Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.[C:9](Cl)(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:9]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1)(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NC1CCCC(=O)C1
Product: CCCCCCCCCCCCCCCC(=O)NC1CCCC(=O)C1

Procedure:
2-Cyclohexenone is reacted with benzylamine to give 3-benzylaminocyclohexanone. Hydrogenolysis of the benzylamino group then gives 3-aminocyclohexanone. Reaction with hexadecanoyl chloride affords 3-hexadecanamidocyclohexanone, which is then reduced with sodium borohydride to produce a cis/trans mixture of 3-hexadecanamidocyclohexanol. Separation by column chromatography then gives the pure isomers. Reaction with bromoethylphosphodichloridate, then with trimethylamine will produce 3-hexadecanamido-cyclohexyl-phosphocholine.
Reaction SMILES: [CH2:1]([S:6](Cl)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1>N1C=CC=CC=1.ClCCl>[F:34][C:31]([F:32])([F:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([NH:10][S:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[CH:12][CH:13]=2)[CH2:22][CH2:21]1)=[O:24]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Reactant: CCCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCS(=O)(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4 %

Procedure:
1-Pentanesulfonyl chloride (0.034 g, 0.30 mmol) was added slowly to a solution of [4-(5-aminopyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone in pyridine (2 mL) at 0° C. The mixture was stirred at 25° C. for 16 hours and then diluted with dichloromethane. The organic phase was washed with water and saturated NaCl solution, dried over anhydrous MgSO4. After removal of dichloromethane, the product was purified by column chromatography to afford the title compound in 4% yield (2.7 mg). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.87, 7.74, 7.61, 7.36, 6.94, 4.47, 4.11, 3.87, 3.68, 3.60, 3.42, 2.99, 1.77, 1.32, 0.88. MS (ES+) m/z 485.2 (M+1).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl.[CH2:16](O)[CH3:17]>>[NH2:4][C:5]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: CCO
Reactant: CC(=O)Nc1cc(Br)ccc1C(=O)O
Agent: Cl
Product: CCOC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Yield: 21 %

Procedure:
A solution of 119 g (0.461 mol) of 2-acetylamino-4-bromobenzoic acid and 3 liters of absolute ethanol was cooled to 0° C. and was then saturated with a stream of dry hydrogen chloride gas. The solution was then heated under reflux for 24 hours. Upon cooling to room temperature, the solution was evaporated to about 750 ml and then poured into 2 liters of aqueous saturated sodium bicarbonate. The aqueous phase was extracted three times with 300 ml portions of chloroform. The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to afford 23.8 g (21%) of ethyl 2-amino-4-bromobenzoate as an oil: ir(CHCl3) 3504 cm, 3390, 1685, 1610, 1580 among others; 1H-NMR(CDCl3) 1.3 ppm (triplet, 3H, CH2CH3), 4.3 (quartet, 2H, CH2CH3), 5.8 (broad singlet, 2H, NH2), 6.6 [doublet of AB pattern), 1H, aromatic H.], 6.8 (singlet, 1H, aromatic H), 7.7 [doublet (part of AB pattern), 1H, aromatic H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[NH:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:16][C:17](C)([O-])[CH3:18].[K+].BrCCC.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[N:5]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH2:16][CH2:17][CH3:18])[CH3:2]
Reactant: CCOC(=O)Nn1ccc2ccccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCBr
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C(=O)OCC)n1ccc2ccccc21
