platinum on carbon (1.00 g). This mixture was shaken in a Parr hydrogenation reactor overnight to complete formation of the Schiff base. The reaction was then hydrogenated under 4 atmospheres of hydrogen until the theoretical uptake of hydrogen had been consumed. The catalyst was removed by filtration through a 0.45 m nylon frit and washed with methanol. The filtrate was concentrated under reduced pressure and the residue obtained dissolved in ether (500 mL). The ether solution was washed with water (2 ×100 mL), 10% sodium bicarbonate solution (2×100 mL), and water (2×100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude title compound (121.34 g). GC-MS showed this material to be 98.5% pure product containing 1.5% of the desbromo compound; the yield is 96.93% based on the GC purity of the product obtained. A sample of this material was purified by bulb-to-bulb distillation (bath temperature 130°-150° C., 0.18 torr). 1H NMR (CDCl3, 300 MHz) d 0.92 (t, J=7.4 Hz, 3H), 1.36 (bs, 1H), 1.53 (tq, J1 =J2 =7.4Hz, 2H), 2.57 (t, J=7.4Hz, 2H), 3.74 (s, 2H), 7.20 (d, J=9Hz, 2H), 7.44 (d, J=9Hz, 2H). IR (film) 1430, 1060 cm-1. MS (DCl/NH3) m/e 228, 230 (M+H)+.
Reaction SMILES: [CH2:1]([Hf:8](CC1C=CC=CC=1)(CC1C=CC=CC=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=[C:36]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[C:47]([NH:54][C:55]4[C:60]([CH3:61])=[CH:59][CH:58]=[CH:57][C:56]=4[CH3:62])[CH:48]=[CH:49][CH:50]=3)[N:45]=2)[C:35]=1[OH:63])([CH3:33])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C:30]([C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=[C:36]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[C:47]([NH:54][C:55]4[C:60]([CH3:61])=[CH:59][CH:58]=[CH:57][C:56]=4[CH3:62])[CH:48]=[CH:49][CH:50]=3)[N:45]=2)[C:35]=1[O-:63])([CH3:31])([CH3:32])[CH3:33].[CH2:9]([Hf+2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:30]([C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=[C:36]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[C:47]([NH:54][C:55]4[C:60]([CH3:61])=[CH:59][CH:58]=[CH:57][C:56]=4[CH3:62])[CH:48]=[CH:49][CH:50]=3)[N:45]=2)[C:35]=1[O-:63])([CH3:31])([CH3:32])[CH3:33]
Reactant: Cc1cccc(C)c1Nc1cccc2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc12
Reactant: c1ccc(C[Hf](Cc2ccccc2)(Cc2ccccc2)Cc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1Nc1cccc2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3[O-])nc12
Product: c1ccc(C[Hf+2]Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A solution of tetrabenzylhafnium (0.47 g, 0.86 mmol) in toluene (5 mL) is added at 0° C. to a solution of 2,4-di-tert-butyl-6-[8-(2,6-dimethylanilino)-2-quinolinyl]phenol (0.30 g, 0.66 mmol) in toluene (10 mL). The color of the mixture changes from pale yellow to yellow-orange. The resulting mixture is allowed to warm to room temperature and is then stirred for 8 days at 40° C. The mixture is evaporated, and pentane (20 mL) is added. The crystalline precipitate is separated by decantation, washed with pentane, and dried in vacuo. Yield of 34, a yellow crystalline powder: 0.26 g (48%). 1H NMR (C6D6) δ: 7.74-7.66 (m, 3H); 7.45 (d, 1H); 7.22 (d, 1H); 7.15-7.13 (m, 3H); 6.99 (t, 1H); 6.79-6.62 (m, 10H); 6.18 (d, 1H); 2.40 (d, 2H); 2.31 (s, 6H); 1.97 (d, 2H); 1.75 (s, 9H); 1.36 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[CH:14]=[O:15])[CH3:2].[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[CH:5][C:4]=1[CH:14]([OH:15])[CH3:16])[CH3:2]
Reactant: C[Mg+]
