Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[CH3:7][C:8](=[O:11])[CH2:9][CH3:10]>>[F:1][C:2]([F:6])([F:5])[S:3][CH:9]([CH3:10])[C:8](=[O:11])[CH3:7].[F:1][C:2]([F:6])([F:5])[S:3][CH2:7][C:8](=[O:11])[CH2:9][CH3:10]
Reactant: FC(F)(F)SCl
Reactant: CCC(C)=O
Product: CC(=O)C(C)SC(F)(F)F
Product: CCC(=O)CSC(F)(F)F

Procedure:
Using the method of Example 3, 2-butanone was reacted with trifluoromethanesulfenyl chloride. The reaction mixture was distilled, b.p. 30°-72°C/55 to 60 mm. Vapor phase chromatography of the distillate showed two products to be present in major quantities. Fractional distillation gave 3-trifluoromethylthio-2-butanone, b.p. 66°C/62 mm Hg, and 1-trifluoromethylthio-2-butanone, b.p. 85°C/62 mm Hg. These structures were established by spectral and elemental analyses.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[CH2:18][CH2:19][CH2:20][C:21]#N)[CH2:10][CH3:11].C(O)(C(F)(F)F)=[O:24].CC#N>CCOCC.C(Cl)Cl>[CH2:9]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[CH2:18][CH2:19][CH2:20][C:21]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])=[O:24])[CH2:10][CH3:11]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCC1CCCCN1CCCC#N
Reactant: Cc1ccccc1I
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: CCCC1CCCCN1CCCC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 10 mL oven-dried flask was added Mg turnings (97 mg, 4.1 mmol) which were activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a suspension of 2-iodotoluene (380 μl, 2.8 mmol) in Et2O (3 mL) and the reaction mixture was allowed to reflux for 1 hour. A mixture of compound 8 (0.43 g, 2.2 mmol) in CH2Cl2 (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and stirred at rt for 12 hours followed by addition of NaOH (10 mL, 2 M). Addition of THF (15 mL) was followed by extraction with ethyl acetate (3×50 mL) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), dried (MgSO4) and evaporated to dryness to produce 0.43 g of crude 9. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN+0.1%TFA] to produce an analytically pure sample of compound 9; LC-MS [M+H]+ 287 (cald. 287.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:30])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27]Br)=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([OH:29])[CH:12]=3)=[CH:4][CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:30])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([OH:29])[CH:12]=3)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Cl
Product: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-chlorophenyl)-4-(4-(2-bromoethoxy)benzyl)-7-hydroxychromen-2-one (8.3 g, 17.2 mmol) in 200 mL of THF was treated with 8 mL of pyrrolidine and the reaction mixture was heated at reflux for 5 h. The reaction mixture was concentrated and the crude product was purified using flash chromatography. The product was suspended in 250 mL of acetone and 4 mL of 5 M HCl(aq) was added. The mixture was stirred at room temperature overnight and the resulting solid was collected by filtration. The solid was suspended in 200 mL of ethyl acetate and the suspension was heated at reflux for 2h. The solution was cooled to room temperature and the final product was collected by filtration and dried under vacuum. The final yield was 4.96 grams (56%). 1H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 10.42 (s, 1H), 7.47 (d, 2H, J=8.5 Hz), 7.43 (d 1H, J=8.8 Hz), 7.34 (d, 2H, J=8.5 Hz), 7.09 (d, 2H, J=8.5 Hz), 6.87 (d, 2H, J=8.5 Hz), 6.77 (d, 1H, J=2.5 Hz), 6.71 (dd, 1H, J=2.5, 8.8 Hz), 4.26 (t, 2H, 4.9 Hz), 3.96 (s, 2H), 3.59-3.51 (m, 4H), 3.15-3.02 (m, 2H), 2.03-1.88 (m, 4H). MS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][Cl:11])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl-:11].[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1ccc(/C=C/CCl)cc1Oc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1ccc(/C=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Product: [Cl-]

