Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1C(O)=C(OC)C=C(C=1)C=O.[O:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1.S(OC)(O[CH3:28])(=O)=O.C(=O)([O-])[O-]>CC(C)=O>[CH3:19][O:18][C:17]1[CH:16]=[C:15]([CH:23]=[C:22]([O:1][CH3:2])[C:20]=1[O:21][CH3:28])[CH:14]=[O:13]
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1cc(C=O)cc(O)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: COc1cc(C=O)cc(OC)c1OC

Procedure:
U.S. Pat. No. 3,855,306 discloses methylation of 5-hydroxyvanillin (initially prepared from vanillin by bromination and subsequent hydrolysis) with dimethyl sulfate in the presence of an alkali carbonate in an organic medium such as acetone. 3,4,5,-Trimethoxybenzaldehyde in yields of about 94% are obtained in this method, but the reaction is slow and operating with organic solvents presents disadvantages of operation and cost.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22]([S:24][CH3:25])[C:19]([C:20]#[N:21])=[C:18](F)[CH:17]=2)[CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.[NH2:36][NH2:37]>CCO>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:17]=[C:18]3[C:19]([C:20]([NH2:21])=[N:36][NH:37]3)=[C:22]([S:24][CH3:25])[CH:23]=2)[CH:9]=1)[CH3:2]
Reactant: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(SC)c2)nc(NC)n1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1CCCN1c1cc(-c2cc(SC)c3c(N)n[nH]c3c2)nc(NC)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
In a microwave tube, 4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methylthio)benzonitrile (136 mg, 0.366 mmol), 5 mL of EtOH, Hunig's base (0.064 mL, 0.366 mmol), and hydrazine anhydrous (0.069 mL, 2.197 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), dried under reduced pressure to afford the title compound (90 mg). LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.91 (t, J=7.3 Hz, 3H), 1.36 (m, 1H), 1.80 (m, 2H), 1.93 (m, 3H), 2.59 (s, 3H), 2.83 (d, J=4.6 Hz, 3H), 3.53 (m, 1H), 4.06 (m, 1H), 5.08 (s, 2H), 6.22 (s, 1H), 6.44 (s, 1H), 7.38 (s, 1H), 7.71 (s, 1H), 11.75 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].[C:10]1([CH2:16][O:17][CH2:18][C@@H:19](O)[C@H:20](O)[CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OC(C)C)(C)C.O>[F:1][C:2]1[C:3]2[O:9][C@@H:19]([CH2:18][O:17][CH2:16][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:20]([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H](COCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: Oc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: Fc1cccc2c1O[C@@H](COCc1ccccc1)[C@H](COCc1ccccc1)O2

