Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:9][C:7]1[CH:8]=[C:3]([CH:4]=[C:5]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][NH:11]2)[CH:6]=1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1c1cc(F)cc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(F)cc([C@H]2C[C@H](F)CN2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4S)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidine-1-carboxylate (I-14) (0.6 g, 1.95 mmol) in DCM (2 mL) at room temperature was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours. All the solvents were removed under reduced pressure. The crude was diluted with EtOAc, washed with aqueous NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated to yield 3-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile (I-15). 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1 H), 7.43-7.37 (m, 1 H), 7.24-7.20 (m, 1 H), 5.28 (dt, J=3.6, 53.6 Hz, 1 H), 4.57 (dd, J=6.4, 9.6 Hz, 1 H), 3.44-3.18 (m, 2 H), 2.63-2.50 (m, 1 H), 1.72 (dddd, J=4.4, 10.0, 14.4, 39.6 Hz, 1H). MS m/z 209.1 (M+1)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@:9]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C>ClCCl>[C:1]([NH:8][C@@:9]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](N)(C(=O)OCC)[C@@H]21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](NC(C)=O)(C(=O)OCC)[C@@H]21
Reaction time: 2 h

Procedure:
Add acetic acid anhydride (5 mL, 50.8 mmol) to a stirred solution of diethyl (1S,2S,5R,6R)-2-amino-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (7.2 g, 28.2 mmol) and triethylamine (7.9 mL, 56.4 mmol) in dry dichloromethane (72 mL) at room temperature. After 2 hours, quench with water (100 mL) and stir vigorously for 20 minutes. Separate the dichloromethane layer via a hydrophobic frit and evaporate to a light brown oil (9.6 g). Purify by flash chromatography eluting with ethyl acetate:iso-hexane (70:30 to 90:10) to give the title compound as a pale yellow glass foaming on drying (6.53 g, 22 mmol). MS (m/z): 298 (M+1), 320 (M+23), 617 (2M+23).
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:8]=[C:9]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:10](COCC[Si](C)(C)C)[C:11]=1[Br:12].[Cl:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C1COCC1.O=[Mn]=O>[Br:12][C:11]1[N:10]=[C:9]([C:21]([CH3:22])([CH3:23])[CH3:24])[NH:8][C:7]=1[C:28]1[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)c1nc(Br)c(Br)n1COCC[Si](C)(C)C
Agent: O=[Mn]=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(Br)c(-c2ccnc(Cl)n2)[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
n-BuLi (1.5 M in hexane, 40 mL, 60 mmol) was added dropwise to a cooled solution of 4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (23.6 g, 57.2 mmol) in anhydrous THF (250 mL) at −78° C. After 30 min at −78° C., a solution of 2-chloropyrimidine (7.21 g, 63.0 mmol) in anhydrous THF (2 mL) was added dropwise and the reaction was stirred at −78° C. for 1 h. The reaction was quenched by the addition of saturated aqueous NH4Cl solution and allowed to warm to rt. The mixture was partitioned with EtOAc and the layers separated. The aqueous portion was extracted with EtOAc (3×) and the combine organic layers were washed with water, brine, dried (MgSO4), and concentrated. The resulting residue was dissolved in dry EtOAc, treated with MnO2 (5.2 g, 60 mmol), and heated to reflux for 3 h. The reaction was allowed to cool to rt and filtered through Celite. The filter cake was washed thoroughly with EtOAc and the combine filtrates were concentrated. The remaining residue was purified by flash chromatography (SiO2, 100:0-90:10 hexanes-EtOAc) to give 10 g (37%) of 4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)-2-chloropyrimidine: LCMS (m/z): 447.10 (MH+), tR=1.30 min. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J=5.3 Hz, 1H), 7.83 (d, J=5.3 Hz, 1H), 5.85 (s, 2H), 3.45 (m, 2H), 0.76 (m, 2H), −0.08 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH:18]=[N:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cc(Cl)ccc1OCc1ccccc1
Reactant: Nc1cccnc1
Solvent: ClCCl
Product: Clc1ccc(OCc2ccccc2)c(C=Nc2cccnc2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of pyridin-3-amine (2.13 mmol), 2-(benzyloxy)-5-chlorobenzaldehyde (1.93 mmol) and Mg(ClO4)2 (0.579 mmol) was stirred at 50° C. in dichloromethane (10 mL) for 4 h. After cooling to room temperature, the solution was filtered through 0.45 micron filter and the solvent was evaporated to afford solid. Yield 96%. 1H NMR: 5.16 (s, 2H), 6.97 (d, 1H, J=8.96 Hz), 7.28-7.40 (m, 8H), 7.48-7.52 (m, 1H), 8.15 (d, 1H, J=2.70 Hz), 8.45-8.48 (m, 2H).
Reaction SMILES: OCC(CO)([C:9]([O:11]CC)=[O:10])C(OCC)=O.Br.[C:17]([S:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])(C)C.[K]>>[CH3:23][C:22]([CH:25]([C:22]([S:21][CH2:17][CH3:20])([CH3:24])[CH3:23])[C:9]([OH:11])=[O:10])([S:21][CH2:17][CH3:20])[CH3:24]
Reactant: CC(C)(C)SC(C)(C)C
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Agent: Br
Agent: [K]
Product: CCSC(C)(C)C(C(=O)O)C(C)(C)SCC

