Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:17][CH:18]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1cnc(Br)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Nc2cnc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.4 %

Procedure:
Into a 50 mL roundbottom flask, was placed 4-methoxyphenylboronic acid (5.4 g, 35.54 mmol). To this was added 5-bromo-pyrazin-2-ylamine (3 g, 17.24 mmol). Cu(OaC)2 (3.45 g, 19.06 mmol) was added, followed by addition of a solution of DMAP (4.2 g, 34.43 mmol) in CH2Cl2 (20 mL). The resulting solution was stirred at room temperature for 12 hours. The reaction progress was monitored by thin layer chromatography (TLC) (ethyl acetate/petroleum ether=1:2). When the reaction was complete, the mixture was filtered, then concentrated under vacuum. The residue was dissolved in ethyl acetate (EtOAc), then washed with water. The organic layer was dried over Na2SO4, then filtered and concentrated. The crude product was purified by silica gel chromatography (SGC) eluting with ethyl acetate/petroleum ether (1:5, v/v) to provide (5-bromo-pyrazin-2-yl)-(4-methoxy-phenyl)-amine (i) (500 mg, yield 10%) as a yellow solid.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:11][CH2:10][N:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:8]2[CH:23]=[CH:24][CH:25]=[N:26][C:7]=2[C:6]1=O)C.O.[NH2:29]N>>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:9]2[CH2:10][CH2:11][C:5]3[CH:4]=[N:2][NH:29][C:6]=3[C:7]3[N:26]=[CH:25][CH:24]=[CH:23][C:8]2=3)=[O:22])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: NN
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc2C1=O
Solvent: O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cn[nH]c2-c2ncccc21

Procedure:
As described for Reference Example 223, 8-[(dimethylamino)methylene]-5,6,7,8-tetrahydro-5-(4-nitrobenzoyl)-9H-pyrido[3,2-b]azepin-9-one is reacted with hydrazine hydrate to give the product as a solid, m.p. 255°-256° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].C(OC([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24](O)=O)[CH2:19][CH2:18]1)=O)(C)(C)C.OP(O)(O)=O.S1(CCCC1)(=O)=O>CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:24]([CH2:23][CH:20]3[CH2:21][CH2:22][NH:17][CH2:18][CH2:19]3)[S:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1S
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: Brc1ccc2nc(CC3CCNCC3)sc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
2-Amino-5-bromobenzenethiol (326 mg, 1.597 mmol), 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (480 mg, 1.973 mmol), PPA (115% as H3PO4) (1637 mg, 6.82 mmol), and sulfolane (3.9 mL) were placed in a microwave vial and heated carefully with vial open to air at 80° C. for 10 min. The vial was then sealed and heated in microwave at 140° C. for 20 min. The mixture was diluted with MeOH, and purified via preparative HPLC (PHENOMENEX® Axia 5u C18 30×100 mm, Flow rate: 40 mL, Solvent A: 90% H2O and 10% MeOH with 0.1% TFA, Solvent B: 90% MeOH and 10% H2O with 0.1% TFA. 20% to 100% B in 10 min gradient, stop at 12 min, the product RT=6.86 min) to afford Compound 41A as an orange solid (380 mg, 76% yield). 1H NMR (400 MHz, methanol-d3) δ 8.16 (d, J=1.9 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.63 (dd, J=8.7, 1.8 Hz, 1H), 3.40 (d, J=12.8 Hz, 2H), 3.14 (d, J=7.1 Hz, 2H), 3.01 (t, J=12.2 Hz, 2H), 2.27 (tdt, J=11.2, 7.3, 3.5 Hz, 1H), 2.02 (d, J=12.6 Hz, 2H), 1.56 (td, J=14.9, 3.7 Hz, 2H). LCMS (m/z)=311 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1)([O-])=O.Cl.[H][H]>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH:21]([CH3:22])[CH3:23])[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](NC(=O)Cc3ccc([N+](=O)[O-])cc3)[C@H]2SC1
Reactant: [H][H]
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](NC(=O)Cc3ccc(N)cc3)[C@H]2SC1
Reaction time: 0.08 h

Procedure:
