Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.59 g, 8.46 mmol), p-toluenesulfonyl chloride (1.93 g, 10.1 mmol) and triethylamine (TEA) (2.35 mL, 16.9 mmol) in CH2Cl2 (15 mL), dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) was added. As soon as the DMAP was added, the suspension became clear. The solution was then stirred at room temperature for 1 h. It was washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (2.55 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[CH:28]=[CH:27][C:26]2[C@@H:25]3[C@H:16]([C@H:17]4[C@@:21]([CH2:23][CH2:24]3)([CH3:22])[CH:20]=[CH:19][CH2:18]4)[CH2:15][C:14](=[O:29])[C:13]=2[CH:12]=1)(=O)C.C[C@]12CC[C@H]3[C@@H](CC(=O)C4C=C(CC([O-])=O)C=CC=43)[C@@H]1CC=C2>C1COCC1>[CH3:22][C@:21]12[CH2:23][CH2:24][C@H:25]3[C@@H:16]([CH2:15][CH:14]([OH:29])[C:13]4[CH:12]=[C:11]([OH:10])[CH:28]=[CH:27][C:26]=43)[C@@H:17]1[CH2:18][CH:19]=[CH:20]2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: C[C@@]12C=CC[C@H]1[C@@H]1CC(=O)c3cc(CC(=O)[O-])ccc3[C@H]1CC2
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC(O)c3cc(O)ccc3[C@H]1CC2
Yield: 10 %