Procedure:
A mixture of E-3-(4-fluoro-3-phenoxyphenyl)-1-chloro-prop-2-ene (42 g), triphenylphosphine (42 g) an (300 cm3) was heated at the reflux temperature for 16 hours. After cooling, crystals of E-3-(4-fluoro-3-phenoxyphenyl)prop-2-er-1-yl triphenyl phosphonium chloride (68 g) were filtered from the reaction mixture, washed with dry diethyl ether, dried by suction and stored in a desiccator under vacuum.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:12].C(N(CC)CC)C.[Cl:26][CH2:27][C:28]1[N:32]=[C:31](Cl)[S:30][N:29]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:12][C:31]1[S:30][N:29]=[C:28]([CH2:27][Cl:26])[N:32]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Reactant: ClCc1nsc(Cl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(CCl)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.3 %

Procedure:
A solution of N-L-leucyl-L-proline methyl ester hydrochloride (2.22 g, 8 mmol) and triethylamine (2.8 mL, 20 mmol) in DMF (50 mL) was stirred at room temperature for 15 min. Then, a solution of 3-chloromethyl-5-chloro-[1,2,4]thiadiazole (0.34 g, 2 mmol) in DMF (10 mL) and tetra-butylammonium bromide (100 mg) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water and extracted into ethyl acetate. The organic layer was washed with a saturated ammonium chloride solution, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (7/3, 6/4 and 1/1) afforded N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester as a white foam, 0.49 g, 65.3% yield. 1H-NMR (CDCl3) δ7.56 (d, J=8.2 Hz, 1H, NHCH), 4.78 (m, 1H, NHCH), 4.60 (dd, J=8.5, 4.6 Hz, 1H, CHCO2), 4.46 (s, 2H, CH2Cl), 4.09 (m, 1H), 3.69-3.73 (m, 1H), 3.74 (s, 3H, OMe), 2.25-2.30 (m, 1H), 1.68-2.11 (m, 6H), 0.99-1.03 (2d, 6H, 2Me); MS (m/z) 375 (M+ +1), 357, 305, 246, 218, 162, 150, 130.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].[CH3:7][O:8][C:9](=[O:52])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH:24]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=3[O:40][CH3:41])[CH2:23][CH:22]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH2:21]2)=[C:14]([O:50][CH3:51])[CH:13]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:51][O:50][C:14]1[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:9]([O:8][CH3:7])=[O:52])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][CH:20]1[CH2:25][CH:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=2[O:40][CH3:41])[CH2:23][CH:22]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:4][C:3](=[O:5])[C:2]([CH3:1])=[CH2:6])[CH2:21]1
Reactant: COC(=O)/C=C/c1ccc(OCC2CC(COc3ccc(/C=C/C(=O)OC)cc3OC)CC(OCCCCCCCl)C2)c(OC)c1
Reactant: C=C(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCCCCOC1CC(COc2ccc(/C=C/C(=O)OC)cc2OC)CC(COc2ccc(/C=C/C(=O)OC)cc2OC)C1
Temperature: 80 °C
Reaction time: 20 h
Yield: 94.1 %

Procedure:
786 mg (5.16 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) in 5 ml N,N-dimethylformamide were added dropwise to a solution of 413 mg (4.8 mmol) 2-methylacrylic acid in 5 ml N,N-dimethylformamide over a period of 30 minutes. After addition of 4 mg phenothiazine, 146 mg tetrabutylammonium iodide and 2.6 g (3.9 mmol) (E)-3-[4-[[3-[(6-chlorohexyl)oxy]-5-[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]cyclohexyl]methoxy]-3-methoxyphenyl]acrylic acid methyl ester dissolved in 10 ml N,N-dimethylformamide the resulting mixture was stirred at 80° C. for 20 hours. The reaction mixture was poured into 50 ml of an ice cold 1 M HCl solution. The aqueous phase was extracted three times with 50 ml ethyl acetate. The organic phase was washed with 50 ml of a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfate, filtered and concentrated by vacuum evaporation. Purification of the residue by column chromatography on 270 g silica gel using toluene/ethanol (9:1) as eluent yielded 2.6 g (92%) of 2-methylacrylic acid 6-[3,5-bis[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]cyclohexyloxy]hexyl ester as yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:17][CH3:18])[C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11](Cl)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:19][CH2:20][O-:21].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:17][CH3:18])[C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([O:21][CH2:20][CH3:19])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC[O-]
Reactant: COc1cc(Br)cc2[nH]c3c(Cl)nc(Cl)nc3c12
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1[nH]c1cc(Br)cc(OC)c12
Temperature: 25 °C
Yield: 74.2 %