The catalyst was added to a solution of 406 mg of DL cis 7-p-nitrophenylacetamido-3-isopropyl-3cepheme-4-carboxylic acid in 3.8 ml of dimethylformamide and 1.12 ml of N hydrochloric acid and a current of hydrogen was passed therethrough until saturated. The mixture was filtered and the filter was washed with a 50--50 water-ethanol solution containing a few drops of hydrochloric acid. The filtrate was evaporated to dryness and the residue was taken up in 3 ml of water. Ammonium formate was added thereto to a pH of 4.5 and the mixture was stirred 5 minutes and vacuum filtered. The precipitate was empasted with water and dried to obtain DL cis 7-p-aminophenylacetamido-3-isopropyl-3-cepheme-4-carboxylic acid melting at 150°C with decomposition. The product occurred as ocre crystals slightly soluble in water, ethanol and chloroform and insoluble in ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][OH:9].[CH2:10]=O>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][O:9][CH2:10]1
Reactant: C=O
Reactant: OCCCNCCCO
Solvent: Cc1ccccc1
Product: OCCCN1CCCOC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a glass reaction vessel equipped with stirrer, thermometer, and condenser fitted with a water trap is added di-(3-hydroxypropyl) amine (3.0 mole, 399 g.) and toluene (500 g.). Paraformaldehyde (3.15 mole, 90% pure, 105 g.) is weighed out and about 1/3 is added to the amine solution. The resulting mixture is stirred and heated to 90° C. while slowly adding the remaining paraformaldehyde in about 70 minutes. The reaction is heated to reflux and the water separated. After 4 hours, a total of 63 ml. of water is removed. Toluene is removed at reduced pressure. The residue is distilled at high vacuum to yield 3-(γ-hydroxypropyl)tetrahydro-1,3-oxazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[N:10].C(OC(=O)C)(=O)C>>[OH:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Cc1ccc(O)cn1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(CCc2ccc(O)cn2)cc1
Yield: 20.8 %

Procedure:
A mixed solution of 3-hydroxy-6-methylpyridine (3.3 g, 0.03 mol), 4-cyanobenzaldehyde (3.9 g, 0.03 mol) and acetic anhydride (6.1 g, 0.06 mol) was heated under reflux for 25 hours, followed by cooling the reaction mixture, thereafter adding toluene (30 cc), separating the resulting solids by filtration, washing the solids with toluene till the toluene filtrate became colorless, adding methanol (20 cc) and conc. hydrochloric acid (20 cc) to the solids, heating the mixture for 3 hours, cooling, neutralizing with aqueous ammonia, filtering, dissolving the resulting precipitate in ethanol (50 cc), adding Pd-C catalyst (0.3 g), and subjecting the mixture to catalytic reduction at room temperature and the atmospheric pressure. After completion of the reaction, the catalyst was filtered off, followed by distilling off the solvent under reduced pressure and recrystallizing the remaining solids from a mixed solvent of methanol/water (2:1) to obtain 3-hydroxy-6-[β-(4-cyanophenyl)ethyl]pyridine (1.4 g). To this compound were then added toluene (50 cc) and pyridine (3 cc), followed by adding 4-pentoxybenzoyl chloride (1.4 g) to the resulting solution, allowing the mixture to stand overnight, washing with water, then with 2N-hydrochloric acid, further with 2N-NaOH aqueous solution and finally with water till the washing water became neutral, distilling off toluene under reduced pressure and recrystallizing the remaining solids from ethanol to obtain the objective 6-[β-4-(cyanopheny)ethyl]-3-(4-pentyloxybenzoyl)pyridine (0.7 g) having as its phase transition points, a crystalline-nematic point (C-N point) of 107.8°-108.7° C. and a nematic-clearing point (N-I point) of 156.5°-156.8° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:13][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:15]1)=[O:12].I[CH:32]([CH3:34])[CH3:33]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:32]([CH3:34])[CH3:33])[N:6]=[C:5]2[C:11]([NH:13][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:15]1)=[O:12]
Reactant: CC(C)I
Reactant: COC(=O)C[C@@H]1C[C@H](NC(=O)c2n[nH]c3ccc(F)cc23)CN1C(=O)OC(C)(C)C
Product: COC(=O)C[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccc(F)cc23)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 4 from tert-butyl (2S,4S)-4-{[(5-fluoro-1H-indazol-3-yl)carbonyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (step 1 of Example 25) and 2-iodopropane.
