Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:16])=[C:7]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[C:8]([O-:10])=[O:9])(=[O:3])[CH3:2].[Na+].[CH2:18]([O:20][CH2:21]Cl)[CH3:19]>CN(C)C=O>[C:1]([NH:4][C:5]1[C:6]([I:16])=[C:7]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[C:8]([O:10][CH2:21][O:20][CH2:18][CH3:19])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(I)cc(I)c(C(=O)[O-])c1I
Reactant: CCOCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCOC(=O)c1c(I)cc(I)c(NC(C)=O)c1I
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a stirred slurry of sodium 3-acetamido-2,4,6-triiodobenzoate (14.5 g, 0.025 mole) in dimethylformamide (150 ml) was added chloromethyl ethyl ether (2.56 g, 0.027 mole). A white solid (NaCl) precipitated promptly. The mixture was stirred overnight, filtered, and evaporated to near dryness under reduced pressure to yield 17.8 g. of residue. The residue was dissolved in 200 ml. of chloroform, filtered and the filtrate was extracted with 5% aqueous sodium bicarbonate, washed with water and dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. The residue (10.5 g.) obtained was recrystallized from carbon tetrachloride (200 ml.) and chloroform (enough to dissolve the residue), to yield the product 5.05 g. (31.5%), m.p. 174°-177.7° C. The ir and and nmr spectra were in agreement with the structure as assigned.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:18])=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:8][CH:7]=[N:6]2.[N:19]1([CH2:25][CH2:26][CH2:27]O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][C:2]1[C:3]([O:18][CH2:27][CH2:26][CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:8][CH:7]=[N:6]2
Reactant: Cc1c(O)cn2ncnc(Oc3ccccc3)c12
Reactant: OCCCN1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(OCCCN2CCCCC2)cn2ncnc(Oc3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a mixture of 5-methyl-4-phenoxypyrrolo[2,1-f][1,2,4]triazin-6-ol (1.47 g, 6.1 mmol, for preparation see WO 0071129), 1-piperidinepropanol (1.74 g, 12.2 mmol) and triphenylphosphine (3.2 g, 12.2 mmol) in tetrahydrofuran (20 mL) at 0° C. under argon, was added DEAD (1.9 mL, 12.2 mmol). The resulting mixture was stirred at 0° C. for 30 min, and then at RT for 1 hr. The volatiles were removed in vacuo. The residue was purified by silica gel flash column chromatography using 5% (2M NH3 in MeOH)/20% ethyl acetate/CH2Cl2 to afford the desired product as beige solid (1.6 g, 72% yield). MS: (M+H)+=367.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:37](=[O:40])[NH:38][OH:39])[CH:16]([OH:36])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:36][CH:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:35])[CH:26]=2)=[CH:21][CH:22]=1)[CH:15]([CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:37]([NH:38][OH:39])=[O:40]
Reactant: Cc1cc(COc2ccc(C(O)C(CN3CCN(C(=O)OC(C)(C)C)CC3)C(=O)NO)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(O)C(CN3CCNCC3)C(=O)NO)cc2)c2ccccc2n1
Reaction time: 2 h
Yield: 154.7 %

Procedure:
4-{3-Hydroxy-2-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (0.077 g, 0.099 mmol) from Example 19 was taken up in methylene chloride (3 mL) and TFA (2 mL) under nitrogen atmosphere at room temperature. The reaction was complete after 2 h, was concentrated, taken up in water (5 mL), and freeze-dried to give the title compound (0.069 g, 88%) as a white solid. MS found: (M+H)+=451.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11](N)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.N([O-])=O.[Na+].[OH-].[Na+]>[PH2](O)=O.O.[Cu-]=O>[CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cc1
Agent: O=[Cu-]
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (±)-tert-butyl 3-methyl-4-(4-aminophenyl)piperazine-1-carboxylate (325 mg) in 50% hypophosphorous acid (1.27 ml) containing copper(I) oxide (8.0 mg) was added dropwise a solution of sodium nitrite (92 mg) in water (2 ml) at 0° C. with stirring. After 2 hours, the reaction mixture was made alkaline with 40% NaOH solution and extracted with ethyl acetate twice. The organic layers were combined and washed with water and brine. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate 1:1) to give the title compound in a pure form as colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[S-:12][C:13]#[N:14].[K+]>O>[N:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:14]=[C:13]([SH:12])[NH:2][CH:3]=2)=[CH:7][CH:8]=1