Procedure:
To a suspension of lithium aluminum hydride (LAH, 95%, 46.9 mg, 1.17 mmol) in 5 ml of anhydrous THF was added estra-1,3,5(10),16-tetraen-6-one-3-yl acetate, 6 (422.9 mg, 1.360 mmol) in 5 ml of anhydrous THF dropwise, with stirring. See FIG. 156. The reaction was stirred 50 min., after which further LAH (46.5 mg, 1.16 mmol) was added and the reaction stirred 22 h. After refluxing 4 h TLC still showed starting material. The reaction was quenched with 0.5 ml of water+0.5 ml of 20% (w/w) sulfuric acid and concentrated under reduced pressure. The residue was extracted four times with 10 ml portions of hot ethyl acetate and filtered through Celite. The combined filtrates were concentrated and purified twice by flash chromatography to give solid product (0.05 g, 0.2 mmol, 10%), m.p. 150-157° C.
Reaction SMILES: [CH:1]1([CH2:4]Br)C[CH2:2]1.CCN(CC)CC.[CH3:13][N:14]1[C@@H:24]2[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]4[O:33][C@H:18]5[C:19]([CH:21]=[CH:22][C@:23]2([OH:34])[C@:17]5([C:27]=34)[CH2:16][CH2:15]1)=[O:20]>CN1CCCC1=O.ClCCl>[CH:31]1[C:26]2[CH2:25][C@H:24]3[N:14]([CH2:13][CH:1]4[CH2:4][CH2:2]4)[CH2:15][CH2:16][C@:17]45[C@H:18]([C:19]([CH2:21][CH2:22][C@@:23]34[OH:34])=[O:20])[O:33][C:28]([C:27]=25)=[C:29]([OH:32])[CH:30]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: BrCC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 70 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Cyclopropylmethyl bromide (64 mg; 0.479 mmol) and Et3N (45 μl; 0.327 mmol) were added to a suspension of noroxymorphone (Example 5, 100 mg; 0.348 mmol) in a mixture of N-Methyl-2-pyrrolidone (NMP)/H2O (10:1; 0.35 mL). The reaction vessel was purged with argon and the reaction mixture was stirred at 70° C. for 2 h. At that time, additional Et3N (45 μl; 0.327 mmol) was added and the mixture was stirred for an additional 6 h at 70° C. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (15 mL) and washed with saturated NaHCO3 (3×3 mL). The aqueous layer was re-extracted with dichloromethane (5 mL) and the combined organic layers were dried over MgSO4. Column chromatography of the residue (dichloromethane/methanol 4:1) afforded 103 mg (87%) of naltrexone as a white solid: mp 173-175° C. (acetone), mp 159-161° C. (MeOH), [lit. mp 174-176° C. (acetone)]xvii identical in all respects to the material described in the literature.xviii
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:18](=O)[CH3:19])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.N.C([BH3-])#[N:25].[Na+].C(Cl)Cl>CO.C(O)(=O)C>[NH2:25][CH:18]([CH3:19])[CH:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Reactant: [BH3-]C#N
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(N)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Benzyl 2-(4-chlorobenzyl)-3-ketobutyrate (317 mg, 1 mmole, obtained from Step A) was added to a cooled mixture of 7M ammonia in MeOH (2.42 mL) and glacial acetic acid (1.6 mL). To this solution, at ˜10° C., was added sodium cyanoborohydride (101 mg, 1.75 mmol) in small portions. This mixture was stirred at room temperature for 40 h. The excess sodium cyanoborohydride was destroyed by the addition of 6M HCl (to pH 1). The residue obtained after removal of volatiles was taken up in a minimal amount of water and extracted with ether. The aqueous layer was basified to pH 10 using solid KOH. This layer was then saturated with sodium chloride and then extracted with EtOAc. Further analyses of the ether and the EtOAc layers suggest that the desired product resides the EtOAc layer. This material was used in the ensuing coupling reaction without further purification. Proton NMR spectrum show that the two pairs of diastereomers are obtained in ˜1:1 ratio, homogeneous by TLC, Rf=0.4 in 95:5 CH2Cl2: MeOH. LC/MS m/e=318 (M+1). 400 MHz 1H NMR (CDCl3) δ 1.27, 1.29 (2 d, J=7 Hz, 3H), 2.85 (m, 1H), 3.03 (m, 1H), 3.15 (m, 1H), 3.55 (m, 1H), 4.85 (br, 2H), 5.00-5.18 (m, 2H), 7.0-7.2 (m, 9H).
Reaction SMILES: C(=O)(O)[O-].[NH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[NH:14][CH2:15][CH2:16][CH3:17])[C:9]#[N:10].C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=O>C(OCC)(=O)C.O.C(O)(=O)C>[CH2:15]([N:14]1[C:13]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=2[N:5]=[C:27]1[CH2:26][Cl:25])[CH2:16][CH3:17]
Reactant: CCCNc1ccc(C#N)cc1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCn1c(CCl)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-4-n-propylaminobenzonitrile (7.38 g, 42.1 mmol) and ethyl chloroacetimidate hydrochloride (9.92 g, 63.2 mmol) in ethanol (100 mL) is heated at reflux for 17 h, then cooled and concentrated to give 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole hydrochloride. Prior to use in the next step, this material is converted to free base by adding aqueous bicarbonate and extracting with dichloromethane, drying (Na2SO4), and concentrating. ii) Alternatively, chloroacetylchloride rather than ethyl chloroacetimidate can by used: To a solution of 3-amino-4-n-propylaminobenzonitrile (5.15 g, 29.4 mmol) and triethylamine (4.51 mL) in ethyl acetate (52 mL) at room temperature, chloroacetyl chloride (2.57 mL) is added slowly. After stirring the reaction mixture for 30 minutes at room temperature, acetic acid (5 mL) is added and the reaction mixture heated to reflux. After heating for 20 h, the reaction mixture is cooled to room temperature and diluted with water (50 mL). The organic solution is washed twice with 1.0 M sodium hydroxide (2×50 mL), then washed with an aqueous solution of 0.25 M KH2PO4 (50 mL), followed by brine (50 mL). The organic layer is dried (sodium sulfate), concentrated in vacuo, and the solid recrystallized by heating in ethyl acetate (20 mL), adding hexane (40 mL) and cooling to room temperature with stirring to afford 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole as brown crystals. 1H NMR (CDCl3): δ 8.08 (d, J=0.8 Hz, 1H), 7.57 (dd, J=1.65, 8.52 Hz, 1H), 7.45 (d, J=8.24 Hz, 1H), 7.26 (s, 1H), 4.84 (s, 2H), 4.24 (t, J=7.6 Hz, 2H), 1.94 (pentet, J=7.4. 7.6 Hz, 2H), 1.03 (t, J=7.4 Hz, 3H). (B) Preparation of 1-Propyl-2-{([2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=3)[C:17]([OH:19])=O)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:39][C:40]1[N:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(#N)C.C1(C)C=CC=CC=1>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=3)[C:17]([NH:46][C:43]3[CH:42]=[N:41][C:40]([CH3:39])=[CH:45][N:44]=3)=[O:19])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc(N)cn1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid (1.0 eq), and acetonitrile (10 vols) followed by pyridine (3 eq) under a nitrogen atmosphere. Thionyl chloride (1.2 eq) as a solution in acetonitrile (0.225 vols) was added slowly, drop-wise via syringe pump over at least 2 hours. 5-Methylpyrazin-2-amine (1.2 eq) was added to the mixture as a solid. After 2.5 hours the reaction was quenched by adding toluene (10 vols) and 1.0M sodium carbonate solution (2.5 eq). The layers were separated. The organic layer was retained in the flask, then 1.0M hydrochloric acid (1.94 eq) was added. The mixture was agitated for 15 minutes then separated. The organic layer was washed with two aliquots of water (5 vols) then the solvent was removed on the rotary evaporator. Toluene (5 vols) was added to the residue, and warmed to 45° C. Isohexane (1.7 vols) was added, the mixture was seeded, and allowed to cool to ambient temperature overnight. The mixture was cooled to 0° C. for 4 hours, and then cooled to −10° C. for 3 hours. The solid was isolated by filtration then washed with iso-hexane (2.5 vols). After drying in the vacuum oven at 40° C. overnight, the desired product was obtained as a solid (corrected yield 85%).
Reaction SMILES: O.[OH-].[Na+].[CH2:4]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([C:21]([O:23]CC)=[O:22])[C:12]1=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:4]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([C:21]([OH:23])=[O:22])[C:12]1=[O:26])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Water (15 ml) and sodium hydroxide (1.3 g) were added to a methanol (30 ml) solution of ethyl 4-benzyl-3,4-dihydro-3-oxo-2-quinoxalinecarboxylate (3.5 g). The reaction mixture was stirred at room temperature for 2 hours and concentrated. 2N Hydrochloric acid was added to the residue to adjust the pH to 4, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (2.9 g).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCCC1>[NH2:1][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN=[N+]=[N-])C1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CN)C1
Reaction time: 0.75 h
Yield: 92.9 %

