Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:18](O)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CC(N(C)C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[CH:12]=1)([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccc(I)c1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Boc-3-iodo-D-phenylalanine (6.32 g, 16.2 mmol) and 4-methyl-morpholine (1.87 ml, 17 mol) in THF (13 mL) was added dropwise to a −15° C. solution of isobutyl chloroformate (2.22 mL, 17 mmol) in THF (13 mL) and the resulting suspension was stirred for 1 h. The cold reaction mixture was filtered and the filter cake was rinsed with THF. The filtrate was added dropwise to a 0° C. solution of NaBH4 (0.92 g, 24.2 mmol) in dimethylacetamide (7 mL) and the resulting suspension was warmed to RT and stirred for 1 h. The reaction mixture was cooled back to 0° C. and quenched with 1M aq. citric acid. Additional water was added and the mixture was concentrated in vacuo. The remaining aqueous phase was acidified with 1M aq. HCl before being filtered. The filter cake was rinsed with water and dried under HV to give the title compound as an orange solid that was used further without purification. LC-MS A: tR=0.84 min; [M-Me]+=362.93.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([OH:18])=O.[CH3:19][CH:20]([CH3:40])[CH2:21][NH:22][C@@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][C@H:25]([C:36]([O:38][CH3:39])=[O:37])[CH2:24]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:22]([CH2:21][CH:20]([CH3:40])[CH3:19])[C@@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][C@H:25]([C:36]([O:38][CH3:39])=[O:37])[CH2:24]1)=[O:18]
Reactant: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCn1c(C(=O)O)cc2ccccc21
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 7.4 %

Procedure:
1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (247 mg), 1-tert-butyl 3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (314 mg) and diisopropylethylamine (862 μl) were dissolved in methylene chloride (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (337 mg) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give 1-tert-butyl 3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) as an oil. The obtained 1-tert-butyl 3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) was dissolved in methanol (2 ml), 4M hydrogen chloride-ethyl acetate (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the object product (13 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH2:28]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:28][CH2:27][CH2:26][C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: NCCc1cccs1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCc2cccs2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 70.2 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-(2-thienyl)ethylamine (0.0234 g, 0.184 mmol) gives the title compound (0.0495 g, 70.3%): TOF MS ES+384.1 (M+H)+, HRMS calcd for C20H22N3O3S 384.1382 (M+H)+, found 384.1375, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.1 min, 100% purity.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=2[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1>C(O)C>[O:1]=[C:2]1[CH:7]=[CH:6][C:5](=[N:8][C:9]2[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=2[C:11]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12])[CH:4]=[CH:3]1
Reactant: O=C(c1ccccc1Nc1ccc(O)cc1)N1CCCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1C=CC(=Nc2ccccc2C(=O)N2CCCCC2)C=C1
Yield: 35.1 %

Procedure:
A mixture of 8.9 g (0.03 mole) 1-[2-(4-hydroxyphenylamino)benzoyl]piperidine, 6.4 g (0.03 mole) of mercuric oxide, 80 ml of toluene and 20 ml of ethanol was heated at reflux for three hours. The reaction mixture was filtered through an alumina column and eluted with ethyl acetate. The solvent was removed in vacuo and the residue subjected to high pressure liquid chromatography, eluting with 20% ethyl acetate in hexane. The resulting 5.4 g of oil was partitioned between water and ether, the ether fraction dried over anhydrous sodium sulfate and concentrated, and the residue recrystallized from hexane to give 3.1 g of 1-{2-[(4-oxo-2,5-cyclohexadien-1-ylidene)amino]benzoyl}piperidine, orange powder, m.p. 74°-76° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]O)([O-:3])=[O:2].[C:15]1([C:21]2[C:22]([NH:24][C:25](=[O:27])[CH:26]=2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][N:24]2[C:25](=[O:27])[CH:26]=[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:22]2=[O:23])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Reactant: O=C1C=C(c2ccccc2)C(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1C=C(c2ccccc2)C(=O)N1Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 24 h
Yield: 74 %