Reaction SMILES: [ClH:1].[C:2]([O:10][C@H:11]1[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(O)C.[Pd]>[ClH:1].[C:2]([O:10][C@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O[C@H]1CCN(Cc2ccccc2)C1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: O=C(O[C@H]1CCNC1)c1ccccc1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
A warm suspension of (S)-3-Benzoyloxy-N-benzyl-pyrrolidine hydrochloride (11.8 Kg, 37.0 mole) in 2-propanol (118 L) at 40° C. was hydrogenated over 10% palladium on carbon (2.35 Kg, 50% water wet) under 50 psig for 12 hours. Upon confirmation of reaction completion, the mixture was filtered over Celite and the latter was rinsed with additional 2-propanol (38 L). The combined filtrate and rise solutions were concentrated by atmospheric distillation (total volume of 35 L). At this stage, diisopropyl ether (105 L) was slowly added over 15 minutes, and the resulting slurry was further stirred at 55° C. for 15 minutes. The reaction mixture was gradually cooled to −10° C., and stirred an additional 2 hours. The solids were isolated by filtration, washed with diisopropyl ether (30 L) and dried under vacuum at 40° C. to provide the title pyrrolidine (7.3 Kg, 86.6%) as a colorless crystalline material. mp 140-141° C.; 1H NMR (400 MHz, d-6 DMSO) δ 9.65 (bs, s, 2H), 8.04-8.01 (m, 2H), 7.68-7.64 (m, 1H), 7.53-7.49 (m, 2H), 5.53-5.51 (m, 1H), 3.42-3.41 (m, 2H), 3.33-3.28 (m, 2H), 2.25-2.15 (m, 2H); 13C NMR (100 MHz, d-6 DMSO) δ 165.8, 134.3, 130.2, 130.0, 129.3, 74.2, 50.4, 43.7, 31.3; MS [(m+1)/z] 192.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[CH:3]=1.[CH3:16][O:17]C(Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[C:3]=1[CH:16]=[O:17]
Reactant: COC(Cl)Cl
Reactant: CCC1(C)Cc2c(C)cc(Cl)c(C)c2C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1(C)Cc2c(C)c(Cl)c(C=O)c(C)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 19 g of the 6-chloro-2-ethyl-2,4,7-trimethylindane in 100 ml of dry dichloromethane was continuously added 9.5 ml of α,α-dichloromethyl methyl ether and 11.5 ml of TiCl4 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 100 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 20.85 g of the title compound as yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[O:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17]>>[Br:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:17][CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][O:11]2)[N:4]=1
Reactant: OCC1CCCO1
Reactant: BrCc1cccc(CBr)n1
Product: BrCc1cccc(COCC2CCCO2)n1
Yield: 19 %

Procedure:
Prepared from 2,6-bis(bromomethyl)pyridine and (RS)-tetrahydrofuran-2-methanol by the alkylation method described for the final step of Example 32 to give the title compound (19%); NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 7.5 Hz), 7.42 (1H, d, J 7.5 Hz), 7.33 (1H, d, J 7.5 Hz), 4.73-4.65 (2H, m), 4.52 (2H, s), 4.17-4.10 (1H, m), 3.93-3.87 (1H, m), 3.82-3.77 (1H, m), 3.62-3.55 (2H, m), 2.03-1.85 (3H, m), 1.71-1.62 (1H, m); (M+H)+ 286, 288.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][C@@H:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][CH2:26]4)[C:18]=3[CH:17]=[CH:16]2)[CH:12]=[CH:11]1)(C(C)(C)C)(C)C.F.N1C=CC=CC=1>N1C=CC=CC=1.C1COCC1>[C@@H:25]1([NH:24][C:23]2[C:18]3[CH:17]=[CH:16][N:15]([C@@H:13]4[CH2:14][C@@H:10]([CH2:9][OH:8])[CH:11]=[CH:12]4)[C:19]=3[N:20]=[CH:21][N:22]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a solution of 7-[(1R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopent-2-en-1-yl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (81.9 mg, 0.178 mmol) in pyridine (0.800 mL) and THF (0.800 mL) at 0° C. under an atmosphere of nitrogen was added dropwise pyridine hydrofluoride (0.0500 mL, 0.555 mol). The solution was warmed to rt and stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM to afford the title compound as a white solid (˜70% purity, 35.7 mg, 41%). LC/MS: Rt=1.03 min, ES+ 347 (FA standard).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:18])[CH2:10][CH2:11][CH2:12][C:13](OCC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>C1COCC1>[OH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:18]
