Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[CH:5]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])C.B(O)O>C(O)C>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH3:11]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)C(F)(F)F
Agent: OBO
Solvent: CCO
Product: CCOC(=O)CCC(=O)C(F)(F)F
Temperature: 170 °C
Yield: 43.2 %

Procedure:
In a one-necked round-bottomed flask equipped with a distillation head and cooler, a mixture of 2-(2,2,2-trifluoro-acetyl)-succinic acid diethyl ester (54.6 g, 202 mmol) and boronic acid (12.5 g, 202 mmol) is heated to 170° C. Heating is continued for 4 h, during which time ethanol is gradually distilled off as it is formed. After cooling to room temperature, the reaction mixture is poured onto ice and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4 and concentrated at reduced pressure to afford a brown oil. The crude product is purified by distillation (60° C., 10 mbar) to afford the title compound as a colorless liquid (17.3 g, 87.3 mmol, 43%). 1H NMR (400 MHz, CDCl3, 298 K): δ=4.15 (q, J=7.1 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H). MS (ES+): 199 (M(C7H9F3O3)+H)+.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[O:1]=[C:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C2(CCCC2)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of tert-butyl 4-hydroxy-2-azaspiro[4.4]nonane-2-carboxylate (10.87 g, 45.04 mmol) in DCM (200 mL) were added 4 Å molecular sieve (20.00 g) followed by PCC (24.27 g, 112.6 mmol) slowly and the mixture was stirred at rt overnight. The resulting mixture was filtered and the filter cake was washed with EtOAc (50 mL×3). The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/50 to 1/10) to give the product as a white solid (8.56 g, 79.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].Cl.[CH2:10]([OH:12])[CH3:11]>>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]([O:12][CH2:10][CH3:11])=[NH:7])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)CC#N
Agent: Cl
Product: CCOC(=N)CC(=O)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
113 g 2-cyanoacetic acid ethyl ester (1 mol) and 1000 mL anhydrous ethyl alcohol were added to a three-necked bottle, into which hydrogen chloride gas was bubbled with stirring at 0° C. After 4 hours, a lot of white solid were isolated and the reaction was stopped. After sucking filtration and drying, 60.0 g white solid was obtained. Yield: 91.6%, MS: 160 (M+1).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:28])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][C:11]1[CH:29]=[CH:30][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reaction time: 1 h
Yield: 97 %

Procedure:
Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate (8.62 g, 19.91 mmol) was diluted with DCM (40 mL) followed by portionwise addition of TFA (30 mL). After stirring for 1 hour, the reaction was concentrated and placed under vacuum over the weekend. The residue was taken up in DCM and washed with saturated bicarbonate and 1N HCl. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to provide the desired product (7.278 g, 19.32 mmol, 97.00% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(N(CC)CC)C>[CH3:16][C:15]1[CH:17]=[CH:18][C:12]([S:9]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOCC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1

Procedure:
Commercially available (tetrahydro-2H-pyran-4-yl)methanol (Maybridge), tosyl chloride and triethylamine were processed using the method described in Example 184B to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.05-1.25 (m, 2H), 1.40-1.53 (m, 2H), 1.73-1.94 (m, 1H), 2.43 (s, 3H), 3.14-3.28 (m, 2H), 3.71-3.84 (m, 2H), 3.88 (d, J=6.4 Hz, 2H), 7.48 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Br.[CH2:9]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CO>CC#N>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][N:16]1[CH2:17][CH2:18][CH:13]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15]1
Reactant: COC(=O)CCCBr
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: CCCCC1CCN(CCCC(=O)OC)CC1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a 25 mL reaction flask was added 4-bromo-butyric acid methyl ester (2.04 g, 11.2 mmol), compound 3 (1.51 g, 10.8 mmol) and potassium carbonate (1.63 g, 11.8 mmol) suspended in CH3CN (10 mL). The reaction mixture was stirred over-night at rt followed by filtration and evaporation to dryness. Addition of H20 (50 mL) was followed by extraction with ethyl acetate (3×100 mL). The combined organic phases were dried (MgSO4) and evaporated to dryness, to produce 2.84 g of crude 23. The crude product was subjected to CC [eluent: CH2Cl2 MeOH (99:1)] to give pure 23 (1.93 g, 75%). LC-MS [M+H]+ 241 (cald. 241.2).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH2:10](O)[CH3:11]>OS(O)(=O)=O.C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:10]([O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9])[CH3:11]
Reactant: O=C(O)c1csc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(Br)c1