Procedure:
In a 500 ml three-necked flask equipped with a stirring means and a dropping funnel were placed 7.92 g of 3,5-dinitrobenzyl alcohol, 6.90 g of α-phenylmaleimide and 11.5 g of triphenylphosphine, and the mixture was dissolved in 200 ml of THF with stirring. To the solution was added dropwise 20.9 g of diethyl azodicarboxylate (as a 40% toluene solution) at 0° C. or lower. After the dropwise addition, the temperature was allowed to rise to room temperature and stirring was continued for 24 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The organic layer was washed three times with water and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the organic layer was concentrated under reduced pressure. The resulting pale yellow crystal was collected by filtration with n-heptane and recrystallized twice from ethyl acetate to afford 10.41 g of N-(3,5-dinitrophenyl)methyl-α-phenylmaleimide.
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCCCCCC>C1COCC1>[CH3:5][C:4]([CH3:6])([CH:3]=[CH2:2])[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)=CCCl
Solvent: C1CCOC1
Solvent: CCCCCCCCCC
Product: C=CC(C)(C)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
4-Chloro-2-methyl-2-butene (2.00 mmol) was weighed into a vial and sealed with a septum. Using a freeze-pump-thaw technique, air was removed and replaced with argon. THF (4 ml) was added to the vial and then cooled to -78° C. The allyl chloride was then cannulated to the active coppersolution (8.00 mmol) at -108° C. The solution was stirred at -108° C. for 10 minutes and then warmed to -95° C. Benzoyl chloride (8.80 mmol) and decane (2.00 mmol) were admixed with 4 ml of THF in a vial, cooled to -78° C. and then cannulated to the organocopper solution at -95° C. The reaction mixture was allowed to warm to -78° C. and stirred for 30 minutes. The solution was then quenched with saturated NH4Cl(aq), extracted with ether (3×20 ml), washed with brine (3×50 ml), and the organic layer dried over MgSO4. Flash silica gel chromatography using hexanes afforded 2,2-dimethyl-1-phenyl-3-butene-1-one (1.12 mmol), for a 56% yield: IR (neat) 3085, 3059, 2975, 2934, 2872, 1679, 1635, 1597, 1578, 1466, 1412, 1380, 1363, 1259, 1173, 1157, 1001, 971, 918, 796,719,694, 667. 1H NMR (300 MHz) 7.85-7.89 (m, 2H), 7.32-7.46 (m, 3H), 6.11-6.26 (dd, J1 =17.52 Hz, J2 =10.63 Hz, 1H), 5.17-5.27 (m, 2H), 1.39 (s, 6H). 13C NMR (300 MHz) 204.5, 143.8, 137.1, 131.5, 129.1, 127.8, 113.9, 50.1, 25.9.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].C(N(CC)CC)C.[I-].[Na+].[NH2:14][CH2:15][CH2:16][O:17][CH:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:49])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])=[CH:33][C:32]=2[O:47][CH3:48])[CH2:21][CH2:20][CH2:19]1>CN(C)C=O.O>[C:3]([CH2:2][NH:14][CH2:15][CH2:16][O:17][CH:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:49])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])=[CH:33][C:32]=2[O:47][CH3:48])[CH2:21][CH2:20][CH2:19]1)#[N:4]
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCN)c2cc(Cl)ccc21
Reactant: N#CCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCNCC#N)c2cc(Cl)ccc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
0.01 ml of chloroacetonitrile, 0.22 ml of triethylamine and 0.24 ml of sodium iodide were added to 50 ml of a solution of 0.7 g of 5-(2-aminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in dimethylformamide. The mixture was stirred at 60° C. for 2 hours. The reaction mixture was mixed with water, followed by extraction with ethyl acetate-n-hexane (10:1). The organic layer was water-washed, dried and subjected to vacuum distilation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=50/1) and crystallized from acetone-n-hexane to obtain 0.5 g of 5-(2-cyanomethylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[N:4][CH:3]=1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].CCN(C(C)C)C(C)C>C(OC(O)C)C>[CH2:18]([N:20]([CH2:21][CH3:22])[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[N:4][CH:3]=1)[CH3:19]
Reactant: CCNCC
Reactant: Nc1ccc2ncn(-c3cncc(Cl)n3)c2c1
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1cncc(-n2cnc3ccc(N)cc32)n1

Procedure:
A solution of 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6-amine (100 mg, 0.41 mmol) and diethylamine (430 μL, 4.1 mmol) in ethoxyethanol (2 mL) containing DIPEA (140 μL) was heated in a sealed tube overnight under N2. The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (20 mL) and washed successively with H2O (20 mL) and brine (20 mL). After drying (Na2SO4) the solvent was removed under reduced pressure and the residue chromatographed eluting with dichloromethane-methanol (9:1-94:6) to separate pure product from the lower fractions (110 mg).
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH2:1]([C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCCC1
Reactant: BrCCc1ccccc1
Product: OC1(CCc2ccccc2)CCCCC1
Yield: 96 %