Reactant: CCc1c(C=O)cnn1-c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1c(C(C)O)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0° C. solution of 7.55 (37.7 mmol) of 5-ethyl-1-phenyl-1H-pyrazole-4-carbaldehyde (Example 86) in anhydrous THF (100 mL) under N2 was added over 5 minutes 15.7 (47.1 mmol) of 3.0 M MeMgBr in Et2O. The mixture was warmed to room temperature and stirred for 16 h, then 25 mL of 5% NH4Cl was added and the mixture was extracted with CH2Cl2 (70 mL), and the extract was washed with saturated NaCl (15 mL). The organic layer separated, dried over MgSO4, and concentrated to give 1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanol (7.91 g). ESI MS m/z 217 [C13H16N2O+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:11]3=[N:10][C:9]=2[CH3:17])=[CH:4][CH:3]=1.[CH3:18][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:17][C:9]1[N:10]=[C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:18])=[CH:3][CH:4]=1
Reactant: Cc1nc2ncccn2c1-c1ccc(Br)cc1
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C)nc3ncccn23)cc1
Temperature: 130 °C
Yield: 64.5 %

Procedure:
Add 3-(4-bromophenyl)-2-methyl-imidazo[1,2-a]pyrimidine (1.00 g, 3.470 mmol) and DMF (17 mL) to a 50 mL screw-cap vial (fitted with stir bar). Degas the solution with nitrogen for 3 min. Add tetramethylstannane (1.91 mL, 13.88 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.36 g, 520.57 μmol) to the vial, and close the vial. Heat the mixture in an oil bath to 130° C. for 2 hours. Cool the reaction to room temperature, and quench with an excess of water. Extract the mixture with EtOAc. Wash the combined organic extracts with brine. Dry the organic extracts over potassium carbonate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the crude mixture by silica gel chromatography with a gradient of 50-100% hexane/EtOAc to give the title compound as a white solid (0.50 g, 64% yield). LCMS (m/z) 224.2 (M+1). 1H NMR (399.83 MHz, d6-DMSO) δ 8.81-8.79 (m, 1H), 8.51-8.49 (m, 1H), 7.73 (d, J=7.9 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 7.09-7.06 (m, 1H), 2.64 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:38][C@@H:39]([OH:42])[C:40]#[CH:41]>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:41]=[C:40]([C@H:39]([OH:42])[CH3:38])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#C[C@@H](C)O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@@H](O)c1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (39.2 mg), CuI (12.8 mg), and Et3N (0.16 mL) in CHCl3 (5.6 mL) is added (R)-(+)-3-butyn-2-ol (0.053 mL). The reaction is stirred at room temperature for 2 days. The reaction is condensed to remove CHCl3. The solvent is replaced with EtOH (5.6 mL) and additional Et3N (0.16 mL) is added to the reaction mixture. N2 is passed over the surface and the reaction is heated at 60° C. overnight, then allowed to cool to room temperature. The reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2. Product-containing fractions are combined, condensed, and recrystallized from hot acetonitrile to afford 33.8 mg (13%) of N-(4-chlorobenzyl)-2-[(IR)-1-hydroxyethyl]-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a tan solid. m.p. 155-159° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.16, 9.42, 8.05, 8.01, 7.40, 7.02, 5.90, 5.26, 4.59, 3.71, 3.58, 2.40, 1.61; IR (diffuse reflectance) 1662, 1629, 1592, 1569, 1541, 1490, 1349, 1294, 1279, 1271, 1245, 1229, 1114, 879, 807 cm−1;
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:24]Br>C(Cl)(Cl)Cl>[Br:24][C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: c1ccc(-c2nc(-c3ccncc3)cs2)cc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1sc(-c2ccccc2)nc1-c1ccncc1
