Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][SiH:9]([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=[CH:14][CH2:15][CH2:16][CH:17]=[CH2:18]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:1]1([CH:7]([CH3:12])[CH2:8][Si:9]([CH:13]([Si:9]([Cl:10])([Cl:11])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCCC=C
Reactant: CC(C[SiH](Cl)Cl)c1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCC([Si](Cl)(Cl)CC(C)c1ccccc1)[Si](Cl)(Cl)CC(C)c1ccccc1
Yield: 66 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 21.3 g (0.097 mole) of 3-(phenyl)-1,1-dichloro-1-silabutane and 100 μl of 1% chloroplatinic acid solution in isopropanol were placed and then 3.2 g (0.039 mole) of 1,5-hexadiene was added dropwise for 5 min. The solution was reacted for 15 hours at reflux under the dry nitrogen atmosphere. Vacuum distillation gave 13.4 g (185°-187° C./0.03 mmHg) of bis{(2-phenylpropyl)dichlorosilyl}hexane in 66.0% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][NH2:21].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:21]([CH2:20][CH2:19][CH2:18][OH:17])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: Cc1occc(=O)c1OCc1ccccc1
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, is reacted with 3-hydroxypropylamine under substantially similar conditions to those described under Example 9 for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one as white crystals, m.p. 111°-113° C.; νmax (nujol) 1630, 3150, 3350 cm-1, δ(d6DMSO) 1.8 (m, 2H), 2.4 (s, 3H, 3.35 (t, 2H), 4.33 (t, 2H), 7.3 (d, 1H), 8.2 (d, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>CC(C)=O.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:4]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(NC2CCCCC2)n1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CSc1nc(NC2CCCCC2)c([N+](=O)[O-])c(N2CCSCC2)n1
Temperature: 25 °C

Procedure:
3.0 gm of 2-methylmercapto-4-chloro-5-nitro-6-cyclohexylamino-pyrimidine were dissolved in 30 ml of acetone, a solution of 1.38 gm of potassium carbonate in 1.5 ml of water was added, and the mixture was admixed with a solution of 1.2 gm of thiomorpholine in 10 ml of acetone. The resulting mixture was stirred at room temperature, whereby after a short time a voluminous, crystalline precipitate was formed which was further increased by addition of water. The mixture was suction-filtered and the filter cake, 2-methylmercapto-4-thiomorpholino-5-nitro-6-cyclohexylamino-pyrimidine, was recrystallized from isopropanol. Yield: 2.3 gm (62% of theory), m.p. 145°-146°C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17](F)[CH:16]=1.O>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Sc1ccncc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1Sc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Mercaptopyridine (1.1 1 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) were suspended in DMF (10 mL) and stirred at room temperature for 15 min. The mixture was treated with 4-chloro-2-fluoro-1-nitro-benzene (1.75 g, 10 mmol) and heated at 50° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the mixture extracted 3 times with ethyl acetate. The organic layer was combined the ethyl acetate and then reduced in vacuo. The residue was dissolved in DMF (30 mL) and treated with SnCl2.2H2O. The mixture was heated at 50° C. for 16 hr. The DMF was distilled off under vacuum and the reduction product was purified by flash chromatography on silica gel column (50-100% EtOAc/hexane) to afford 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine as light yellow solid. The title sulfonamide compound was prepared according to the general procedure using 118 mg of 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine prepared above and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.33 (s, 9H), 7.06 (d, 2H, J=6.8 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.51 (m, 2H), 7.66 (d, 2H, 8.4 Hz), 7.71 (d, 1H, J=9.2 Hz), 8.43 (d, 2H, J=6.4 Hz). MS: m/z 433.9 (M++1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][CH:18]=2)=[CH:4][C:3]=1[C:24]([NH:26][C@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]1[OH:33])=[O:25].[C:34](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[OH:33][C@H:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@@H:27]1[NH:26][C:24]([C:3]1[CH:4]=[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][CH:18]=2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[O:1][CH3:34])=[O:25]
Reactant: O=C([O-])[O-]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(-n3cccn3)nc2)c2ccccc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccc(-n3cccn3)nc2)c2ccccc12
Reaction time: 24 h