Procedure:
Synthesis analogous to Example 13. The bis-(1,1-dimethyl-ethylthiomethyl)-acetic acid was synthesized from diethyl bis-(hydroxymethyl)-malonate by reaction with hydrogen bromide and subsequent replacement of the resulting β,β'-dibromoisobutyric acid with potassium tert.-butylsulfide.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4](=[O:5])[NH2:6])=[C:2]([OH:1])[CH:10]=1)[CH3:26]
Reactant: CCOC(=O)CCCBr
Reactant: NC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(N)=O)c(O)c1
Temperature: 70 °C

Procedure:
To 2,4-dihydroxybenzamide (16.5 g, 108.3 mmol) in DMF (100 mL) was added Cs2CO3 (39.0 g, 119.1 mmol) followed by ethyl 4-bromobutyrate (17.0 mL, 119.1 mmol). The mixture was heated to 70° C. for 2 h, cooled, diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate, concentrated, and chomatographed over silica gel (60% EtOAc/hexane) to a white solid (4.2 g, 15%). MS [M+H]− 267.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:29])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22]O)=[C:20]([CH3:24])[N:19]=[C:18]1[CH2:25][N:26]([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]1(=[O:59])[NH:53][C:52](=[O:54])[C:51]2=[CH:55][CH:56]=[CH:57][CH:58]=[C:50]12.N(C(OCC)=O)=NC(OCC)=O>>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[C:21]([CH2:22][N:53]3[C:49](=[O:59])[C:50]4=[CH:58][CH:57]=[CH:56][CH:55]=[C:51]4[C:52]3=[O:54])=[C:20]([CH3:24])[N:19]=[C:18]2[CH2:25][N:26]([CH3:28])[CH3:27])=[C:10]([C:9](=[O:29])[C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:15]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2c(F)cccc2F)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2c(F)cccc2F)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 2',6'-difluoro-5-chloro-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-chloro-2-(2,6-difluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(N(C(C)C)CC)(C)C.[C:19]1([C@@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:27][C@H:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:26])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C[C@H](N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Cl)nc(Cl)n1)c1ccccc1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
To a solution of cyanuric chloride (25.0 g, 0.135 mol), diisopropylethylamine (17.5 g, 0.135 mol) in THF (500 mL) at 0° C. was added dropwise a solution of (1S)-1-phenylethylamine (16.4 g, 0.135 mol) in THF (100 mL) while maintaining the reaction temperature at or near 0° C. The reaction mixture was allowed to warm to ambient temperature then was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL) and extracted with 1 N HCl (250 mL), H2O (250 mL) and brine (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a white solid (35 g, 96%) MP 146-147° 1H NMR (CDCl3) δ 7.39 (m, 5H), 6.40 (b d, 1H), 5.25 (m, 1H), 1.59 (d, 3H); MS (ESI+) (M+) 269.1 obs.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][NH2:20]>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][N:20]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: NCCc1ccccn1
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCc1ccccn1
Temperature: 100 °C
Yield: 65.9 %