Procedure:
5-bromo-thiophene-3-carboxylic acid (18.2 g, 0.09 mol) was dissolved in absolute ethanol (150 ml) and H2SO4 (5 ml), and the mixture was refluxed for 5 hours. The mixture was concentrated under vacuum to give a yellow oil, then diluted with a mixture of ethyl acetate (100 ml) and saturated brine (200 ml), and mixed, let standing for layer separation. The aqueous layer was washed with ethyl acetate (25 ml twice). The extract and the organic layer was adjusted with Na2CO3 (10%) to pH=8, and the organic phase was separated and washed with saturated brine to pH=7, dried over anhydrous Na2SO4 over night. The organic layer was concentrated under reduced pressure to give 5-bromo-thiophene-3-carboxylic acid ethyl ester as yellow oil (15 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
4-Nitrobenzenesulfonyl chloride (4.4 g) was added to a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (4.0 g) and pyridine (2.25 ml) in methylene chloride (80 ml) and stirred at ambient temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over sodium sulfate. The solution was evaporated under vacuum and triturated with diethylether and filtered to remove undesired solids. The diethylether liquors were evaporated under vacuum and dissolved in methylene chloride before purification by column chromatography on silica eluting with ethyl acetate/isohexane (20/80). The fractions containing the expected product were combined and evaporated under vacuum to give tert-butyl 3-[(4-nitrophenyl)sulfonyloxy]piperidine-1-carboxylate as a yellow crystalline solid (6.77 g); 1H NMR Spectrum: (CDCl3) 1.43 (s, 9H), 1.40-1.54 (m, 1H), 1.70-1.94 (m, 3H), 3.22-3.60 (m, 4H), 4.67 (m, 1H), 8.11 (s, 2H), 8.40 (s, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-:17].[Na+].[Na+]>>[OH:17][CH2:2][C:3]([N:5]([CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: CC(C)N(C(=O)CCl)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)N(C(=O)CO)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
In a 500 ml flask, 23.0 g (0.1 mol) of N-chloroacetyl-N-isopropyl-4-fluoroaniline and 11.7 g (0.11 mol) of sodium carbonate in 340 ml of solvent or solvent mixture are heated with stirring to reflux temperature (100° C.). The reaction is monitored by gas chromatography (sampling after in each case 1 hour). The results are compiled in the table which follows.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:32]=[C:33]([C:37]2[O:41][CH:40]=[N:39][CH:38]=2)[CH:34]=[CH:35][CH:36]=1>CC(O)C.Cl>[ClH:1].[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[O:41][CH:40]=[N:39][CH:38]=5)[CH:32]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1)C(F)(F)F
Temperature: 120 °C
Yield: 98 %

Procedure:
To a mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (0.5 g, 1.2 mmol) in i-PrOH (4 mL) was added 5-(3-aminophenyl)oxazole (0.25 g, 1.56 mmol) and 2 drops of conc. HCl. The reaction was heated in a microwave to 120° C. for 40 min. and allowed to cool to rt. The resulting solid was filtered off, washed with i-PrOH and dried to give the title compound as a tan solid (0.68 g) in 98% yield. ES-LC/MS m/z=542 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10](Cl)[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CO.CCCCCC.[C:28](OCC)(=[O:30])C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:30][CH3:28])[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncc(-c2cccc(Cl)c2)cc1Cl
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: COc1cc(-c2cccc(Cl)c2)cnc1C#N
Temperature: 25 °C
Yield: 96 %

Procedure:
To a 500 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine, 1, (10 g, 40 mmol), sodium methoxide (13.8 mL, 60 mmol) and methanol (200 mL). With stirring, the reaction solution was heated to reflux for 20 hours. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction mixture was cooled to room temperature and combined with water (500 mL). A solid began to form. The mixture was cooled to 0° C. to 5° C. and stirred for 3 hours. The resulting solid was collected by filtration and washed with water, then hexane. The resulting cake was dried in vacuo at 40° C. to afford 9.4 g (96% yield) of the desired product as an off-white solid. 1H NMR (DMSO-d6) δ 8.68 (d, 1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59 (s, 1H), 7.57 (s, 1H) and 4.09 (s, 3H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N#N>O>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: NCCCCCO
Reactant: O=C1OC(=O)c2ccccc21
Agent: N#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCO
Temperature: 145 °C
Yield: 100 %