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of NaHCO3 (50 g, 0.7 mole) in 100 ml dichloromethane (DCM) was added a solution of 1H-indol-1-amine (36 g, 0.27 mole) in 200 ml DCM. After cooling to 0° C. with an ice bath, a solution of ethyl chloroformate (29 ml, 0.30 mole) in 50 ml DCM was added over a period of thirty minutes. After stirring at ambient temperature for three hours, the mixture was filtered, and the filtrate washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil which was eluted on a silica gel column with DCM, via high performance liquid chromatography (HPLC) to give N-(1H-indol-1-yl) carbamic acid ethyl ester, 33.6 g (61%) as an oil. To a cold solution of N-(1H-indol-1-yl) carbamic acid ethyl ester (15 g, 0.07 mole) in 100 ml tetrahydrofuran, was added potassium t-butoxide (9 g, 0.08 mole), and the mixture stirred at 5° C. for one hour. To this was added 1-bromopropane (7.3 ml, 0.08 mole), and the mixture stirred at ambient temperature for five hours. The mixture was poured into 300 ml iced-water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated, NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester as an oil, 16.5 g (91%). To a solution of N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester (16.5 g, 0.067 mole) in 35 ml ethylene glycol, was added a solution of NaOH (10 g, 0.25 mole) in 30 ml water. After stirring at 120° C. for four hours, the mixture was poured into 300 ml ice water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylamine, 9.0 g (78%) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([OH:10])(=[O:9])[CH3:8].[CH2:11]([C:18]1[C:23]([I:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:29][C@H:28]([O:30][CH3:31])[C@@H:27](OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:26]2)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O>[CH2:11]([C:18]1[C:23]([I:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:29][C@H:28]([O:30][CH3:31])[C@H:27]([O:9][C:7](=[O:10])[CH3:8])[CH2:26]2)[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1OS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a mixture of 7.9 g of cesium carbonate and 15 ml of dimethyl sulfoxide was added 4.2 ml of acetic acid. After foaming ceased, a mixture of 14.4 g of 2-benzyl-3-iodo-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidin-1-yl]pyridine and 35 ml of dimethyl sulfoxide was added and the resultant mixture was heated under stirring under nitrogen atmosphere in an oil bath at 70° C. for 6 hours. After the reaction mixture was cooled, it was extracted with ethyl acetate-water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (10–15% ethyl acetate/hexane), to give 7.5 g of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.Cl[C:19](N(C)C)=[C:20]([CH3:22])C.Cl.[CH3:27][C:28]([CH3:36])([C:30]1[N:34]=[C:33]([CH3:35])[O:32][N:31]=1)[NH2:29].C(N(C(C)C)C(C)C)C>ClCCl.CN(C=O)C>[CH3:27][C:28]([NH:29][C:15]([C:5]1[CH:4]=[N:3][C:2]([CH:22]2[CH2:20][CH2:19]2)=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])([C:30]1[N:34]=[C:33]([CH3:35])[O:32][N:31]=1)[CH3:36]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: CC(C)=C(Cl)N(C)C
Reactant: O=C(O)c1cnc(Br)c(-c2cccc(Cl)c2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(C3CC3)c(-c3cccc(Cl)c3)n2)no1
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
5-Bromo-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid (0.200 g, 638 μmol) was suspended in dichloromethane (1 mL) and 1-chloro-N,N,2-trimethylpropenylamine (98.0 mg, 97.0 μl, 734 μmol) was added dropwise at room temperature. After 30 min stirring the brown solution was added drop by drop to a solution of α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine hydrochloride (CAN 1240526-27-5; 142 mg, 797 μmol) and ethyldiisopropylamine (206 mg, 264 μl, 1.59 mmol) in DMF (1 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate and 1M citric acid solution; the organic phase was dried with MgSO4; filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 5% to 50% ethyl acetate in n-heptane) to give the desired product (126 mg, 45%) as white foam; MS (EI): 436.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].N1CC[O:29]CC1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[O:29])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Product: CCOC(=O)c1[nH]c(=O)n(C)c(=O)c1OCc1ccccc1
Yield: 30 %

Procedure:
5-Benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.215 g, 0.58 mmol) was reacted with morpholine as described in the preparation of compound 1J. Chromatography on silica gel (elution toluene-ethyl acetate 8:2 to 6:4) gave first 0.050 g (30% yield) of 5-benzyloxy-1-methyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid ethyl ester as white crystals; mp 184–187° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (3H, t, J=7.1 Hz, CH3), 3.40 (3H, s, NCH3), 4.39 (2H, q, J=7.1 Hz, OCH2), 5.16 (3H, s, OCH2), 7.35–7.5 (5H, m, aromatics), 8.12 (1H, broad s, NH). Anal. Calcd for C15H16N2O5: C, 59.20; H, 5.30; N, 9.20. Found: C, 59.20; H, 5.08, N 9.19 . The end fractions then gave 0.102 g (47% yield) of the title ester as a white syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.29 (3H, t, J=7.1 Hz, CH3), 3.20 (4H, m, NCH2), 3.53 (3H, s, NCH3), 3.82 (4H, m, OCH2), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.17 (2H, s, OCH2), 7.29–7.49 (5H, m, aromatics). HRMS (FAB POS) calculated for C19H24N3O5 [M+H+]: 374.171596. found: 374.1709485
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CC(C)(O[CH:17](N(C)C)[N:18]([CH3:20])[CH3:19])C>CN(C=O)C>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1C#N
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc([N+](=O)[O-])ccc1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
A mixture of 2-methyl-4-nitrobenzonitrile (Aldrich, 5.0 g, 31 mmol) and 1-(1,1-dimethylethoxy)-N,N,N′,N′-tetramethyl-methanediamine (Aldrich, 12.2 mL, 59 mmol) in dry DMF (8 mL) was stirred at 70° C. for 2 h under N2. After cooling to rt, DMF was removed in vacuo and the crude product was triturated with hexanes/ethyl acetate (5:1). The solid was collected by filtration and washed with hexane to give (E)-2-(2-(dimethylamino)vinyl)-4-nitrobenzonitrile (6.5 g, 97% yield) as a black solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.97 (s, 6H) 5.36 (d, J=513.18 Hz, 1H) 7.16 (d, J=13.62 Hz, 1H) 7.52 (d, J=8.79 Hz, 1H) 7.60 (m, 1H) 8.11 (d, J=1.76 Hz, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)=[C:26]([CH2:45][CH2:46][CH2:47][CH3:48])[N:25]=[C:24]1[CH3:49]>C(OCC)(=O)C>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:3][C:4](=[O:7])[O:5][N:44]=3)=[CH:33][CH:32]=2)=[C:26]([CH2:45][CH2:46][CH2:47][CH3:48])[N:25]=[C:24]1[CH3:49]
Reactant: CCCCc1nc(C)n(Cc2nc3ccccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2nc3ccccc3s2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.31 g), sodium hydrogen carbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[1-(1,3-benzothiazol-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 28%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]acetic acid (0.200 g) in N,N-dimethylformamide (5 mL) were added morpholine (0.053 mL), triethylamine (0.169 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (116 mg) and 1-hydroxybenzotriazole (93 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=40:60-100:0, volume ratio) and recrystallized from hexane-acetone to give the title compound (0.174 g, yield 76%) as pale-yellow crystals. MS: 564 (MH+). melting point 202-203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH3:21]N(C)C=O.C[I:27]>C(OCC)(=O)C>[I-:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: CN(C)C=O
Reactant: COc1cccc([C@H](C)N(C)[C@@H](C)c2ccccc2)c1
Solvent: CCOC(C)=O
Product: COc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Product: [I-]
Temperature: 60 °C
Yield: 70 %

Procedure:
Mix 5.5 g (0.02 mol) of (S)-1-(3-methoxyphenyl)-N-methyl-N—((S)-1-phenylethyl)ethanamine (formula IV) with 12 ml N,N-dimethylformamide and 14.2 g (0.1 mol) of methyl iodide at room temperature, heat the mixture to 60° C. for 12 hours. Let it cool to room temperature, and add 100 ml of ethyl acetate. A yellow solid is produced. Filter and dry it to receive 5.8 g light yellow solid with a yield of 70%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][OH:26])[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:19][CH2:20][CH:21]([CH2:24][CH2:25][O:26][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:22][CH2:23]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N2CCC(CCO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(N2CCC(CCOS(C)(=O)=O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol (0.93 g), which was prepared in the similar method as shown in example 1, in CHCl3 (10 mL), was added methanesulfonyl chloride (0.47 g) and pyridine (0.64 g) and the mixture was stirred at room temperature for 3 hours. Water was added into the reaction mixture and the mixture was extracted with CHCl3. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a brown oil. The oily product was crystallized from diisopropylether to obtain methanesulfonic acid 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethyl ester (1.0 g).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]1[O:10][N:9]=[C:8](Cl)[CH2:7]1)[C:3]([OH:5])=[O:4].[OH-:12].[Na+].Cl>>[CH2:7]1[C:8]([OH:12])=[N:9][O:10][CH:6]1[CH:2]([NH2:1])[C:3]([OH:5])=[O:4]