Procedure:
A mixture of phthalic anhydride 4 (5.0 g, 33.7 mmol) and pyridylethylamine (4.04 mL, 33.7 mmol) were heated together at 100° C. for 4 h. The resulting red oil upon cooling to room temperature yielded an off-white solid that was filtered and dried under vacuum to provide 5 as a white solid (5.6 g, 66%).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH:9]2[C:21]2([OH:32])[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)C=CC=CC=1.[H][H]>CO.[Pd]>[OH:32][C:21]1([CH:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CN(Cc3ccccc3)CCN2Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O)(C2CNCCN2)C1
Yield: 94.6 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate (408 mg, 0.93 mmol) in methanol (15 mL) was added 10% palladium on carbon (wet), and the resulting suspension was subjected to an atmosphere of hydrogen for 21 hours. The catalyst was removed by filtration through celite, and the filter cake was rinsed with methanol. The combined filtrate was concentrated to provide 1,1-dimethylethyl 3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate as a brown syrup (227 mg, 0.88 mmol, 95% yield). 1H NMR (400 MHz, CDCl3): 3.94-3.76 (m, 5H), 3.12 (m, 1H), 3.01 (m, 1H), 2.94-2.81 (m, 3H), 2.78-2.70 (m, 2H); MS (EI) for C12H23N3O3: 258 (MH+).
Reaction SMILES: C(I)I.[C:4](=O)([O-])[O-].[K+].[K+].[C:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:28]=[C:27]3[C:22]([C:23]([OH:35])=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([SH:29])=[N:26]3)=[CH:21][C:20]=2[Cl:36])[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>CN(C)C=O>[C:10]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:28]=[C:27]3[C:22]([C:23](=[O:35])[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:25]4[S:29][CH2:4][N:26]43)=[CH:21][C:20]=2[Cl:36])[CH2:17][CH2:18]1)(=[O:12])[CH3:11]
Reactant: CCOC(=O)c1c(S)nc2cc(N3CCN(C(C)=O)CC3)c(Cl)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ICI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCN(C(C)=O)CC4)c(Cl)cc3c1=O)CS2
Yield: 80.6 %

Procedure:
Into 50 ml of N,N-dimethylformamide were placed 2.35 g of methylene iodide and 2.5 g of potassium carbonate and a solution of 3.0 g of ethyl 7-(4-acetyl-1-piperazinyl)-6-chloro-4-hydroxy-2-mercaptoquinoline-3-carboxylate in 30 ml of N,N-dimethylformamide was gradually dropped in with stirring. After that, the mixture was stirred at room temperature for 1 hour, concentrated in vacuo, water was added to the residue, and insoluble crystals were collected by filtration. They were washed with water, dried, and recrystallized from a mixed solvent of ethanol and chloroform to give 2.49 g of colorless powdery crystals, m.p. 266°-268° C. (decompn).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:12]3[NH:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)=[C:12]3[NH:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:7][CH:8]=1)=[O:32]
Reactant: CSc1ccc(-c2nn3c(c2-c2ccncc2)NCCC3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2nn3c(c2-c2ccncc2)NCCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of 2-(4-methylthiophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (190 mg) in dichloromethane (6 ml) was added m-chloroperbenzoic acid (127 mg) under ice cooling. The mixture was stirred at ambient temperature for 30 minutes and diluted with dichloromethane. The solution was washed with an aqueous saturated sodium thiosulfate solution, an aqueous saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained crude solid was recrystallized from a mixture of 2-propanol and ether to give 2-(4-methylsulfinylphenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (168 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]3[CH2:19][O:18]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[N-:20]=[N+:21]=[N-:22].[Na+].[NH4+].[Cl-].O>CCO>[N:20]([CH2:19][CH:17]([OH:18])[CH2:16][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)=[N+:21]=[N-:22]
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21

Procedure:
3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (500 mg, 1.3 mmol), NaN3 (111 mg, 1.7 mmol), NH4Cl (91 mg, 1.7 mmol), were combined in 4 ml of EtOH and 1 ml of H2O and heated to 80° C. overnight. Upon completion, the EtOH was evaporated and the mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine and dried over Na2SO4 and concentrated. The material was used in the next step without further purification.
Reaction SMILES: CCN(CC)CC.[C:8]1([S:14]([C:17]2[C:18]([S:34][CH3:35])=[N:19][N:20]3[C:25]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][C:23](Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCO.[Pd]>[C:8]1([S:14]([C:17]2[C:18]([S:34][CH3:35])=[N:19][N:20]3[C:25]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[CH:24][CH:23]=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CSc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSc1nn2c(N3CCN(C)CC3)ccnc2c1S(=O)(=O)c1ccccc1
Yield: 49.6 %

Procedure:
0.15 g of Pd/C (10%) and 0.3 ml of NEt3 were added to a solution of 0.189 g (0.4 mmol) of 3-benzenesulphonyl-5-chloro-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 30 ml of EtOH and hydrogenated at RT for 12 hrs. The reaction mixture was filtered over Dicalite and the filtrate was evaporated. Chromatography of the residue (SiO2, CH2Cl2/MeOH 20:1) yielded 0.08 g (49%) of 3-benzenesulphonyl-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 107-109°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][O:15][C:16]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:17]=1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:19]([CH2:18][C:17]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:16]=2[O:15][CH3:14])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Yield: 50.4 %