Procedure:
A mixture of 3-fluorobenzene-1,2-diol (5.12 g) and (R*,R*)-(±)-1,4-bis(phenylmethoxy)-2,3-butanediol, bis(4-methylbenzenesulphonate) (24.4 g) was stirred with dimethylformamide (D.M.F.) (160 ml) under a nitrogen stream for 45 min. Anhydrous cesium carbonate (13.0 g) was added and the mixture was heated to 150° under reflux for 18 hours. The dark brown mixture was cooled to 30° and diluted with di-isopropyl ether (370 ml) and water (320 ml). The layers were separated and the aqueous layer was re-extracted with di-isopropyl ether (150 ml then 100 ml). The extracts were sequentially washed with M hydrochloric acid (300 ml), 30% aqueous sodium chloride (100 ml) and were combined and evaporated in vacuo to a dark brown oil (12.6 g) which was dissolved in light petroleum-dichloromethane (3:1) (40 ml) and chromatographed over Sorbsil (126 g) using light petroleum-dichloromethane mixtures of gradually increasing polarity. Combination of appropriate fractions and evaporation of the solvents gave the title compound as a yellow oil (7.0 g), NMR τ (CDCl3) 2.6-2.8 (10H, m, Ph), 3.18-3.38 (3H, m, 6-H, 7-H, 8-H), 5.32-5.58 (4H, m, CH2Ph), 5.64 (2H, m, 2-H, 3-H), 6.06-6.32 (4H, m, CH2O).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH3:3].Cl[CH2:17][C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:17][C:18]3[O:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:21][N:22]=3)[CH:11]=2)[CH2:6]1)[CH3:1]
Reactant: ClCc1nnc(-c2ccccc2)o1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC1CCc2cc(OCc3nnc(-c4ccccc4)o3)ccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(N,N-dimethylamino)methyl-6-hydroxytetralin (206 mg, a free form of Reference Example 16) and 2-chloromethyl-5-phenyl-1,3,4-oxadiazole (231 mg) in DMF (5 ml) was added potassium carbonate (215 mg) and the reaction mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate:hexane=1:2) to obtain the titled compound (307 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:34])[CH2:17][N:16]([CH2:18][CH2:19][N+:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])([CH3:22])[CH3:21])[C:15](=[O:33])[NH:14]1.C(O[Cl:40])(C)(C)C>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[Cl:40][N:14]1[C:13]([CH3:34])([CH3:12])[CH2:17][N:16]([CH2:18][CH2:19][N+:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])([CH3:22])[CH3:21])[C:15]1=[O:33]
Reactant: COCCOCCOCC[N+](C)(C)CCN1CC(C)(C)NC1=O
Reactant: CC(C)(C)OCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: COCCOCCOCC[N+](C)(C)CCN1CC(C)(C)N(Cl)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A solution of 2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N,N-dimethylethanaminium 4-methylbenzenesulfonate (162 mg, 0.32 mmol) in methanol (1 ml) was cooled to 0° C. tert-Butylhypochlorite (45 ul, 0.4 mmol) was added. The resulting solution was stirred for 2 hours at 0° C. and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC eluting from a C18 column with a gradient of 5 to 95% CH3CN in water (with 0.01% acetic acid) to give 75 mg of a clear oil. 1H NMR (D2O, 400 MHz) δ 1.21 (s, 6H), 2.29 (s, 3H), 3.09 (s, 6H) 3.26 (s, 3H), 3.31 (s, 2H), 3.48-3.36 (m, 14H), 3.84 (br m, 2H), 7.25-7.27 (d, J=8.1 Hz, 2H), 7.58-7.60 (d, J=8.2 Hz, 2H). 13C NMR (D2O, 100 MHz) δ 161.2, 142.4, 139.6, 129.4, 125.3, 70.9, 69.7, 69.4, 69.4, 63.9, 63.6, 62.4, 61.1, 58.0, 55.5, 51.8, 38.9, 22.3, 20.5; LRMS (ESI/APCI) m/z 366 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([OH:11])[CH2:9][CH2:8][S:7][CH2:6]1)=[O:4].[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13].N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([O:11][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[S:13])[CH2:9][CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSCC[C@@H]1O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CSCC[C@@H]1OC(=S)n1ccnc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 55.5 %

Procedure:
A solution of 4(S)-hydroxy-tetrahydro-thiopyran-3(R)-carboxylic acid methyl ester (1.00 g, 5.674 mmol) in dry tetrahydrofuran (50 mL), under argon, was treated with 1,1′-thiocarbonyldiimidazole (2.085 g, 11.35 mmol) and pyridine (6.88 μL, 8.511 mmol). The reaction mixture was stirred at 25° C. for 36 h and was then diluted with ethyl acetate (100 mL). The resulting solution was washed sequentially with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 4(S)-(imidazole-1-carbothioyloxy)-tetrahydro-thiopyran-3(R)-carboxylic acid methyl ester (901 mg, 55.4%) as a beige oil: EI-HRMS m/e calcd for C11H14N2O3S2 (M+) 286.0446, found 286.0438.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[F:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:7]/[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccncc1
Reactant: O=Cc1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: Fc1ccc(/C=C/c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A mixture of 4-picoline (15.6 ml, 161 mmol) and 4-fluorobenzaldehyde (20 g, 161 mmol) in acetic anhydride (125 ml) was heated at reflux overnight. The reaction was cooled and the solvent evaporated. Water (100 ml) was added to the residue, and the mixture stirred at room temperature for 30 minutes. Saturated sodium carbonate solution (100 ml) and ethyl acetate (150 ml) were then added, and stirring continued for a further 30 minutes. The two phases were separated, and the aqueous phase extracted with ethyl acetate (3×200 ml). The combined organic phases were dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting with 50% ethyl acetate/petrol (60°-80°). The appropriate fractions were combined and concentrated to yield (E)-4-[2-(4-fluorophenyl)ethenyl]pyridine (19 g, 60%) as a beige solid. δH (CDCl3) 6.93 (1H, d, J 16.3 Hz, ArCHCH), 7.05-7.13 (2H, m, ArH), 7.26 (1H, d, J 16.3 Hz, ArCHCH), 7.34-7.36 (2H, m, ArH), 7.48-7.54 (2H, m, ArH) and 8.56-8.60 (2H, m, ArH).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C@H:14]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][CH:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:11][N:10]3[CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[CH3:29][O:30][CH2:31][C:32]([N:13]1[CH:12]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][N:10]2[CH:28]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C@@H:14]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:33]
Reactant: c1ccc(C[C@@H]2NC(c3ccccc3)Cn3cc(-c4ccccc4)nc32)cc1
Reactant: COCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: COCC(=O)N1C(c2ccccc2)Cn2cc(-c3ccccc3)nc2[C@@H]1Cc1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-2,6-diphenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine (29 mg) in chloroform were successively added morpholinom thylpolystyrene resin (Novabiochem, loading=3.51 mmol/g, 50 mg, 2eq) and methoxyacetylchloride (10 mL, 1.3 eq). After about 3 hours of stirring at about 20° C., chloroform was added to the mixture followed by aminomethylpolystyrene resin (Novabiochem, loading=1.2 mmol/g, 132 mg, 2 eq). The reaction mixture was stirred for another 2 hours and then filtered. The filtrate was concentrated under reduced pressure to afford 23 mg of the title compound (yield=68%). NMR (1H, 100 MHz, CDCl3): 7.9-7.0 (m, 16H, arom. H), 6.6 (m, 1H, H8), 5.3 (m, 1H, H6), 4.6 (dd, 1H, 2J=13 Hz, H5), 4.35 (dd, 1H, 2J=13 Hz, 3J=5 Hz, H5′), 3.7-2.9 (m, 5H, CH2Ph, OCH3).
Reaction SMILES: [OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8]([O:10]C)=O.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][CH:22]([F:24])[F:23])=[CH:15][CH:14]=1>C(#N)CCC>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][CH:22]([F:24])[F:23])[C:8]([C:3]2[C:4](=[O:7])[O:5][CH2:6][C:2]=2[OH:1])=[O:10])=[CH:15][CH:14]=1
Reactant: COC(=O)C1=C(O)COC1=O
Reactant: FC(F)CNCc1ccc(Cl)nc1
Solvent: CCCC#N
Product: O=C1OCC(O)=C1C(=O)N(Cc1ccc(Cl)nc1)CC(F)F
Temperature: 65 °C