Reactant: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NC(C(=O)O)C1CC(O)=NO1
Yield: 80 %

Procedure:
To 1.20 g. (6.75 mmole) of (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazol-acetic acid (AT-125), is added 20 ml. of 2 N sodium hydroxide and stirred at 25° for 36 hours. The solution is brought to ~3.5 pH with 6 N hydrochloric acid (dropwise addition) and then stored at -10° (freezer) overnight. The crystals are collected by filtration, washed twice with cold water, and then dried giving 720 mg. of trichloromic acid. The initial filtrate is lyophilized and the resulting powder is taken up in 4 ml. of water, filtered, and washed with two 4 ml. portions of cold water, and dried yielding an extra 160 mg. of tricholomic acid (total 80% yield).
Reaction SMILES: O.[SH-:2].[Na+].Cl[C:5]1[N:10]([CH3:11])[C:9](=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[CH:6]=1>O.C(Cl)(Cl)Cl.C(O)C>[SH:2][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[CH:6]=1
Reactant: [SH-]
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: Cn1c(S)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A solution of sodium hydrosulphide hydrate (74.77 g, 1335.243 mmol) in water (125 ml) was added dropwise to a stirred solution of Step 1 (50.0 g, 286.532 mmol) in chloroform (250 ml) and ethanol (636 ml) in an ice water bath, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo at room temperature. The residue obtained was dissolved in water (100 ml) and extracted with dichloromethane (2×100 ml). The aqueous layer was acidified with 1 N HCl. Precipitated solid was filtered, washed with water (2×100 ml) and dried to obtain 49.22 g of the product as a pale yellow solid; 1H NMR (300 MHz, CDCl3) δ 3.33 (s, 3H), 3.74 (s, 3H), 4.17 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:17]([N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[C:4]1=[O:9])[CH2:18][CH2:19][CH3:20]
Reactant: O=c1[nH]cccc1CO
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1cccc(CO)c1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 3-hydroxymethyl-2(1H)-pyridone (7-008-01) (0.63 g) in DMF (15 mL), and to the reaction mixture were added potassium carbonate (1.4 g) and 1-iodobutane (1.86 g). After stirring at 70° C. for 2 h, the solvent was removed. To the residue were added a saturated aqueous solution of ammonium chloride and ethyl acetate, and the organic layer was separated, and then the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by column chromatography (toluene/ethyl acetone=2/1) to give 1-butyl-3-hydroxymethyl-2-pyridone (7-008-02) (0.56 g, 61%) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([CH2:13][CH3:14])[N:3]=1.[CH2:15]([O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[NH:22])[CH2:16][CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:13]([C:4]1[N:3]=[C:2]2[N:22]=[C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[O:18][CH2:15][CH2:16][CH3:17])[NH:23][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1)[CH3:14]
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)c1cnc(CC)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1-c1nc2nc(CC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 28 reaction of ethyl 4-chloro-2-ethyl-5-pyrimidine carboxylate (0.86 g) with 2-propoxybenzamidine (from sodium, 0.1 g, in ethanol, 10 ml, and 2-propoxybenzamidine methanesulphonate, 1.20 g) and triethylamine (0.4 g) in acetonitrile (25 ml) for 3 days at ambient temperature yielded a crude product, which was recrystallized twice from 2-propanol-ether to yield the title compound, 95 mg, m.p. 118-119° C.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:20][C:19]([F:21])([F:22])[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-4-trifluoromethyl-benzene (0.287 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.135 g, 93%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.86 (s, 2H), 7.39-7.62 (m, 7H), 7.90 (d, 1H).