Procedure:
Since TmI2(DME)x exhibits such high reactivity at room temperature, its viability at reduced temperature is examined. In these reactions, TmI2(DME)x is added as a DME solution by syringe using a saturated stock solution generated in situ from Tm and I2. Phenethyl iodide reacts smoothly at −22° C. in 10 minutes to form phenethylcyclohexanol in 96% yield (entry f). The reaction of phenethyl bromide with cyclohexanone at 0° C. produces a 96% yield of phenethylcyclohexanol in 20 minutes (entry g), while reaction at −22° C. gave a 94% yield in 60 minutes (entry h). Phenethyl chloride reacts at 0° C. to give a 90% yield after 1 hour (entry j). This variation of reaction time as a function of temperature could be used to control regiochemistry in sequenced reactions.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][C:25]([CH3:27])=[CH2:26])[C:21]([OH:28])=[C:20]([C:29]([OH:31])=[O:30])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[I-].[K+].O.C(OCC)(=O)C>ClC1C=CC=CC=1Cl.II>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([C:29]([OH:31])=[O:30])[C:21]4[O:28][C:25]([CH3:27])([CH3:26])[CH2:24][C:22]=4[CH:23]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: C=C(C)Cc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)O)c1O
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(-c2nc(-c3cc4c(c(C(=O)O)c3)OC(C)(C)C4)cs2)cc1OCC
Yield: 50 %

Procedure:
In 40 ml of o-dichlorobenzene was dissolved, with heating, 2 g of 2-(3,4-diethoxyphenyl)-4-[3-carboxy-4-hydroxy-5-(2-methyl-2-propenyl)phenyl]-thiazole. Thereto were added about 10 mg of iodine and 1.5 g of potassium iodide (ground in-a mortar), and the mixture was refluxed for 14 hours with heating. The reaction mixture was mixed with 30 ml of water and phase separation was conducted. The organic layer was mixed with 30 ml of ethyl acetate. The mixture was washed with 20 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane) and recrystallized from diisopropyl ether to obtain 1 g of 2-(3,4-diethoxyphenyl)-4-(2,2-dimethyl-7-carboxy-2,3-dihydrobenzofuran-5-yl)thiazole as white powdery crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:43]([O:45][C:46](=[O:51])[C:47](Br)([CH3:49])[CH3:48])[CH3:44]>CN(C)C=O.C(OCC)(=O)C>[CH2:43]([O:45][C:46](=[O:51])[C:47]([O:25][C:23]1[CH:24]=[C:19]2[CH:18]=[C:17]([C:26]([C:33]3[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=3)=[CH:27][CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:16]([S:13]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:14])=[O:15])[C:20]2=[N:21][CH:22]=1)([CH3:49])[CH3:48])[CH3:44]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
Potassium carbonate (828 mg, 5.99 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 1.6 g, 3.07 mmol) in N,N-dimethylformamide (4.0 mL) at room temperature. The mixture was stirred for 30 min at room temperature and then 2-bromo-2-methyl-propionic acid ethyl ester (0.48 mL, 3.21 mmol) was added. The mixture was heated at 80° C. for 1 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (1.34 g, 68.7%) as a light yellow solid: LC/MS m/e calcd for C33H36N2O7S2 [M+H]+ 637.79, observed 637.5.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C>C1COCC1>[Br:7][C:4]1[S:3][C:2]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: C1CCNC1
Reactant: Brc1cnc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(N2CCCC2)s1
Yield: 108.4 %

Procedure:
4 batches of 2,5-dibromo-1,3-thiazole (250 mg, 1.029 mmol), pyrrolidine (0.089 mL, 1.081 mmol) and DIPEA (0.225 mL, 1.286 mmol) in THF (2.5 mL) were heated in a microwave at 120° C. for 15 minutes. All 4 batches were combined and evaporated to dryness. The residues were purified on silica eluting with cyclohexane and ethyl acetate (0-100%). The appropriate fractions were combined and evaporated to dryness producing the title compound (260 mg). LCMS (A): m/z (M+H)+ 233/235, C7H9BrN2S requires 232/234 (acidic).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[C:7](O)(=O)[CH3:8]>S(=O)(=O)(O)O.C(O)C>[CH3:7][CH2:8][CH2:5][CH3:6].[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: C=COC(C)=O
Product: CCCC