Procedure:
To a solution of 600 mg of (3S)-3-azidomethyl-1-(tert-butoxycarbonyl)piperidine in 12.5 ml of 20% hydrous tetrahydrofuran, 622 mg of triphenylphosphine was added at room temperature, followed by 45 minutes' refluxing under heating. The reaction liquid was rendered acidic by addition of 0.5 N hydrochloric acid, and successively washed with chloroform and ethyl acetate. Then 4N aqueous sodium hydroxide solution was added to the aqueous layer to render the latter basic, followed by extraction with chloroform and drying over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 497 mg of the title compound was obtained.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([Bi:10]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>CO>[Br-:1].[Br-:1].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([Bi:10]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: BrBr
Agent: Oc1ccc([Bi](c2ccc(O)cc2)c2ccc(O)cc2)cc1
Solvent: CO
Product: [Br-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (3 mmol, 0.16 ml) was added dropwise to a stirred mixture of tris (4-hydroxyphenyl) bismuthine (Example 5) (1.5 g, 3 mmol) in methanol (25 ml) at 0° C. The mixture was stirred for 1 hour at ambient temperature. The solvent was removed under reduced pressure. The residue was washed with chloroform and the title compound isolated as a white crystalline material. Yield: 1.20 g (62%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=3)[NH:16][CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[NH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)cc23)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 78.5 %

Procedure:
A mixture of 3-(N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-5-nitro-1H-indole (3.55 g, 10.34 mmol) and 10% palladium on carbon (0.55 g) in absolute ethanol (60 mL) was shaken under a hydrogen atmosphere (3 atm) for 7 hours at room temperature. The resulting reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residual solid was triturated in diethyl ether to afford the title compound (2.56 g, 78%) as a pale pink solid: mp, decomposes 215° C.; 13C NMR (CDCl3) δ155.0, 139.0, 131.3, 127.3, 120.4, 119.8, 112.9, 111.8, 104.1, 79.4, 44.5, 33.8, 32.7, 28.5. Anal. calcd. for C18H25N3O2.1.4 H2O: C, 67.57; H, 8.03; N, 13.13. Found: C, 67.20; H, 8.07; N, 13.44.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[NH:33][C:34]([SH:37])=[N:35][N:36]=2)[CH:27]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:37][C:34]3[NH:33][C:32]([C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[N:36][N:35]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Sc1nnc(-c2cccnc2)[nH]1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(-c4cccnc4)[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 5-(3-pyridinyl)-4H-1,2,4-triazole-3-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.53-1.69 (m, 8H) 2.03 (m, 1H) 2.11 (m, 1H) 2.35 (m, 1H) 2.57 (m, 1H) 2.63 (m, 1H) 2.82 (d, J=17.6 Hz, 1H) 2.96 (d, J=15.0 Hz, 1H) 3.77 (s, 3H) 6.95 (d, J=8.5 Hz, 1H) 7.09 (d, J=8.5 Hz, 1H) 7.23 (d, J=1.4 Hz, 1H) 7.41 (m, 1H) 8.13 (s, 1H) 8.60 (d, J=4.1 Hz, 1H) 9.03 (s, 1H). MS (APCI) calcd for C26H27ClN4O4S: 527.04; found M=527.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:15]([CH3:17])[CH3:16].Cl>CO>[CH:15]([N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1)([CH3:17])[CH3:16]
Reactant: CC(C)Br
Reactant: OC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)N1CCC(O)CC1
Yield: 72.8 %

