Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][S:4]([N:7]=[C:8]=[O:9])(=[O:6])=[O:5].[NH2:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[N:22]=1>ClCCl>[CH3:28][C:23]1[CH:24]=[C:25]([CH3:27])[N:26]=[C:21]([NH:20][C:8]([NH:7][S:4]([CH:3]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:2]2[Cl:1])(=[O:5])=[O:6])=[O:9])[N:22]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: CCCCCCCCCCC(Cl)CS(=O)(=O)N=C=O
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)C2CCCCCCCCCCC2Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
15.4 g (0.05 mole) of 2-chlorododecylsulfonyl isocyanate in 100 ml of dichloromethane were initially introduced and 6.2 g (0.05 mole) of 2-amino-4,6-dimethylpyrimidine were added in portions at 0° C. The mixture was initially stirred at 0° C. for 2 hours and then at room temperature for 18 hours and was then worked up in analogy to Example 5. 15.2 g (71% of theory) of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-chlorocyclododecylsulfonamide were obtained (pale yellow solid material, melting point 84° C.).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OCC)OCC.[H-].[Na+].[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=O)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=[CH:3][C:2](=[O:1])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOP(=O)(CC(=O)c1ccccc1)OCC
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=CC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Diethyl (2-oxo-2-phenylethyl)phosphonate (0.96 mL, 1.1 g, 4.4 mmol) was added in one portion to a stirred suspension of sodium hydride (60% oil dispersion, 158 mg, 3.95 mmol) in THF (20 mL). After 15 min. at rt, the clear solution was cooled in an ice bath and 1-(benzyloxycarbonyl)-4-piperidinecarboxaldehyde (840 mg, 3.40 mmol) was added in THF (1.0 mL) with additional THF (2×1.0 mL) for rinsing. Stirring was continued for a total of 2 h, with slow warming to rt. The mixture was then partitioned between ether (120 mL) and 2.5 N aq. NaOH (60 mL). The organic layer was washed with saturated aq. brine (60 mL), dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 15-20% ethyl acetate in hexane, to give 0.95 g of the title compound as a colorless syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:46][CH3:47])=[C:5]([CH:43]=[CH:44][CH:45]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@H:23]([O:34][NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C@@H:22]1[OH:42])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:48]([C:51]1[CH:56]=[C:55]([N+:57]([O-:59])=[O:58])[CH:54]=[CH:53][C:52]=1F)([O-:50])=[O:49]>CO>[CH3:1][O:2][C:3]1[C:4]([O:46][CH3:47])=[C:5]([CH:43]=[CH:44][CH:45]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@H:23]([O:34][N:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:52]2[CH:53]=[CH:54][C:55]([N+:57]([O-:59])=[O:58])=[CH:56][C:51]=2[N+:48]([O-:50])=[O:49])[C@@H:22]1[OH:42])([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCNO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CO
Product: CCCCCCN(O[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(=O)[nH]c1=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
5′-O-(dimethoxytrityl)-2′-O-(hexylamino)uridine (0.88 grams, 1.37 mmol) was dissolved in methanol (20 mL). 2,4-Dinitrofluorobenzene (DNFB, 0.25 grams, 1.37 mmol) was added and the mixture shaken on a mechanical shaker. The reaction was monitored by TLC. After 90 minutes, another 0.25 grams of DNFB was added and the reaction mixture shaken an additional 30 minutes, followed by addition of another 0.25 grams of DNFB. After shaking 2.5 hours, the mixture was concentrated in vacuo and chromatographed on a silica gel column, eluting with a gradient of 25% ethyl acetate in hexanes to 100% ethyl acetate. The desired product (0.51 grams, 46%) eluted with 100% ethyl acetate (Rf 0.85 by TLC).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.O[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1ccc(CCl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Temperature: 0 °C
Yield: 54.5 %

Procedure:
4-(Chloromethyl)benzyl alcohol (4.68 g), methyl 3-(4-hydroxyphenyl)propanoate (5.40 g) and triphenylphosphine (9.20 g) were dissolved in a mixed solvent of toluene (60 mL)-tetrahydrofuran (30 mL), cooled to 0° C. and diethyl azodicarboxylate (40% toluene solution, 15.2 g) was added dropwise with stirring. After completion of the dropwise addition, the reaction mixture was allowed to warm to room temperature and further stirred for 1 hr. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give the title compound (5.19 g, yield 54%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)([OH:21])[CH3:22])[C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1(c2cccnc2)CO1
Reactant: CC1Cc2[nH]c3ccc(Cl)cc3c2CN1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1Cc2c(c3cc(Cl)ccc3n2CC(C)(O)c2cccnc2)CN1C