Procedure:
600 mg (1.7 mmol) 7-bromo-2,4-dichloro-9-methoxy-5H-pyrimido[5,4-b]indole was suspended in 20 ml ethanol and mixed with 174 mg (2.6 mmol) sodium ethylate. The mixture was refluxed for 3 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 450 mg (73%) 7-bromo-2-chloro-4-ethoxy-9-methoxy-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 354, 356 [M−H]−
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][CH:9]=[C:8]([C:11](=O)[CH2:12]Br)[CH:7]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:8]3[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[S:10][CH:9]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cc(C(=O)CBr)cs1
Product: CCOc1ccc(-c2nc(-c3csc(C(=O)O)c3)cs2)cc1OCC

Procedure:
5-Ethoxycarbonyl-3-(α-bromoacetyl)thiophene and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-3-thienyl)thiazole.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:15]3([OH:22])[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([CH3:11])[CH:13]=4)[NH:17][C:16]3=[O:21])[C:10]=2[O:9][CH2:8]1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: Brc1cccc2c1OCO2
Product: Cc1ccc2c(c1)C(O)(c1cccc3c1OCO3)C(=O)N2
Yield: 68.9 %

Procedure:
With 7.80 g of 4-bromo-1,3-benzodioxol and 1.61 g of 5-methyl isatin as starting materials, 1.95 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CNc1nc(Cl)ncc1[N+](=O)[O-]

Procedure:
To a solution of 5 g of 2,4-dichloro-5-nitro-pyrimidine in 150 ml of dichloromethan 3.1 g of neopentylamine and 10.5 ml of diisopropylethylamine were added in succession at 0° C. After 2 hours the mixture was washed with saturated NaHCO3 solution, dried over sodium sulfate and evaporated to dryness yielding (2-Chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine as yellow cristals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCCC#N)c1
Reactant: [H][H]
Solvent: CCO
Product: COc1cccc(CCCCN)c1
Reaction time: 72 h
Yield: 78 %

Procedure:
To a Parr bottle flushed with nitrogen was added ~1.0 g of Raney Nickel (50% suspension in H2O), ethanol (125 mL), ammonium hydroxide (30 mL), and a solution of 4-(3-methoxyphenyl)butyronitrile (8.49 g, 48.4 mmol) in ethanol (150 mL). The bottle was charged with hydrogen (60 psi) and rocked 3 d. The suspension was filtered through Celite, the cake rinsed with fresh ethanol (400 mL), and the combined filtrate concentrated in vacuo. The resulting suspension was treated with dichloromethane (200 mL) and water (200 mL), the layers separated, and the aqueous portion back-extracted with fresh dichloromethane (2×50 mL). The combined organic portions were washed with saturated sodium chloride solution (300 mL), dried (K2CO3), filtered, and concentrated in vacuo. Kugelrohr distillation (0.1 torr, 120° C.) provided the desired product as a clear liquid (6.77 g, 78%) which was identical spectroscopically to that previously reported. Venit, J. J.; DiPierro, M.; Magnus, P. J. Org. Chem. 1989, 54, 4298-4301. 1H NMR (CDCl3) δ 7.20 (t, J=8 Hz, 1H), 6.79-6.70 (m, 3H), 3.80 (s, 3H), 2.75-2.68 (m, 2H), 2.61 t J=8 Hz, 2H), 1.82-1.45 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+].C(OC(O)=O)(O)=O.[C:21](=O)([O:27]C(C)(C)C)[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCOCC1.O>[C:23]([O:22][C:21]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(C(=O)O)c(O)c1
Agent: O=C(O)OC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c(O)c1
Yield: 55.5 %