Reactant: NCC(=O)c1ccncc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Sc1nc(-c2ccncc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
2-Amino-1-pyridin-4-yl-ethanone hydrochloride (0.75 g, 4.348 mMol) was dissolved in water (15 mL), and to clear yellow solution was added potassium thiocyanate (0.7 g, 7.203 mMol). The mixture was heated to reflux for 4.0 h during which period HPLC showed complete disappearance of starting material. On cooling to room temperature, a yellow solid precipitate formed, which was collected by filtration. The solid was then re-suspended in a saturated solution of NaHCO3 (30 mL), stirred at room temperature for 0.5 h, and the resulting free base thiol was collected by filtration. The solid was dried under vacuum to yield 576 mg (59%) of a fluorescent yellow solid. MS(ES) 178 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[C:4]([F:18])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([F:18])[CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccc(O)cc1)c1ccc(Br)cc1F
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 75 (1.50 g, 5.08 mmol) and AlCl3 (3.50 g, 26.2 mmol) were refluxed in benzene (50 mL) for 3 h and then cooled to RT. Water (100 mL) was cautiously added dropwise, and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration afforded 1.39 g (97%) of 76 that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 5.73 (br s, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.35-7.41 (m, 3H), 7.77 (d, J=8.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](=O)[CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.Cl.[CH:30]([NH2:32])=[NH:31].[OH-].[Na+]>>[CH2:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:19]3[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:32]=[CH:30][N:31]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)C=Cc3ccccc3)n2)CC1
Reactant: N=CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cc(-c4ccccc4)ncn3)n2)CC1
Temperature: 25 °C
Yield: 153 %

Procedure:
A mixture of 1-(3-amino-6-(4-(ethylsulfonyl)piperazin-1-yl)pyrazin-2-yl)-3-phenylprop-2-en-1-one (45 mg, 0.1121 mmol), formamidine hydrochloride (9.026 mg, 0.1121 mmol) and NaOH (4.932 mg, 0.1233 mmol) were heated at reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature and the solvent removed in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B, (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (73 mg, 4% Yield). 1H NMR (400.0 MHz, DMSO) d 1.25 (t, 3H), 3.12 (q, 2H), 3.36-3.38 (m, 4H), 3.56-3.59 (m, 4H), 7.15 (br s, 2H), 7.60-7.61 (m, 3H), 8.25-8.26 (m, 3H), 8.76 (s, 1H) and 9.31 (s, 1H) ppm; MS (ES+) 426.0
Reaction SMILES: CN[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].C(N)CCC.C(NCCCC)CCC.C(NCC1N=CNC=1C)CCC.C(N(CC1N=CNC=1C)CCCC)CCC.[NH2:52][CH2:53][CH2:54][SH:55].[ClH:56]>>[ClH:56].[ClH:56].[NH2:52][CH2:53][CH2:54][S:55][CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9]
Reactant: CNCc1nc[nH]c1C
Reactant: NCCS
Agent: CCCCN(CCCC)Cc1nc[nH]c1C
Agent: CCCCNCc1nc[nH]c1C
Agent: Cl
Solvent: CCCCN
Solvent: CCCCNCCCC
Product: Cc1[nH]cnc1CSCCN

Procedure:
By the same procedure, using methylene in place of dimethylamine, 4-(N-methylaminomethyl)-5-methylimidazole is prepared. In the same way, using butylamine and dibutylamine, 4-(N-butylaminomethyl)-5-methylimidazole and 4-(N,N-dibutylaminomethyl)-5-methylimidazole are prepared. Refluxing these intermediates with cysteamine by the above procedure and treating with hydrochloric acid gives 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11]([F:17])([F:16])[C:12](Br)([F:14])[F:13].O>CN(C=O)C>[Br:10][C:11]([F:17])([F:16])[C:12]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([F:14])[F:13]
Reactant: Sc1ccccc1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(Br)C(F)(F)Sc1ccccc1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
In a three-necked round-bottomed flask placed under nitrogen, topped with a dry-ice condenser and a dropping funnel, thiophenol (10.2 ml, 100 mmol) was added dropwise (30 min) at 0° C. to a suspension of NaH (6 g, 150 mmol) in anhydrous DMF (100 ml). The mixture was then stirred at this temperature for 20 min then cooled to −50° C. 1,2-dibromo-1,1,2,2-tetrafluoroethane (15 ml, 125 mmol) was then added dropwise at −50° C. over 10 min. The mixture was then stirred for 2 h at this temperature, then 1 h at ambient temperature. Water (150 ml) was added to the reaction mixture, then the product was extracted with ethyl ether (3×100 ml). The organic phases were washed with water (3×100 ml) and dried over MgSO4. After evaporation of the solvent, the residue was purified by distillation under reduced pressure (99° C./40 mmHg). The product [(2-bromo-1,1,2,2-tetrafluoroethyl)sulfanyl]benzene was then obtained in the form of a colorless liquid (26.07 g, 90%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])[CH2:11][O:12][N:13]=[C:14]([C:18]1[N:19]=[C:20]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:21][CH:22]=1)[C:15](O)=[O:16].