Procedure:
A mixture of phthalic anhydride (6.46 g, 43.6 mmol) and 5-aminopentanol (4.5 g, 43.6 mmol) was heated to 145° C. in an open flask for 30 min. A stream of N2 was applied to expel water vapor. After cooled to room temperature, the reaction residue was dried on vacuum pump. The product was obtained as colorless oil: yield 100%; 1H NMR (CDCl3) δ 1.4-1.5 (m, 2H), 1.6-1.8 (m, 4H), 3.6 (t, 2H, J=6.5), 3.7 (t, J=7.2 Hz), 7.7 (m, 2H), 7.8-7.9 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](O)=[O:23])[CH:4]=1)#[N:2].[C:25]1([CH:31]([NH2:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>C(Cl)Cl>[C:32]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:38][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:23])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in step (b) above], 1.0 ml of diphenylmethylamine and 1.0 ml of triethylamine were dissolved in 10 ml of dry methylene chloride, and 0.75 ml of diethyl cyanophosphate was added to the resulting solution at room temperature. The reaction mixture was stirred at room temperature overnight, after which it was diluted with 100 ml of methylene chloride, and then washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The solution was then dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 40 g of silica gel using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 1:99 to 4:96 by volume as the eluent, to give 0.85 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccccn2)cc1
Reaction time: 6 h
Yield: 9.9 %

Procedure:
4-Aminothiophenol (0.065 moles, 8.1 g) in 275 ml DMF was stirred at room temperature for 1 hr with sodium hydride (0.065 moles previously washed with hexane). 2-Chloropyridine (0.06 moles, 6.8 g) was added and the reaction mixture was stirred for 6 hr. An additional 5.2 g of 4-aminothiophenol was added and the reaction stirred at room temperature for 16 hr. Water was added and the product extracted with ethyl acetate. The solution was washed thoroughly with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 30% ethyl acetate/hexane to yield 2-(4-aminophenylthio)pyridine 1.2 g, 10%. Mass spec (FD) 202. Calculated for C11H10N2S: C, 65.32; H, 4.98, N, 13.85 Found: C, 65.23; H, 5.09; N, 13.63.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Cl)cc1CBr

Procedure:
A mixture of 5-chloro-2-fluorotoluene (2.9 g; prepared by a modified Schiemann reaction on 4-chloro-2-methylaniline), NBS(3.6 g) benzoyl peroxide (100 mg) and carbon tetrachloride (25 ml) was refluxed 2 h. The mixture was cooled, filtered and the solvent removed. Distillation gave 5-chloro-2-fluorobenzyl bromide (3 g), b.p. 104°/15 mm.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.[Cl-].[Na+]>O1CCCC1>[CH3:8][S:9]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)(=[O:11])=[O:10]
Reactant: CN1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCC(OS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
13.3 ml of triethylamine and subsequently 7.4 ml of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 10 g of 4-hydroxy-1-methylpiperidine dissolved in 100 ml of dry tetrahydrofuran. The mixture was then stirred at 0° to 5° C. for 2 hours and then at room temperature for 1.5 hours, after which it was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, to afford 12.74 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25]CC1C=CC=CC=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCc1ccccc1
Agent: [Pd]
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1O
Yield: 104.8 %