Procedure:
4-piperidinol (2.13 g, 21.1 mmol) was added to methanol (21 mL), and potassium carbonate (5.83 g, 42.2 mmol) and 2-bromopropane (11.2 g, 90.7 mmol) were further added thereto, followed by refluxing for 12 hours while stirring. Then, the reaction mixture was mixed with 2M HCl (40 mL) and extracted three times with dichloromethane (50 mL). The organic layer thus obtained was dried over anhydrous magnesium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (2.2 g) as oil.
Reaction SMILES: S(F)(=O)(=O)O.[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH3:7][CH2:8][CH2:9][CH2:10][O:6][C@H:9]([CH2:10][OH:6])[CH2:8][CH3:7]
Reactant: C1CCOC1
Agent: O=S(=O)(O)F
Product: CCCCO[C@@H](CC)CO
Temperature: 20 °C

Procedure:
In the experiment in Example 7, fluorosulfuric acid was added to tetrahydrofuran while maintaining the latter at 20° C. and they were reacted at the same temperature for 6 hours and then treated in the same manner as in Example 7 to obtain colorless PTMG. The final conversion was 67%, and the obtained PTMG had a number-average molecular weight of 1,930, a hydroxyl number of 58 and a functionality of 2.0. The catalytic efficiency β was 0.87.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1COCCN1
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Yield: 96.3 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and morpholine (1.88 g, 22 mmol) to give the title compound (5.90 g, 98%) as a white crystalline solid. MS (ISP) 306.1 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromobenzene-1-sulfonyl chloride (2.56 g, 10.0 mmol) and triethylamine (1.82 mL, 13 mmol) in DCM (50 mL) was added morpholine (960 mg, 11.0 mmol) dropwise and the mixture was stirred for 30 minutes at room temperature. Then the mixture was concentrated and extracted with EA, washed with 0.1M HCl water solution (2×100 mL), NaHCO3 solution (2×100 mL) and brine, dried and concentrated to give product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11][CH:12](Br)[CH3:13]>>[Br:11][CH2:12][CH2:13][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(Br)Br
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(OCCBr)cc1

Procedure:
This compound was synthesized from 4′-hydroxyacetophenone and dibromoethane according to general method 4 described earlier.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].C(N(CC)CC)C.[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>CN(C)C=O>[C:17]12([C:27]([O:9][C:8]3[N:7]=[CH:6][NH:5][C:4]=3[C:1](=[O:3])[NH2:2])=[O:28])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1[nH]cnc1OC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 15 h
Yield: 61.3 %

Procedure:
To a suspension of 4-carbamoylimidazolium-5-olate (4.064 g) in dimethylformamide (80 ml) was added triethylamine (7.768 g) at 0°-5° C. and then 1-adamantanecarbonylchloride (14.00 g) in dimethylformamide (80 ml) dropwisely over 22 minutes. The reaction mixture was stirred at 0°-5° C. for 15 hours. The solvent was removed under reduced pressure. To the residue was added ethyl acetate (100 ml) and water (100 ml), and stirred at room temperature for 1 hours. The insoluble solid was filtered and washed with ethyl acetate to give almost pure 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate (5.67 g, β form, m.p. 207°-210° C. (dec.)).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:13])[CH3:12]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
o-Nitroaniline (300 g, 2.17 mols) was dissolved in acetic anhydride (620 ml) and stirred at 40°-50° C. for 3 hours. The reaction mixture was poured in ice water. Crystals which formed were collected by filtration and dried. o-Acetylaminonitrobenzene thus-obtained was suspended in methanol (2.4 l). After adding 20 g of 10% palladium-carbon, the suspension was subjected to catalytic reduction at room temperature and atmospheric pressure. After completion of reaction, the catalyst was removed by filtration and the solvent was distilled off under reduced pressure to precipitate crystals which then were washed with ethanol and dried over phosphorus pentoxide under reduced pressure to give 248 g of o-aminoacetanilide.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:14](O)(=[O:23])[C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>O.Cl.CN(C)CCCN=C=NCC.CN(C)C=O.C(N(CC)CC)C>[OH:16][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[O:23]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccc([N+](=O)[O-])cc1)[C@H](O)c1ccccc1
Temperature: 87 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a mixture of 5.90 kg of 4-nitrophenylethylamine monohydrochloride, 4.43 kg of (R)-mandelic acid, 2.94 kg of triethylamine and 22 liters of N, N-dimethylformamide were added 3.93 kg of hydroxybenztriazole and 5.58 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) followed by stirring at about room temperature for 2 hours. EDC (0.28 kg) was further added thereto and the mixture was stirred at about room temperature throughout one night. The reaction solution was diluted with 110 liters of water and extracted with ethyl acetate (60 liters, 30 liters). The organic layer was successively washed with 60 liters of 1M aqueous hydrochloric acid, 60 liters of 20% aqueous solution of potassium carbonate and water (60 liters, 60 liters) and concentrated in vacuo at 10 to 19° C. The residue was dissolved in 35 liters of toluene with heating at 87° C., cooled and stirred at 20° C. throughout one night. The resulting crystals were filtered and washed with 10 liters of toluene. This was dried in vacuo to give 7.66 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide as light yellow crystals.