Procedure:
To a solution of 1-hydroxy-N-[(1S,2S)-2-hydroxycyclohexyl]-4-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}-2-naphthamide (Example 6, 0.120 g, 0.271 mmol) in 4 mL of DMF was added potassium carbonate (0.041 g, 0.30 mmol) and iodomethane (0.042 g, 0.30 mmol). After 24 hours, the reaction was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% methanol in dichloromethane to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 457.4 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.50 (br s, 1H), 8.30 (br s, 1H), 8.22-8.11 (m, 2H), 8.03 (s, 1H), 7.92 (d, J=6.9 Hz, 1H), 7.84 (br s, 1H), 7.70 (br s, 1H), 7.57 (br s, 2H), 6.44 (br s, 1H), 4.44 (s, 2H), 4.03 (s, 3H), 3.98 (br s, 1H), 3.53 (br s, 1H), 2.36-2.14 (m, 3H), 1.79 (br s, 2H), 1.47-1.26 (m, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC([O:24][CH:25]([CH3:27])C)=O.O[CH:35]([CH2:47][CH2:48][CH3:49])[CH2:36][CH2:37][N:38]([CH3:46])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].[S:50]1C=CC=C1CC(O)=O>O1CCCC1>[C:25]([S:50][CH:35]([CH2:47][CH2:48][CH3:49])[CH2:36][CH2:37][N:38]([CH3:46])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:24])[CH3:27]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)SC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To an ice-cooled stirred solution of triphenylphosphine (25.0 g, 95.4 mmol) in tetrahydrofuran (450 ml) under nitrogen was added dropwise diisopropyl azodicarboxylate (19 ml, 93.3 mmol). After 0.5 h, a solution of (3-hydroxyhexyl)methylcarbamic acid, 1,1-dimethylethyl ester (11.5 g, 49.8 mmol) and thiolacetic acid (6.8 ml, 95.2 mmol) in tetrahydrofuran (50 ml) was added slowly. The resulting mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stir overnight. The mixture was concentrated to near dryness, the residue triturated with hexanes, the solids removed by filtration, and the filtrate concentrated and the crude material subjected to flash chromatography using ethyl acetate/hexanes as eluent to give the title compound (12 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]([C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:24])=[O:22])([CH3:19])([CH3:18])[CH3:17].BrC1C2C(S([Cl:44])(=O)=O)=CC=CC=2C=NC=1.C(OC(N(C1CCNC1)C)=O)(C)(C)C>>[C:16]([O:20][C:21]([N:23]([C@H:25]1[CH2:29][CH2:28][N:27]([S:12]([C:10]2[C:11]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH2:26]1)[CH3:24])=[O:22])([CH3:19])([CH3:17])[CH3:18].[ClH:44]
Reactant: O=S(=O)(Cl)c1cccc2cncc(Cl)c12
Reactant: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Agent: CN(C(=O)OC(C)(C)C)C1CCNC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Product: Cl

Procedure:
That is, (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]-1-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 21a) was prepared by using 4-chloro-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 31, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in the method of Example 31, Step B in a similar manner to obtain the compound of Example 19-3 as hydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1.N1CCCCC1>C(O)C.CCOCC>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])=[CH:21][C:20]=1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(C=O)cc1-c1cccs1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)cc1-c1cccs1
Reaction time: 8 h
Yield: 14.6 %

Procedure:
A mixture of 6-pyridin-3-yl-1,3-dihydro-indol-2-one (100 mg, 0.5 mmol), 4-methoxy-3-thiophen-2-yl-benzaldehyde (110 mg, 0.5 mmol) and piperidine (0.23 mL) in ethanol (4 mL) was heated to reflux and stirred overnight. The reaction mixture was then cooled and diluted with ether to afford a precipitate which removed by filtration. Thefiltrate was column chromatographed (eluant—isopropanol/dichloromethane) to give 30 mg (15%) of 3-(4-methoxy-3-thiophen-2-yl-benzylidene)-6-pyridin-3-yl-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].C1C(=O)N([Br:19])C(=O)C1>OS(O)(=O)=O>[Br:19][C:8]1[C:7]([CH3:11])=[C:3]([C:2]([F:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(F)c1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(Br)ccc(F)c1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a 0° C. solution of 2-fluoro-6-methyl-benzoic acid (1.48 g, 9.60 mmol) in conc. H2SO4 (40 mL) was added NBS (1.79 g, 10.1 mmol). The mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into ice water (200 mL), and extracted with ether (2×200 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum to give the title compound (Compound QQ, 2.15 g, 96% yield) as a solid. 1H NMR (400 MHz, chloroform-d) δ 7.64 (dd, J=8.84, 5.31 Hz, 1H), 6.92 (t, J=8.84 Hz, 1H), 2.54 (s, 3H); MS 231.0 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH2:20])=[O:19])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](C(C)C)[C:6]=2[N:17]=1.Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].BrC(C)C>>[NH2:1][C:2]1[C:3]([C:18]([NH2:20])=[O:19])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:6]=2[N:17]=1
Reactant: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CC(C)Br
Product: CC(C)(C)[Si](C)(C)OCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21