Procedure:
(S)-3-(2-Benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (3.54 g) in TBF(50 mL) was treated with 20% Pd/C (0.30 g) at 50 psi hydrogen until uptake was complete. The reaction was filtered and the filtrate was evaporated to give (S)-3-(2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a colorless oil (3.01 g, 100%). 1H NMR (CDCl3) 8.82(s,1H), 7.63(d,1H), 7.44(t,1H), 6.98(m,2H), 5.95(d,1H), 4.62(bs,1H), 3.62(s,3H), 3.03(s,3H), 2.65-2.40(AB quartet, 2H), 1.43(s,9H).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][CH:6]=[N:5]2)[CH2:3][CH2:2]1.[Br:9]Br>C(Cl)(Cl)Cl>[Br:9][C:7]1[CH:6]=[N:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:8]=1
Reactant: BrBr
Reactant: c1cnn(C2CC2)c1
Solvent: ClC(Cl)Cl
Product: Brc1cnn(C2CC2)c1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a golden solution of 1-cyclopropyl-1H-pyrazole (2.360 g, 22 mmol) in 100 mL chloroform, was added bromine (1.2 ml, 24 mmol) as a soln in 100 mL CHCl3 dropwise over 1.5 h. the mixture was heated in oil bath to 60 C for 2 h. The mixture was allowed to cool to RT, washed with sat NaHCO3, dried over Na2SO4, filtered and evaporated to afford the title compound as a tan liquid (3.64 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][CH:3]1[CH2:4][CH2:5]2
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2CCC1CC(O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
Tropine (50 g) and triethylamine (60 mL, 43.56 g) in dichloromethane (1 L) were cooled to −10° C. Methane sulphonyl chloride (36 mL, 53.28 g) in dichloromethane (0.2 L) was added over 1 h at −5+/−2° C. After 0.5 h a solution of potassium carbonate (150 g) in water (0.4 L) was added and the mixture warmed to 20° C. The phases were separated and the aqueous phase extracted with further dichloromethane (1×0.2 L). The combined dichloromethane solution was concentrated by distillation collecting 1 L. n-Heptane (0.875 L) was added and the mixture stirred for 0.5 h. The solution was decanted off and then concentrated by distillation at 610 to 650 mbar until a solution temperature of 63° C. was reached. The solution was cooled to 0° C. with crystallization occurring during the cooling. The mixture was stirred for 1 h, the product isolated by filtration, washed and dried at <30° C. to give the title compound (60.62 g, 78.1%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][Br:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:11]([O-])([OH:13])=[O:12].CCCCCC.CCOC(C)=O>CCOCC>[N+:11]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][Br:10])=[CH:2][CH:3]=1)([O-:13])=[O:12]
Reactant: BrCCCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CCCBr)cc1

Procedure:
2 g of P2O5/silica gel (65% w/w) (10 mmol) (Hajipour; Kooshki; Ruoho. Tetrahedron Letters 2005, 46, 5503) and 3-phenylpropylbromine (10 mmol, 1.98 g) was ground for 30 seconds, and then 5 mL of HNO3 65% was added. The mixture was ground with a pestle at r.t. until a deep-yellow color appeared (2 minutes). When TLC analysis (n-hexane:EtOAc 90:10) showed complete disappearance of 3-phenylpropylbromide (10 min), ether (100 ml) was added to the reaction mixture and the solid was separated through a short pad of silica gel and washed with ether (3×20 mL). The filtrate was washed with 10% NaHCO3 (3×20 mL) and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue was purified by short column chromatography (n-Hexane:EtOAc, 90:10). 3-(4-nitrophenyl)-propylbromide was obtained (8.3 mmol, 2.02 g 83%) as a yellow oil. 1H NMR (CDCl3): δ 8.2 (d, J=6.3), 7.38 (d, 2H, 6.3), 3.3 (t, 2H, J=7.8), 2.55 (t, 2H, J=7.8), 2.12 (m, 2H). 13C NMR (CDCl3): δ 145.7, 144.9, 129.7, 123.5, 36.7, 34.7, 32.4. Anal. Calculated for C9H10BrNO2: C, 44.29H, 4.13; N, 5.74%. Actual: C, 44.50; H, 48.30; N, 5.80%.
Reaction SMILES: CC1(C)O[C@H](CON)CO1.FC1C(NC2C=CC(I)=CC=2F)=C(C=CC=1F)C(O)=O.[OH:31][C@H:32]([CH2:55][OH:56])[CH2:33][O:34][NH:35][C:36](=[O:54])[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[C:38]=1[NH:45][C:46]1[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=1[F:53]>>[OH:31][C@@H:32]([CH2:55][OH:56])[CH2:33][O:34][NH:35][C:36](=[O:54])[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[C:38]=1[NH:45][C:46]1[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=1[F:53]
Reactant: O=C(NOC[C@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: CC1(C)OC[C@@H](CON)O1
Agent: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=C(NOC[C@@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
Prepared from (S)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine and 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid by the alternative procedure described above for N-[(R)-2,3-Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide: m.p. 118-119° C.