[NH2:53][CH:54]1[C:79](=[O:80])[N:56]2[C:57]([C:63]([O:65][CH:66]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[O:64])=[C:58]([CH2:61][Cl:62])[CH2:59][S:60][C@H:55]12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[Cl:62][CH2:61][C:58]1[CH2:59][S:60][C@@H:55]2[CH:54]([NH:53][C:15](=[O:16])[C:14](=[N:13][O:12][CH2:11][C:10]3[CH:43]=[CH:44][C:45]([O:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:9]=3)[C:18]3[N:19]=[C:20]([NH:23][C:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[S:21][CH:22]=3)[C:79](=[O:80])[N:56]2[C:57]=1[C:63]([O:65][CH:66]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)=[O:64]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: COCCOCOc1ccc(CON=C(C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1OCOCCOC
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COCCOCOc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1OCOCCOC
Reaction time: 0.5 h

Procedure:
1.0 g (1.4 mmol) of 2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) and 0.56 g (1.4 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate were dissolved in 0.77 ml (6.3 mmol) of N,N-dimethylaniline at 0° C., and 0.12 ml (1.7 mmol) of phosphorus oxychloride was dropwise added thereto. The mixture was stirred for 30 minutes and the reaction solution was washed with sequentially with 1N hydrochloric acid, a 10% sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The water layer was further extracted with ethyl acetate, and the organic layer was added thereto. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain benzhydryl 3-chloromethyl-7-{2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tritylaminothiazol-4-yl)acetamido}-3-cephem-4-carboxylate (syn-isomer), which was used for the next reaction without purification.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[O:1]=[C:2]1[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([NH:24][CH:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]1)=[O:23]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid, obtained in Example 1E (0.95 g, 3.08 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (CAS 87120-72-7) in dichloromethane (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.171 g, 3.08 mmol) and diisopropylethylamine (2.6 mL, 13.86 mmol). The reaction mixture was stirred at ambient temperature overnight, then diluted with dichloromethane and washed with 1 N HCl (10 mL), water, 1 N NaOH (10 mL), water, dried over MgSO4, and evaporated to yield tert-butyl 4-(2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamido)piperidine-1-carboxylate (0.8 g, 60%). To a solution of this product in methanol (10 mL) was added 4 N HCl/dioxane (2 mL), and the reaction mixture was stirred at room temperature for 3 hours. It was concentrated in vacuo and partitioned between 1 N NaOH and dichloromethane. The organic layer was concentrated and chromatographed on an Analogix 15-24 g silica column, eluting with a 2-5% gradient of methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.19-7.35 (m, 10H), 6.99 (d, J=6.4 Hz, 1H), 4.01 (s, 2H), 3.75-3.95 (m, 1H), 3.52 (t, J=6.6 Hz, 2H), 3.04-3.14 (m, 2H), 2.63-2.72 (m, 2H), 2.57-2.64 (m, 2H), 1.77-1.95 (m, 4H), 1.37-1.53 (m, 2H); MS (ESI+) m/z 392 (M+H)+.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[S:11]1(=[O:27])=[O:26])(=O)=O.[CH3:28][NH2:29].[ClH:30]>>[ClH:30].[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][C:8]#[C:7][CH2:6][NH:29][CH3:28])[S:11]1(=[O:27])=[O:26]
Reactant: CN
Reactant: CS(=O)(=O)OCC#CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Agent: Cl
Product: CNCC#CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-yn-1-yl methanesulfonate (0.25 g, 0.60 mmol) was treated with methyl amine to give 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbut-2-yn-1-amine hydrochloride (78 mg) after treatment with HCl.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12])[CH3:3].[CH3:13][O:14][N:15]=[CH:16][CH3:17].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:13][O:14][N:15]1[CH:16]([CH3:17])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12]