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To a solution of 8-chloro-2,3-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.13 mmol) in 4 mL of DMF was added sodium hydride (256 mg, 6.40 mmol) at 0° C., and stirred for 10 min. 3-(2-methyloxiran-2-yl)pyridine (432 mg, 3.20 mmol) was added and the mixture was stirred at RT for 12 h. The reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice cold water and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product, which was crystallized in n-hexane to obtain 350 mg of 1-(8-chloro-2,3-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.72 (s, 1H), 8.47 (d, 1H), 7.52 (d, 1H), 7.23 (s, 1H), 6.94 (m, 3H), 4.10 (dd, 2H), 3.65 (m, 1H), 3.40 (m, 1H), 2.86 (m, 2H), 2.38 (s, 3H), 2.36 (m, 1H), 1.62 (s, 3H), 1.07 (d, 3H). Separation by chiral HPLC provided diastereomers II-147a-b.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2.[OH-].[Na+].CN(C)[CH:27]=[O:28]>>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[C:10]2[CH:27]=[O:28]
Reactant: Fc1ccc(-n2ccc3cc(Cl)ccc32)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Phosphorus oxychloride (12.5 g, 0.081 mol) was added to N,N-dimethylformamide (29.5 g, 0.19 mol) at 0°-5° C. After stirring for 10 minutes a solution of 5-chloro-1-(4-fluorophenyl)indole (20 g, 0.081 mol) in N,N-dimethylformamide (50 mL) was added at 0°-5° C. The reaction mixture was stirred for 0.5 h and subsequently poured into ice. The resulting mixture was made alkaline with concentrated NaOH and after stirring for 1 h at room temperature the mixture was extracted with diethyl ether (2×250 mL). The combined organic phases were dried (Na2SO4),the solvents evaporated and the remaining oil was purified by column chromatography (eluted with ethyl acetate/heptane 1:1) affording pure title compound 20.1 g (90%) which crystalized from heptane: mp 152°-154° C.; 1H NMR (CDCl3) δ 7.20-7.35 (m, 4 H), 7.50 (dd, 2 H), 7.85 (s, 1 H), 8.35 (s, 1 H), 10.05 (s, 1 H). Anal. (C15H9NO) C, H, N.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S>O>[CH2:12]([O:8][C:7](=[O:9])[C@H:5]([CH2:4][CH2:3][CH2:2][OH:1])[NH2:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](CCCO)C(=O)O
Reactant: BrCc1ccccc1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CCCO)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Dissolve 5-hydroxynorvaline (13.3 g, 0.1 mol) in 1N sodium hydroxide (200 mL, 0.2 mol). Add a solution of CuSO4.5H2O (12.5 g, 0.05 mol) in water (50 mL). Stir the mixture until solution is complete. Treat with benzyl bromide (17.1 g, 0.1 mol) and stir at room temperature until reaction is complete. Suction filter, wash the residue with 1:3.5 methanol-water and dry at 60° C. to give the copper complex. Suspend the copper complex in water, treat with excess hydrogen sulfide, heat to boiling, then cool to room temperature. Mix with 1N sodium hydroxide and filter. Stir the filtrate with a slight excess of 1N hydrochloric acid and filter. Wash the residue with water and dry to give O-benzyl-5-hydroxynorvaline.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5](N)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].C(O)(=O)C.N([O-])=O.[Na+].[BrH:23]>O>[Br:23][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1Br
Temperature: -10 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
205 g (1 mol) of 4-(trifluoromethyl)anthranilic acid, 600 ml of glacial acetic acid and 400 ml of 47% hydrobromic acid are introduced successively into a three-liter round-bottomed flask. After dissolution, the reaction mixture is cooled to -10° C., diluted with 400 ml of water and then treated dropwise with a solution of 69 g (1 mol) of sodium nitrite in 200 ml of water while maintaining the temperature below 0° C. When the addition is finished, the reaction mixture is stirred at 0° C. for 2 hours. This solution is run in dropwise into a six-liter reactor containing 143.5 g (1 mol) of cuprous bromide in 500 ml of 47% hydrobromic acid maintained at 60° C. When the addition is finished, the reaction mixture is stirred at 60° C. for one hour, cooled to room temperature and then poured into two liters of ice-cold water. The precipitate which forms is filtered on sintered glass, washed with water and then dried under a stream of air. There is thus obtained 216 g (yield: 80%) of 2-bromo-4-(trifluoromethyl)benzoic acid in the form of a solid melting at 118.5° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:29][N:30]1[C:42]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[C:34]([S:43](Cl)(=[O:45])=[O:44])[CH:35]=2>C(Cl)(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:43]([C:34]3[CH:35]=[C:36]4[C:31](=[CH:32][CH:33]=3)[N:30]([CH3:29])[C:42]3[CH2:41][CH2:40][CH2:39][CH2:38][C:37]4=3)(=[O:44])=[O:45])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cn1c2c(c3cc(S(=O)(=O)Cl)ccc31)CCCC2
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc3c(c2)c2c(n3C)CCCC2)CC1

Procedure:
To a solution of 1 g (0.0034 Mol) of 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxoethylamine and 1.1 g (0.011 Mol) of triethylamine in 30 ml of chloroform are added dropwise, at ambient temperature and with stirring, 0.96 g (0.0034 Mol) of 9-methyl-1,2,3,4-tetrahydro-carbazol-6-sulphonic acid chloride dissolved in 10 ml of chloroform. After 12 hours' stirring the mixture is evaporated down in vacuo and the residue obtained is chromatographed over a silica gel column (eluant: ethyl acetate/methanol=9:1). The eluate having an Rf value of 0.3 is collected and evaporated down in vacuo.