Procedure:
4-Aminosalicylic acid (5.00 g, 32.6 mmol) was suspended in dioxane (35 ml) and water (35 ml), and the suspension was added with aqueous sodium hydroxide (2N) and a solution of di-tert-butyl carbonate dicarbonate (8.5 g, 39.0 mmol) in dioxane (35 ml), and then the mixture was stirred at room temperature for seven days. After the dioxane of the reaction mixture was evaporated, the residue was made weakly acidic (pH˜4) with 1N hydrochloric acid, and then extracted with ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting syrup was solidified with hexane and ethyl acetate to obtain the title compound (4.58 g, yield; 55%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2].[Cl:16]N1C(=O)CCC1=O.O>CN(C=O)C>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-(Formylaminothiazol-4-yl)-2-oxoacetate (9.1 g, 39.87 mmol) (obtained from Aldrich, Milwaukee, Wis.) was slurried in 50 mL of anhydrous DMF. N-Chlorosuccinimide (5.6 g, 41.86 mmol) was added as a solid and the suspension was stirred at room temperature. After 18 hours, the reaction mixture was poured into 500 mL of water. The resulting white precipitate was filtered, washed with water and air dried to afford the title intermediate as a white solid.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][S:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:34][CH3:35])=[C:19]([N:21]([CH2:26][CH2:27][NH+:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)=[O:14])([OH:10])=[O:9].[Cl:36][C:37]1[CH:38]=[N+:39]([O-:62])[CH:40]=[C:41]([Cl:61])[C:42]=1[CH2:43][C@@H:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[C:48]([O:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)[CH:47]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[ClH:36].[Cl:36][C:37]1[CH:38]=[N+:39]([O-:62])[CH:40]=[C:41]([Cl:61])[C:42]=1[CH2:43][C@@H:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[C:48]([O:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)[CH:47]=1)[O:9][C:8](=[O:10])[CH2:11][S:12][C:13](=[O:14])[C:15]1[CH:16]=[CH:17][C:18]([O:34][CH3:35])=[C:19]([N:21]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1
Reactant: COc1ccc(C(=O)SCC(=O)O)cc1N(CC[NH+]1CCOCC1)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(CCN1CCOCC1)S(C)(=O)=O
Product: Cl
Temperature: 25 °C
Yield: 86.4 %

Procedure:
4-(2-(N-(5-((carboxymethylthio)carbonyl)-2-methoxyphenyl)-methylsulfonamido)-ethyl)morpholin-4-ium 2,2,2-trifluoroacetate (0.194 g, 0.355 mmol) was suspended in dry DCM (3.5 ml), and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.115 g, 0.273 mmol), EDC (0.157 g, 0.819 mmol), and DMAP (0.0667 g, 0.546 mmol) were sequentially added with stirring at RT under nitrogen. The resulting yellow solution was stirred at the same temperature for 24 hours. The mixture was diluted with DCM and washed twice with 1N HCl and then with brine. The organic phase was dried over Na2SO4, and the solvent was removed under vacuum. The crude was purified by flash chromatography on silica gel column (DCM:MeOH=96:4) followed by preparative HPLC under neutral conditions. The fraction obtained after solvent evaporation was dissolved in Et2O and HCl in Et2O was added; the resulting suspension was stirred at RT for few minutes. The volatiles were removed, and the residue was dried affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(N-(2-morpholinoethyl)-methylsulfonamido)benzoylthio)acetoxy)-ethyl)pyridine 1-oxide hydrochloride (0.103 g, 0.118 mmol, 43.3% yield, LC-MS purity (BPI): 99.7%, MS/ESI+ 834.34 [MH]+, [αD]=−54.00, c=0.5, MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH:25]3[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28]3)[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2c3ccccc3c3cc(C(N)=O)c(N)nc32)C1
Temperature: 150 °C
Yield: 69 %