Procedure:
10 g of methyl 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylate are initially introduced in 111 g of butyronitrile and admixed with 5 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine. The solution is heated at 65° C. for 3 h. The solution is then extracted with 300 ml of water and then washed with 300 ml of 5% strength hydrochloric acid solution. The organic phase is dried over magnesium sulphate and the solvent is removed in vacuo. For purification, recrystallization from isopropanol is carried out.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[O:31]1[C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:36]([C:35]5[O:31][N:32]=[CH:33][CH:34]=5)=[O:37])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: O=C(O)c1ccno1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)c3ccno3)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 37) has been coupled with isoxazole-5-carboxylic acid to yield the title compound as off-white solid. MS: 523.1 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18](=[O:20])[NH:24][C:23]1[C:22]([F:21])=[CH:28][CH:27]=[CH:26][C:25]=1[F:29])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To the solution of (S)-3,4-dihydro-1H-isoquinoline-1,2-dicarboxylic acid 2-tert-butyl ester (500 mg, 1.8 mmol, Eq: 1.00) and 2,6-difluoroaniline (279 mg, 2.16 mmol, Eq: 1.2) in pyridine (10.0 mL) at 0° C. was added POCl3 (415 mg, 252 μL, 2.7 mmol, Eq: 1.5). The mixture was warmed to RT and stirred for 2 h. The solvent was evaporated, water was added and the mixture extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (380 mg) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.COCCOCCOC.NN.[OH-].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCCC(=O)c1cccc(Br)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: O
Product: CCCCc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A mixture of 1-(3-bromophenyl)butan-1-one (1.0 g, 4.4 mmol) and diglyme (10 mL) was treated with hydrazine (1.49 g, 44 mmol), stirred at 100° C. for 2 h, treated with KOH (1.23 g, 22 mmol), stirred at 150° C. for 6 hours, cooled to room temperature, poured into water and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated under vacuum. Purification of the resultant residue on silica gel (ISCO) using hexanes as the eluting solvent gave 1-bromo-3-butylbenzene as a clear oil (0.81 g, 86% yield).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1.[CH3:18][CH:19]([SH:23])[CH:20]([SH:22])[CH3:21].[C:24]1([CH2:30][CH:31]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:30]([CH:31]1[S:23][CH:19]([CH3:18])[CH:20]([CH3:21])[S:22]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(S)C(C)S
Reactant: O=CCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC1SC(Cc2ccccc2)SC1C
Reaction time: 0.5 h