Reaction SMILES: Cl.F[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[C:5]([CH3:15])[CH:4]=1.[Na].[CH2:17]([OH:19])[CH3:18]>>[CH2:17]([O:19][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[C:5]([CH3:15])[CH:4]=1)[CH3:18]
Reactant: Cc1cc(F)nc(N2CCNCC2)c1
Reactant: CCO
Agent: Cl
Agent: [Na]
Product: CCOc1cc(C)cc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(6-Fluoro-4-methyl-2-pyridyl)piperazine hydrochloride (80 mg, 0.34 mmol) was dissolved in anhydrous ethanol (1.5 ml), sodium (50 mg, 1.96 mmol) was added and the mixture was stirred for five minutes at room temperature and then at 140° C. for one hour under microwave heating in a closed vial. The mixture was filtered through kieselguhr, the filtrate was concentrated under reduced pressure and the residue was treated with acetonitrile and then ethylacetate. The liquids were separated from solids by centrifugation and decanting and the combined supernatants were concentrated under reduced pressure to give 85 mg of a solid (quantitative). MS (multi-mode) m/z=222.2 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:21][CH:22]=1)[CH3:2]
Reactant: CC(=O)c1ccc(CCNS(=O)(=O)c2ccc(Br)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(O)c1ccc(CCNS(=O)(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.4 g. (29.8 mmole) 4-Bromobenzenesulphonic acid(4-acetylphenethylamide) are dissolved in a mixture of 40 ml. methanol and 100 ml. ethanol and 0.85 g. (22.4 mmole) sodium borohydride then added portionwise thereto at 0° C. Subsequently, the reaction mixture is stirred at ambient temperature for 2 hours and then evaporated in a vacuum. After the addition of dilute hydrochloric acid, the reaction mixture is shaken out with methylene chloride and the methylene chloride phase is dried with anhydrous sodium sulphate Thereafter, it is evaporated and the residue is recrystallised from toluene. Yield 10.4 g. (91% of theory): m.p. 125°-127° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:21]1[C:22]2[CH:23]=[CH:24][C:25]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]4[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=4)=[CH:18][CH:17]=3)=[CH:26][C:27]=2[O:28][CH2:20]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1csc(COc2ccc(-c3ccc4c(c3)OCO4)cc2)n1

Procedure:
A solution of 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of intermediate 2; 75 mg, 0.2 mmol) in dioxane (4 mL) was added to a reaction tube containing 3,4-methylenedioxybenzeneboronic acid (ASDI Incorporated, Newark, Del.; 100 mg, 0.6 mmol). A solution of potassium carbonate (80 mg, 0.6 mmol) in water (0.4 mL) was added and the mixture was degassed. A solution of bis(tricyclohexylphosphine)-palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) in dioxane (0.5 mL) was added and the tube was heated in a microwave oven at 170 degrees for 25 min. The solution was acidified, filtered through silica gel, evaporated, and triturated with aqueous methanol to give 2-(4-benzo[1,3]dioxol-5-yl-phenoxymethyl)-thiazole-4-carboxylic acid. Mass spectrum MH+=356.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16](O)[CH3:17].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:16][CH2:17][O:11][C:10]([C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:12]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