Reactant: CCOC(=O)CCC[C@@H](C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCCO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
To a solution of (R)-ethyl 5-(tert-butoxycarbonylamino)hexanoate (1.70 g, 6.56 mmol) in THF (20 mL) was added dropwise a 2.0 M lithium borohydride solution in THF (6.56 mL, 13.1 mmol). After the addition, the reaction mixture was stirred at rt for 20 hr and then 45° C. for 7 hr and again at rt overnight. The reaction mixture was cooled to 0° C. and was quenched carefully with pH 3 buffer solution. Then the resulting white suspension was stirred at rt for 1 hr. The mixture was then partitioned between 1 N aqueous HCl and DCM. The aqueous phase was extracted with DCM (2×). The combined DCM extracts were washed with water (2×), saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The obtained oily residue was dried under high vacuum to afford (R)-tert-butyl 6-hydroxyhexan-2-ylcarbamate (1.42 g, 6.53 mmol, 100% yield) as a colorless oil. Anal. Calcd. for C11H23NO3 m/z 217.3. found: 218.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 4.34 (s, 2H), 3.64 (d, J=6.3 Hz, 2H), 1.68-1.50 (m, 2H), 1.44 (s, 9H), 1.51-1.32 (m, 5H), 1.12 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11](OC(=O)C)(=[O:13])[CH3:12].S(=O)(=O)(O)O>O>[C:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[C:7]#[N:8])(=[O:13])[CH3:12]
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Cl)cc1C#N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
5-Chloro-2-hydroxybenzonitrile (39.25 g, 0.25 mol) and acetic anhydride (40 ml) were combined, to which 0.5 ml of concentrated sulfuric acid was added. The reaction mixture was stirred at 60° C. for 10 minutes, followed by the addition of water. Subsequent to extraction with ethyl acetate, the organic layer was washed with 1 N aqueous solution of sodium hydroxide and a saturated aquous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, whereby 45 g of 2-acetoxy-5-chlorobenzonitrile were obtained as a brown solid (yield: 92%). It was provided for immediate use in the next step.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:31]3[CH:30]=[N:29][C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[CH:33][CH:32]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(F)ccc3F)CCN4)cn2)CC1
Yield: 53 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a beige solid (53% yield). M.p. 192-193° C., LCMS: m/z=437.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.52-2.58 (m, 4H, 3.43-3.50 (m, 2H), 3.52-3.59 (m, 4H), 3.60-3.65 (m, 2H), 4.47 (s, 2H), 4.90 (s, 1H), 6.62 (m, 2H), 6.91-7.09 (m, 3H), 7.52 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 8.2 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([NH:11][CH3:12])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC1C=CC=CC=1C(Cl)=O>>[CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNC(C)C(O)c1ccccc1
Agent: Cc1ccccc1C(=O)Cl
Product: CN[C@@H](C)[C@@H](O)c1ccccc1

Procedure:
It was also reported that the reaction of 1-ephedrine with o-methylbenzoyl chloride and subsequent hydrolysis of the resulting amide gave d-pseudoephedrine. Welsh, J. Am. Chem. Soc., 71, 3500 (1949).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[N:25]=3)[C:16]=2[CH:32]=1.CC(C1C=C(C(C)C)C(S([N:48]=[N+:49]=[N-:50])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:48]([CH:19]1[N:18]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[N:25]=2)[C:16]2[CH:32]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:49]=[N-:50]
Reactant: COc1cccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)n1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: COc1cccc(C2=NC(N=[N+]=[N-])C(=O)N(C)c3ccc(Cl)cc32)n1
Yield: 62.3 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (0.19 mL of 0.5 M in toluene, 0.095 mmol), 7-chloro-1,3-dihydro-5-(6-methoxy-2-pyridinyl)-1-methyl-2H-1,4-benzodiazepin-2-one (0.0290 g, 0.0918 mmol), trisyl azide (0.0710 g, 0.229 mmol) and acetic acid (0.023 mL, 0.40 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (49:1 CH2Cl2:EtOAc) provided the title compound (0.0204 g, 62%). 1H-NMR (CDCl3): δ 7.95 (d, J=7.2 Hz, 1H), 7.78-7.70 (m, 2H), 7.54 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 4.64 (s, 1H), 3.80 (s, 3H), 3.44 (s, 3H). MS (ESI) (M+H)+=357.