Procedure:
Into a 100 ml flask equipped with reflux condenser and magnetic stirring bar and hot plate equipped with magnetic stirring apparatus is placed 0.2 grams of para-toluenesulfonic acid, 5 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. With stirring, over a period of 30 minutes, 6.0 grams (0.05 moles) of phenylacetaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and refluxed for a period of 10 hours during which time water of formation is removed. After the 10 hour period, the reaction mass is cooled and transferred to a separatory funnel. The reaction mass is washed with one 50 ml portion of saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. The resulting filtrate is then distilled on a Microvigreux column yielding the following four fractions:
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C@H:5]([CH3:19])[C@H:6]([OH:18])[C@@H:7]([CH3:17])[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[CH2:22](OC(=N)C(Cl)(Cl)Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C@H:5]([CH3:19])[C@H:6]([O:18][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:7]([CH3:17])[CH2:8][O:9][Si:10]([C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:12])[CH3:11]
Reactant: CON(C)C(=O)[C@H](C)[C@H](O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Product: CON(C)C(=O)[C@H](C)[C@H](OCc1ccccc1)[C@@H](C)CO[Si](C)(C)C(C)(C)C

Procedure:
This material is prepared from N-methoxy-N-methyl-2-(R)-methyl-3-(R)-hydroxy-4-(S)-methyl-5-t-butyldimethylsiloxypentanamide using the reagent benzyltrichloroacetimidate and following the procedure described by Bundle et al. in J. C. S. Chem. Comm. 1981, 1240.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24]>>[Br:1][C:2]1[C:7]([F:8])=[C:6]([CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[CH:23]=[O:24]
Reactant: COc1cccc(F)c1Br
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C=O)c(F)c1Br
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-3-fluoroanisol (5.00 g, 24.4 mmol) in trifluoroacetic acid (25 mL) was heated to 80° C. and then a solution of hexamethylenetetramine (6.83 g, 48.8 mmol) in trifluoroacetic acid (25 mL) was added dropwise over 1.5 h. Upon completion of the addition, the reaction was stirred at 80° C. for 1 h under nitrogen. The excess trifluoroacetic acid was removed under vacuum, and the pH was adjusted to 7.5-8.0 by addition of saturated aqueous potassium carbonate (˜100 mL). The white solid that formed was filtered to give I-30 which was used without additional purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ncc2c(c1COC)c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
3.9 g of 5-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is dissolved in 70 ml of dichloromethane with 1.84 ml of triethylamine and 0.54 g of dimethylaminopyridine. The solution is cooled to 0° C. and then mixed by portions with 2.54 g of tosyl chloride. After stirring for 2 hours at room temperature and standing overnight, it is shaken out three times with sodium hydrogen carbonate solution, the organic phase is concentrated and recrystallized from acetic acid. 4 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-beta-carboline-3-carboxylic acid ethyl ester with a melting point of 149°-150° C. is obtained. This 4 g is dissolved in 40 ml of tetrahydrofuran under argon and mixed at room temperature with 17 ml of a 1.7 molar solution of calcium diisopropoxy aluminum hydride in tetrahydrofuran (Capal); after refluxing for one hour, 17 ml of Capal is added once more and refluxing is continued for 2 hours. After cooling, it is mixed with 2N sodium hydroxide solution and shaken out with acetic acid. The organic phase is concentrated and 3.1 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-3-hydroxymethyl-beta-carboline is obtained, which is suspended in 57 ml of toluene and mixed with 1 ml of azodicarboxylic acid ester. After refluxing for 12 hours, it is concentrated and chromatographed over silica gel with cyclohexane:acetic acid=1:1 as eluant, 1.8 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-beta-carboline-3-carbaldehyde with a melting point of 125°-127° C. is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:16][C@H:17]1[C@H:20]([O:21][C:22](=O)[CH3:23])[NH:19][C:18]1=[O:25])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]CCO.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:16][C@H:17]1[C@@H:20]([O:21][CH2:22][CH2:23][Br:26])[NH:19][C:18]1=[O:25])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@@H]1OCCBr
Yield: 12 %

Procedure:
A mixture of (3S,4S)-3-(N-benzyloxycarbonyl-L-alanyl)amino-4-acetoxy-azetidin-2-one (1.36 g, 3.894 mmole), 2-bromoethanol (440 mg, 3.5 mmole), and zinc acetate dihydrate (642 mg, 2.9 mmole) in a mixture of benzene (40 ml) and toluene (40 ml) was refluxed for 5 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate (200 ml), acetone (25 ml) and water (150 ml). The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (2:1) as eluent and (3S,4R)-3-(N-benzyloxycarbonyl-L-alanyl)amino-4-bromoethoxy-azetidin-2-one was obtained (169 mg, 12% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][OH:20]>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCN(CCCO)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
A suspension of 1-acetylpiperazine (3.85 g, 30 mmol), potassium carbonate (8.3 g, 60 mmol) and 3-bromo-1-propanol (4 ml, 45 mmol) in acetonitrile (30 ml) was heated and stirred at 80° C. for 5 hours. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography, eluting with increasingly polar mixtures of methylene chloride and ethanol. The fractions containing the expected product were combined and evaporated to give 3-(4-acetylpiperazin-1-yl)propan-1-ol (3.15 g, 56%).