N-tert-Butoxycarbonylprolin (24.38 g, 113 mmol) was dissolved in dichloromethane (60 ml). Ethanol (7.9 ml, 135 mmol) and 4-dimethylaminopyridine (1.52 g, 12.5 mmol) were added. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (23.88 g, 125 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. Ethyl acetate (400 ml) was added. It was washed with a 10% aqueous solution of sodium hydrogen sulfate (300 ml). The aqueous phase was extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (300 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate (1:4) as eluent, to give 17.11 g of (2S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:30][C@H:31]2[O:33][CH2:32]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C>[O:33]1[CH2:32][C@H:31]1[CH2:30][O:14][C:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]=[CH:2][CH:3]=1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9H-Carbazol-4-ol (0.367 g, 2.0 mmol) was placed in a flask with DMF (10 mL) and NaH (60% dispersion in oil, 77 mg, 2.0 mmol) and stirred for 30 min at room temperature. (S)-glycidyl 3-nitrobenzene sulfonate (0.52 g, 2.0 mmol) was added to the reaction mixture, which was then stirred at room temperature for 14 hours. The reaction was quenched with NaHCO3 (saturated) and then extracted with ethyl acetate (3×). The organic layer was dried with magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield crude product which was purified by silica gel chromatography (60% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[I:14](O)(=O)(=O)=O.II>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[I:14]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Agent: II
Solvent: CO
Product: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reaction time: 0.17 h
Yield: 194 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (2.2 g, 10.8 mmol) was dissolved in methyl alcohol (CH3OH; 20 mL). The solution was treated with periodic acid (880 mg, 3.9 mmol) and iodine (2.2 g, 8.6 mmol) and then heated to reflux for 20 h. The mixture was cooled, and the volatiles were removed under vacuum. The residue was dissolved in EtOAc (50 mL) and then stirred with 10% NaHSO3 solution (20 mL) for 10 min. The organic phase was separated and washed with brine (10 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography (5-50% EtOAc-hexane gradient) to give the title compound as a light orange solid (2.5 g, 70%): mp 149-151° C.; ESIMS m/z 330 ([M]+); 1H NMR (400 MHz, CDCl3) δ 5.17 (s, 2H, NH2), 3.97 (s, 3H, OMe); 19F NMR (376 MHz, CDCl3) δ −135.79 (s).
Reaction SMILES: [Cl:1]OC(C)(C)C.[Cl-:7].[NH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][N+:11]1([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CO>[Cl-:1].[Cl:7][N:8]([Cl:1])[C:9]([CH3:19])([CH3:18])[CH2:10][N+:11]1([CH3:17])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC(C)(N)C[N+]1(C)CCOCC1
Reactant: CC(C)(C)OCl
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C[N+]1(C)CCOCC1)N(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.8 %

Procedure:
tert-Butyl hypochlorite (0.49 mg, 4.5 mmol) was added to a stirred solution of 4-(2-amino-2-methylpropyl)-4-methylmorpholin-4-ium chloride (380 mg, 1.8 mmol) in methanol (25 ml) and stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo, and purified by prep-HPLC to give 64 mg (13% yield) of 4-(2-(dichloroamino)-2-methylpropyl)-4-methylmorpholin-4-ium chloride. 1H NMR (D2O) δ 4.16-3.98 (m, 4 H), 3.86 (s, 2 H), 3.78-3.58 (m, 4 H), 3.43 (s, 3 H), 1.66 (s, 6H); MS (ESI+) calculated for C9H19Cl2N2O+: 241.09, Found: 241 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([CH:16]=O)[S:8][C:7]=2[CH:18]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20].CCCCCC>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:16]/[C:9]1[S:8][C:7]2[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCc1c(C=O)sc2cc(OC)ccc12
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCc1c(/C=C/C(=O)OC)sc2cc(OC)ccc12
Yield: 85 %

Procedure:
As in Example 111, 6-methoxy-3-pentyl-2-benzo[b]thiophenecarboxaldehyde (7.37 g) and (carbomethoxymethylene)triphenylphosphorane (9.7 g) in dichloromethane (100 mL) was stirred at room temperature for 42 hours. Crystallization of the crude reaction product, obtained by using the normal work up, from hexane gave 7.6 g of (E)-3-(6-methoxy-3-pentyl-benzo[b]thien-2-yl)-2-propenoic acid methyl ester, mp 49°-50° C. Anal. Calcd for C18H22O3S: C, 67.90; H, 6.96: S, 10.07 Found: C, 68.21; H, 6.80; S, 10.22