Reactant: CC=NOC
Reactant: C=C(C)C1CCCCCCC1=O
Agent: CON1C(=O)CCCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CON1C(=O)CCCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 23, 2-(prop-1-en-2-yl)cyclooctanone (1.50 g, 9.02 mmol), acetaldehyde O-methyl oxime (0.99 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml) were reacted to give the title product as a colorless liquid (1.91 g, 89% yield). E isomer>95%.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].Cl>C(O)C>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(-c2ccc(N)cc2C(F)(F)F)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Stannous chloride dihydrate (8 g) was added to a solution of 2,2'-bis(trifluoromethyl)-4,4'-dinitro-1,1'-biphenyl (1.9 g) in 5 ml of ethanol. Concentrated hydrochloric acid (12 ml) was added carefully to the mixture while stirring at room temperature. The mixture was refluxed overnight and the ethanol was removed. Water was added to the residue and it was made basic with 20% sodium hydroxide solution. The resulting white precipitate was collected by filtration, washed with water, dried and then extracted in a Soxhlet flask with acetone for four hours. Removal of acetone gave a white residue, 2,2'-bis(trifluoromethyl)-4,4'-diamino-1,1'-biphenyl, ##STR7## which was recrystallized from chloroform-hexane to give 1.2 g (74% yield) of short white needles, m.p. 185°-186° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22]C)=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reaction time: 14 h

Procedure:
Oxycodone (10.0 g) was suspended in chloroform (CHCl3, 150 mL) in a reactor A. Boron tribromide (BBr3, 10.0 mL) was added slowly and an exotherm was observed. The reaction temperature was maintained below 25° C. during the addition. Stirring of the mixture was continued at room temperature for 14 hours. The material was transferred to reactor B that was pre-filled with 85 mL of water. The temperature reached 50 to 55° C. and was maintained below 55° C. during the addition. After transfer of the mixture to reactor B, some solid residue still remained in reactor A. The mixture in reactor B was stirred at 50 to 55° C. to dissolve the solid (about 15 minutes) and then when stirring was stopped, the mixture separated into two clear layers. The aqueous solution in reactor B was transferred back to reactor A. The mixture was stirred at 50 to 55° C. for 15 to 30 minutes to dissolve all the solids. The organic layer in reactor B was extracted with H3PO4/H2O solution (2% wt/wt, 15 mL). The aqueous extraction was transferred to reactor A. The solution in reactor A was extracted with dichloroethane (30 mL) and then allowed to separate into two phases.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23][O:24]S(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23][O:24][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Oc1cccnc1
Product: COC(=O)CCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(3-methoxycarbonylpropyl)propanamide (102.2 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(pyridin-3-yloxy)propanamide (92.8 mg).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[NH:9][CH2:8]1.[Cl:19][CH2:20][CH2:21][CH2:22]Br.O>O1CCCC1>[Cl:19][CH2:20][CH2:21][CH2:22][N:9]1[CH2:8][C:7]([CH3:18])([CH3:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: ClCCCBr
Reactant: CC1(C)CNC(=O)c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CN(CCCCl)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
2-(3-Chloropropyl)-4,4-dimethyl-1,2,3,4-tetrahydro-1-isoquinolinone may be obtained in the following manner: 25.7 cm3 of n-butyllithium (1.6 M in hexane) are added to a solution of 6 g of 4,4-dimethyl-1,2,3,4-tetrahydro-1-isoquinolinone in 120 cm3 of tetrahydrofuran, at -76° C. under a nitrogen stream. The reaction mixture is left for three hours at 0° C. 13 g of 1-chloro-3-bromopropane are then added and the mixture is stirred for 18 hours at a temperature of about 25° C. The reaction mixture is treated with 240 cm3 of water and extracted with three times 100 cm3 ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness at 40° C. under reduced pressure (20 mm of mercury; 2.7 KPa). The residue is purified by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (99.5-0.5 by volume) as eluent. 3.9 g of 2-(3-chloropropyl)-4,4-dimethyl-1,2,3,4-tetrahydro 1isoquinolinone are obtained; melting point =131° C.