Procedure:
2-Amino-9-(2-(tert-butyldimethylsilyloxy)ethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (xxv-a) was prepared following the procedure detailed in the synthesis of 13 substituting (2-bromoethoxy)(tert-butyl)dimethylsilane for 2-bromopropane. The crude silane was used in the following step without further purification. NH4OAc QC conditions. M+H=385.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12](=[O:13])[CH2:11][C:10]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:9]=2[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Br:25])[CH2:7]1)[CH3:2].[C:27](N=P(N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)([CH3:30])([CH3:29])[CH3:28].CCCCCC.ICC(C)C.Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:7][CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Br:25])[C:9]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[CH:11]([CH2:28][CH:27]([CH3:30])[CH3:29])[C:12]1=[O:13])[CH3:2]
Reactant: CCOC(=O)CN1CC(c2ccccc2Br)c2cc(Cl)ccc2CC1=O
Reactant: CN(C)P(=NP(=NC(C)(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C
Agent: CC(C)CI
Agent: Cl
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(c2ccccc2Br)c2cc(Cl)ccc2C(CC(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
440 mg of the compound from Example 12A (1.01 mol) are dissolved in 5.2 ml of THF. At −78° C., 1.51 ml of a 1 M solution of 3-tert-butylimino-1,1,1,5,5,5-hexakis(dimethylamino)-3-[tris(dimethylamino)phosphoranylidene]amino-1λ5,3λ5,5λ5-1,4-triphosphazadiene in n-hexane (1.51 mol) are added drop wise, and the reaction mixture is stirred at −78° C. for 30 min. 278 mg of 1-iodo-2-methylpropane (1.51 mol) are added drop wise, and the mixture is stirred at −78° C. for a further 3 h. The reaction solution is mixed with 14 ml of 1 N hydrochloric acid and water and extracted three times with dichloromethane. The combined organic phases are washed twice with saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 200 mg (40% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4].[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:25][CH3:26])[C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: CCI
Reactant: COC(=O)c1cncn1C1c2ccccc2C(=O)NC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)c2ccccc2C(n2cncc2C(=O)OC)C1(C)C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester (114 mg, 0.381 mmol) (Example 33c) in DMF (6 mL) at −10° C. is added NaH [60% dispersion in oil (20 mg, 0.5 mmol)]. The reaction is stirred at −10° C. for 10 min, placed at room temperature for 5 min, and then recooled to −10° C., at which time ethyl iodide (0.070 mL, 0.875 mmol) is added. After 45 min the reaction is quenched with saturated aqueous NH4Cl, diluted with ethyl acetate and saturated aqueous NaHCO3. The layers are separated and the aqueous layer is extracted two more times with ethyl acetate. The combined organic layers are dried over Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 1:7 to 1:0) to afford 3-(2-ethyl-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester; HRMS: (ESI) m/z 328.1673 [(M+H)+: Calcd for C18H22N3O3: 328.1661]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21 (t, J=7.1 Hz, 3 H), 1.24 (s, 3 H), 1.40 (s, 3 H), 3.47-3.57 (m, 1 H), 3.67-3.78 (m, 1H), 3.94 (s, 3 H), 6.56 (s, 1 H), 7.28-7.33 (m, 1 H), 7.42 (s, 1 H), 7.46-7.55 (m, 2 H), 7.77 (s, 1 H), 8.20-8.26 (m, 1 H).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[C:18](=[O:34])[N:19]([CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])[C:20]2=[O:25])=[O:13])=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[C:18](=[O:34])[N:19]([CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])[C:20]2=[O:25])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 17 h
Yield: 79 %