Procedure:
To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 44 mg, 0.19 mmol) in N,N-dimethylformamide (4.4 mL) was added powdered cesium carbonate (130 mg, 0.39 mmol), and tert-butyl 3-iodoazetidine-1-carboxylate (Harris, L. J., et al. European Patent Application 1176142, 2002; 0.11 g, 0.39 mmol). The mixture was heated in a microwave at 150° C. for 30 min, concentrated and purified by silica gel chromatography (12 g silica, methylene chloride to 90/10 methylene chloride/methanol gradient) to yield tert-butyl 3-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]azetidine-1-carboxylate (xvi-f, 50 mg, 70%). NH4OAc QC conditions. M+H=382. 1H NMR (300 MHz, CDCl3): δ 8.24 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.42-7.34 (m, 1H), 7.30-7.22 (m, 1H), 4.75-4.60 (m, 1H), 4.48-4.39 (m, 2H), 4.17-4.07 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([S:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])=[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:13][C:12]=2[CH:29]=1.Cl.Cl[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH3:1][O:4][C:20]1[CH:19]=[C:18]([S:16]([C:15]2[C:11]3[CH:10]=[CH:9][C:8]([O:7][CH2:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[CH:29][C:12]=3[S:13][C:14]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1sc2cc(O)ccc2c1S(=O)c1ccccc1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(OCc3ccncc3)ccc2c1S(=O)c1cccc(OC)c1
Reaction time: 24 h
Yield: 73 %

Procedure:
Potassium carbonate (240 mg, 1.73 mmol) was added to a solution of ethyl 6-hydroxy-3-(phenylsulfinyl)benzo[b]thiophene-2-carboxylate (Preparation 19, 200 mg, 0.58 mmol) in anhydrous dimethylformamide (3 ml) at ambient temperature under a nitrogen atmosphere. After 15 minutes 4-(chloromethyl)pyridine hydrochloride (104 mg, 0.64 mmol) was added, and stirring continued for 24 hours. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated and washed twice with water, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate as eluant, and crystallised from diisopropyl ether to give the title compound as a colourless solid (198 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([CH2:29][C:30](=[O:32])[CH3:31])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:60])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([CH2:29][C:30](=[O:32])[CH3:31])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:60])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)CC(C)=O
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)CC(C)=O

Procedure:
1-(3-Chloropropylsulfonylamino)-3-hexadecylthio-2-(2-oxopropan-1-yl)propane IIIm2 is allowed to react by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:17])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].[Br:26]Br>CO.O>[Br:26][C:9]1[C:8](=[O:17])[C:4]([C:5]([OH:7])=[O:6])=[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:2]([CH3:1])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: Cn1c(-c2ccccc2)cc(=O)c(C(=O)O)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(-c2ccccc2)c(Br)c(=O)c(C(=O)O)c1-c1ccccc1
Yield: 63.6 %

Procedure:
3.75 gms of 1-methyl-2,6-diphenyl-4-oxonicotinic acid was dissolved in 40 mls of methanol. The pH was adjusted to 12 with the addition of aqueous NaOH. A methanolic solution of bromine (2.95 gms Br2 in 50 mls methanol) was added. Additional NaOH was added as required to maintain a basic medium. Removal of the solvent yielded a semisolid that was taken up in 100 mls of water. Water insoluble material was removed by filtration. Acidification of the aqueous solution provided 3.0 gms of 5-bromo-1-methyl-2,6-diphenyl-4-oxonicotinic acid (mp 242°-243°, with decomposition) as a white solid.