Reaction time: 1 h

Procedure:
To the solution of 2-phenyl-4-(pyridin-4-yl)thiazole (70 mg, 0.3 mmol) in CHCl3 was added Na2CO3 (311 mg, 2.9 mmol) and Br2 (75 μL, 1.470 mmol) at rt. After 1 h, additional charges of Na2CO3 (1 g, 9.4 mmol) and Br2 (0.5 mL, 1 mmol) were added and the reaction maintained for another hour. The reaction was diluted with CHCl3 and filtered through a pad of Celite, washing the filter cake thoroughly with CHCl3. The combined filtrates were concentrated of provide 0.5-bromo-2-phenyl-4-(pyridin-4-yl)thiazole which was carried forward without further purification: LCMS (m/z): 318.9 (MH+), tR=0.75 min.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:20][C:21]1([CH3:31])[CH:23]([CH:24]=[C:25]([Cl:27])[Cl:26])[CH:22]1[C:28](Cl)=[O:29].O>C1(C)C=CC=CC=1>[CH3:20][C:21]1([CH3:31])[CH:23]([CH:24]=[C:25]([Cl:26])[Cl:27])[CH:22]1[C:28]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH:2]([F:12])[F:1])=[O:29]
Reactant: OCc1ccccc1OC(F)F
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
6.09 g (0.035 mol) of 2-difluoromethoxybenzyl alcohol and 3.5 g (0.035 mol) of triethylamine were dissolved in 50 ml of toluene and the solution was added dropwise to a mixture of 7.95 g (0.35 mol) of 2,2-dimethyl-3-(2',2'-dichloro-vinyl)-cyclopropanecarboxylic acid chloride in 100 ml of toluene at 20°-25° C. The reaction mixture was subsequently stirred at room temperature for 3 hours and poured into 150 ml of water, the toluene phase was filtered off, washed with 100 ml of water and dried with sodium sulphate and the toluene was distilled off in vacuo. Last residues of solvent were removed by incipient distillation at a bath temperature of 60° C./0.2 to 1.0 mm Hg. 10.9 g (81% of theory) of 2-difluoromethoxybenzyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylate were obtained as a viscous oil with the refractive index nD20 =1.5190.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13]Br.Br>C(O)(=O)C>[Br:13][CH2:2][C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C(=O)CBr)cc1
Temperature: 45 °C

Procedure:
2.0 g (12.2 mmole) of 4-acetyl benzoic acid was added to 90 ml of acetic acid in a 500 ml erlenmeyer flask and heated at 45° C. until dissolved. Maintaining the temperature at 45° C., 1.95 g (12.2 mmole, 0.61 ml) of bromine dissolved in ~2 ml acetic acid was added slowly over 1 hour with vigorous stirring. The reaction required an induction period of several minutes before proceeding, which became evident by the loss of the red bromine color and the evolution of HBr. The product, BABA (Modifying Reagent II), was precipitated on ice, collected by filtration and recrystallized 3 times from hot (75° C.) ethanol.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:17]([OH:18])[C@H:16]([F:19])[C@@H:15]([CH2:20][OH:21])[O:14][C@H:5]1[O:6]CC1C=CC=CC=1)=[N+]=[N-].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([NH:1][C@H:4]1[C@@H:17]([OH:18])[C@H:16]([F:19])[C@@H:15]([CH2:20][OH:21])[O:14][CH:5]1[OH:6])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=N[C@@H]1[C@H](OCc2ccccc2)O[C@H](CO)[C@@H](F)[C@@H]1O
Product: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](F)[C@@H]1O

Procedure:
The present invention provides a process for preparing 5-acetamido-3,5,7-trideoxy-7-fluoro-D-glycero-β-D-lacto-2-nonulopyranosidonic acid comprising hydrogenating benzyl 2-azido-2,4-dideoxy-4-fluoro-β-D-mannopyranoside in the presence of acetic anhydride to obtain N-acetyl-4-deoxy-4-fluoro-D-mannosamine, and subsequently reacting the product with sodium piruvate, bovine serum albumin and aldolase sialate.