Procedure:
A 4N HCl solution in dioxane (1 ml) was added to a stirred solution of 3-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide (0.5 g, 1.09 mmol) in CH2Cl2 (15 ml) and stirred for 17 hours. The resulting suspension was filtered to give 3-amino-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide hydrochloride (0.34 g, 79%) as a white solid: mp 161–163° C.; 1H NMR (DMSO-d6) δ d 11.15 (s, 1H), 8.88 (t, J=5.8 Hz, 1H), 8.06. (b, 3H), 7.87–7.79 (m, 3H), 5.19–5.12 (dd, J=5.3 and 12.6 Hz, 1H), 4.76 (d, J=5.8 Hz, 2H), 3.03–2.84 (m, 3H), 2.67–2.47 (m, 4H), 2.08–2.04 (m, 1H); 13C NMR (DMSO-d6) δ d 172.74, 169.88, 169.80, 167.45, 166.92, 138.92, 134.74, 133.46, 131.48, 127.09, 121.92, 48.86, 37.69, 35.11, 32.03, 30.92, 21.97; Anal. Calcd. For C17H19N4O5Cl+0.13 CH2Cl2+0.57 H2O: C, 49.44; H, 4.94; N, 13.46; Cl, 10.73. Found: C, 49.22; H, 4.88; N, 13.08; Cl, 10.95.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH:22]([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[F:21][CH:22]([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH:2]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1ccc(OC(F)F)cc1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 4-(difluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 394.01 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:13])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O.N>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:6][CH2:7][CH2:8][O:9][CH3:20])=[C:10]([CH3:12])[CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(Br)cc(C)c1OCCO
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COCCOc1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-(4-bromo-2,6-dimethylphenoxy)ethanol (15 g) in methylene chloride (100 ml) was added to a stirred solution of sodium hydroxide (50 g) in water (50 ml) at 5° C. Dimethyl sulphate (8.6 ml) was added dropwise to the stirred solution at 5° C. over 30 minutes. The mixture was stirred at ambient temperature for 12 hours. Dimethylsulphate (5 ml) was added at ambient temperature and the mixture stirred for a further 2 hours. The mixture was cooled to 0° C. and a solution of ammonia (10 ml, density=0.88 g/cm3) was added. The mixture was stirred for 20 minutes, diluted with iced water (500 ml). The methylene chloride phase was removed and the aqueous phase extracted with methylene chloride (2×150 ml). The organic extracts were combined, washed with water (2×100 ml), saturated brine (100 ml) and evaporated. The residue was distilled using a short path distillation apparatus (furnace temperature 120° C./0.08 bar) to give 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane (11.6 g); NMR(CDCl3): 2.34(6H,s), 3.52(3H,s), 3.78(2H,m), 3.96(2H,m) and 7.2(2H,s).
Reaction SMILES: O.[C:2]([NH2:8])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[S:15](F)(F)(=[O:17])=[O:16]>CC(C)=O>[CH3:6][C:4]1[O:5][S:15](=[O:17])(=[O:16])[NH:8][C:2](=[O:7])[CH:3]=1
Reactant: CC(=O)CC(N)=O
Reactant: O=S(=O)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=CC(=O)NS(=O)(=O)O1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Different quantities of water were added to 150 ml of acetone. 10.1 g (0.1 mol) of acetoacetamide and 69 g (0.5 mol) of finely powdered, dry K2CO3 were added to each of these mixtures. 15.3 g (0.15 mol) of sulfuryl fluoride gas were then passed in--initially at room temperature. The temperature of the reaction mixture increased to about 40° C. during this process. The mixture was stirred for a further 2 hours and the product was filtered off with suction. The filter residue contained Acesulfam K, which was found to be identical to a reference sample by thin layer chromatography (silica gel, solvent system: ethyl acetate/glacial acetic acid 5:1). The filter residue was introduced into a mixture of excess hydrochloric acid with ice and extracted with ethyl acetate. The ethyl acetate extract was dried over Na2SO4 and evaporated in vacuo. Crystalline 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide was obtained and this was converted to Acesulfam K with methanolic KOH. The results are collated in the table which follows. In the last experiment listed in the table, the K2CO3 was used as a 50% aqueous solution.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:15]=1[CH2:16][N:17]1[C:25](=[O:26])[N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]2[C:18]1=[N:19][C:20]([NH:34][C:35]1[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:36]=1[NH2:43])=[N:21][CH:22]=2.C(OC)(OC)OC>CO>[F:13][C:14]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:15]=1[CH2:16][N:17]1[C:25](=[O:26])[N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]2[C:18]1=[N:19][C:20]([N:34]1[C:35]3[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:36]=3[N:43]=[CH:2]1)=[N:21][CH:22]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)n1c(=O)n(Cc2c(F)cccc2F)c2nc(Nc3cc(C#N)ccc3N)ncc21
Solvent: COC(OC)OC
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)n1c(=O)n(Cc2c(F)cccc2F)c2nc(-n3cnc4ccc(C#N)cc43)ncc21

Procedure:
A catalytic amount of para-toluene sulfonic acid monohydrate was added to a solution of the above amine intermediate and trimethyl orthoformate (3 mL) in MeOH (10 mL). After 1 hr the crude material was adsorbed onto silica gel and purified by column chromatography (eluted with 1 and 2% MeOH/DCM) to yield tert-Butyl 9-(2,6-difluorobenzyl)-2-(6-cyano-1H-benzo[d]imidazol-1-yl)-8-oxo-8,9-dihydropurine-7-carboxylate (60) (164 mg), MH+=504 and MH+-BOC=404.