Procedure:
The commercial production of ethyl acetate is mainly by two processes: the Tischenko reaction produces ethyl acetate by direct conversion of ethanol via acetaldehyde using an aluminum alkoxide catalyst; and the production of ethyl acetate by direct esterification of ethanol with acetic acid with a sulphuric acid catalyst. The Tischenko reaction is the main industrial process for the manufacture of ethyl acetate. Industrial scale production by this method took place mainly in Europe during the first half of this century. Ethyl acetate is also produced as a by-product in the liquid phase oxidation of n-butane and as a co-product in the production of polyvinyl butyryl from vinyl acetate and ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](I)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([SH:18])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:12]1([CH3:11])[CH:17]=[CH:16][CH:15]=[C:14]([S:18][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: Cc1cccc(S)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cccc(Sc2cccc([N+](=O)[O-])c2)c1
Yield: 84.8 %

Procedure:
The general procedure in example 39 was followed. 3-Nitroiodobenzene (249 mg, 1.0 mmol), m-thiocresol (119 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-nitrophenyl 3-tolyl sulfide (208 mg, 85% yield) as yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=20/1). Rf=0.4 (hexane/ethyl acetate=20/1). 1H NMR (CDCl3, 300 MHz) δ 7.95-7.99 (m, 2 H), 7.46 (dt, 1 H, J=7.5 Hz, 0.9 Hz), 7.38 (t, 1 H, J=8.1 Hz), 7.12-7.28 (m, 5 H), 2.36 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 141.0, 140.0, 134.3, 134.2, 131.7, 130.8, 130.0, 129.9, 129.8, 123.1, 122.9, 120.9. MS (EI) m/z (relative intensity) 245 (100), 184 (80).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=1[OH:28])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:49]1[C:58]2[C:53](=[C:54]([CH2:59][CH2:60]O)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][CH:50]=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=1[O:28][CH2:60][CH2:59][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[C:53]=1[CH:52]=[CH:51][CH:50]=[N:49]2)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(N)=O)cc1O
Reactant: OCCc1cccc2ncccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
To a methylene chloride solution of 3-(4-carbamoyl-2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester at room temperature was added triphenylphosphine (0.25 g, 0.95 mmol), 2-quinolin-5-yl-ethanol (0.11 g, 0.66 mmol) and diethyl azodicarboxylate (0.17 ml, 1.12 mmol). The reaction was stirred at room temperature for 3 days. The reaction was then concentrated under reduced pressure. The crude residue was chromatographed [silica gel with a gradient of 100% ethyl acetate to 10% (1:9 NH4OH/ethanol) in ethyl acetate] to give 3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a white foam (0.27 g, 69%). 1H NMR(300 MHz, DMSO) 8.90 (d, 1H), 8.73 (d, 1H), 8.08 (s, 1H), 7.93 (d, 1H), 7.62 (m, 8H), 4.43 (m, 3H), 3.71 (m, 2H), 3.47 (bs, 3H), 2.77 (bs, 3H), 2.54 (dd, 1H), 2.34 (dd, 1H), 1.31 (s, 9H). MS(APCI) m/z 585.1 (M−H), 587.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8](C)[C:9](=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[ClH:24].O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH3:9])=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[ClH:24]
Reactant: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCc1ccc(OC)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-methoxy-3-(methylsulfonamido)benzyl(methyl)carbamate (60.4 mg, 0.175 mmol) was dissolved in DCM (5 ml), HCl 4M in dioxane (250 μl, 1.000 mmol) was added, and the reaction was stirred at RT overnight. Additional HCl 4M in dioxane (500 μl, 2.00 mmol) was added over 30 hours with stirring at the same temperature. The solvent was evaporated under vacuum, and the solid so obtained was triturated in DCM and filtered to give N-(2-methoxy-5-((methylamino)methyl)-phenyl)methanesulfonamide as hydrochloride (42.8 mg, 0.175 mmol, 100% yield, MS/ESI+ 245.3 [MH]+) that was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:17]([C:16](=[O:21])[CH3:15])[C:18](=[O:20])[CH3:19])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)C(=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(C)=O

Procedure:
The procedure described in Example 1 was repeated by using 2.53 g 3,5-dinitrobenzaldehyde and 2.43 g of 2,4-pentanedione. Yield 0.8 g, mp 101°-105° C.