Reaction SMILES: [CH3:1][CH:2]1[C:10](=O)[C:9]2[CH:8]=[C:7]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:6]3=[CH:5][C:4]=2[CH2:3]1.[BH4-].[Na+].C(O)C.Cl>C(OCC)C>[CH3:1][C:2]1[CH2:10][C:9]2[CH:8]=[C:7]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC1Cc2cc3c(cc2C1=O)C(C)(C)CCC3(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC1=Cc2cc3c(cc2C1)C(C)(C)CCC3(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
(2,3,5,7-Tetrahydro-2,5,5,8,8-pentamethyl-1H-Benz(f)inden-1-one (14.89 g, 58.08 mmol) and NaBH4 (2.21 g, 58.5 mmol) were stirred in diethylether (200 mL) at 0° C. as ethanol (100 mL) was added slowly. This mixture was allowed to warm slowly to room temperature and then stirred at room temperature overnight. After the reaction period the mixture was poured onto crushed ice and made acidic with HCl. The organic layer was then separated and washed with 1M HCl (1×100 mL). The volatiles were then removed from the organic layer and the residue refluxed in benzene (300 mL) with p-toluenesulfonic acid (0.12 g) using a Dean-Stark apparatus until no more H2O was evolved. The mixture was then washed with 1M NaHCO3 (2×100 mL) and the volatiles were removed from the organic layer resulting in the isolation of a yellow oil. Recrystallization from MeOH (0° C.) gave the desired product as off-white crystals (10.37 g, 74.3 percent yield).
Reaction SMILES: O.[C:2]([NH2:8])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[S:15](F)(F)(=[O:17])=[O:16]>CC(C)=O>[CH3:6][C:4]1[O:5][S:15](=[O:17])(=[O:16])[NH:8][C:2](=[O:7])[CH:3]=1
Reactant: O=S(=O)(F)F
Reactant: CC(=O)CC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=CC(=O)NS(=O)(=O)O1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Different quantities of water were added to 150 ml of acetone. 10.1 g (0.1 mol) of acetoacetamide and 69 g (0.5 mol) of finely powdered, dry K2CO3 were added to each of these mixtures. 15.3 g (0.15 mol) of sulfuryl fluoride gas were then passed in--initially at room temperature. The temperature of the reaction mixture increased to about 40° C. during this process. The mixture was stirred for a further 2 hours and the product was filtered off with suction. The filter residue contained Acesulfam K, which was found to be identical to a reference sample by thin layer chromatography (silica gel, solvent system: ethyl acetate/glacial acetic acid 5:1). The filter residue was introduced into a mixture of excess hydrochloric acid with ice and extracted with ethyl acetate. The ethyl acetate extract was dried over Na2SO4 and evaporated in vacuo. Crystalline 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide was obtained and this was converted to Acesulfam K with methanolic KOH. The results are collated in the table which follows. In the last experiment listed in the table, the K2CO3 was used as a 50% aqueous solution.