Procedure:
5-Chloro-2,4-difluorobenzenesulfonyl chloride (200 mg, 0.81 mmol), N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (Preparation 106, 255 mg, 0.97 mmol) and pyridine (196 μL, 2.43 mmol) in dichloromethane (3 mL) were stirred at room temperature for 36 hours. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (5 g Varian bond-elut cartridge, heptane/ethyl acetate 100/0 to 70/30) to afford the title compound (193 mg) as a gum.
Reaction SMILES: [Br:1][CH:2]([Si:4](Cl)(Cl)Cl)[CH3:3].[CH3:8][O:9][CH2:10][CH2:11][OH:12].Cl>>[Br:1][CH:2]([Si:4]([O:12][CH2:11][CH2:10][O:9][CH3:8])([O:12][CH2:11][CH2:10][O:9][CH3:8])[O:12][CH2:11][CH2:10][O:9][CH3:8])[CH3:3]
Reactant: COCCO
Reactant: CC(Br)[Si](Cl)(Cl)Cl
Agent: Cl
Product: COCCO[Si](OCCOC)(OCCOC)C(C)Br

Procedure:
One-quarter mole of alpha-bromoethyltrichlorosilane is dissolved in 200 ml. of dry hexane and sparged rapidly with nitrogen. 0.85 moles of the beta-methoxyethanol is added slowly and the resulting mixture is stirred until the HCl evolution ceases. Distillation of the residue yields alpha-bromoethyltris(beta-methoxyethoxy)silane. This produce (0.2 moles) is heated with 0.2 moles of the diacetate ester of dodecyldiethanolamine at 135° C. for 16 hours to yield the desired quaternary ammonium salt.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1)([F:4])[F:3].C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([NH2:23])=[O:16])=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: N
Reactant: O=C(O)C=Cc1ccc(SC(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc(SC(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a suspension of 5.24 g (21.1 mmol) 3-(4-trifluoromethylsulfanyl-phenyl)-acrylic acid in 30.0 ml tetrahydrofuran and 0.3 ml N,N-dimethyl formamide a solution of 2.75 ml (32.0 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 20 min. Stirring was continued at 0-5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 100 ml of a 25% aqueous ammonia solution. After evaporation of the organic solvent, 200 ml water were added and the solution cooled. The precipitated amide was collected, washed with water and n-heptane and dried at 40° C. in vacuo. Yield 4.62 g (86%) 3-(4-trifluoromethylsulfanyl-phenyl)-acrylamide
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.CCOCC.[C:43]([CH:48]([CH:50]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[OH:51])[OH:49])([O:45][CH2:46][CH3:47])=[O:44]>C(=O)([O-])[O-].[K+].[K+]>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:51][CH:50]([CH:48]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[OH:49])[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)OC(C(=O)OCC)C(O)C(=O)OCC)cc1

Procedure:
N-trifluoroacetyl-4-(4-tetradecenylamino)benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solvent evaporated from the combined filtrate and washings to yield a solid residue. After dissolving in aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the diethyl tartrate as a white, crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:7](N)=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[B:10]([OH:12])[OH:11].B(O)O.CC1C=C(C)C=CC=1Br.[N+:25]([O-:28])(O)=[O:26].C(O)(C(F)(F)F)=O.CC1C=C(C)C=CC=1B(O)O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:9])[C:5]([N+:25]([O-:28])=[O:26])=[CH:4][C:3]=1[B:10]([OH:11])[OH:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(B(O)O)c(C)c1N
Agent: Cc1ccc(B(O)O)c(C)c1
Agent: Cc1ccc(Br)c(C)c1
Agent: OBO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c([N+](=O)[O-])cc1B(O)O
Temperature: -40 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Example 40(c) was prepared in a similar manner to that of Example 40(a) except that in step (i) 2,4-dimethyl-3-amino-phenyl boronic acid (prepared as described below) was used in place of m-amino-phenyl boronic acid: 1H NMR (DMSO-d6) δ 8.62 (d, 1H, J=3.78 Hz), 8.32 (d, 1H, J=8.48 Hz), 7.99 (d, 1H, J=16.35 Hz), 7.83 (td, 1H, J=7.68 Hz, J=1.8 Hz), 7.80 (s, 1H), 7.69 (d, 1H, J=7.80 Hz), 7.64 (dd, 1H, J=8.47 Hz, J=1.27 Hz), 7.62 (d, 1H, J=16.36 Hz), 7.29 (m, 1H), 6.94 (s, 1H), 6.64 (s, 1H), 4.87 (bs, 2H), 2.12 (s, 3H), 2.10 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 369, found 369. Anal. Calc'd: C, 74.98; H, 5.47; N, 15.21. Found: C, 73.85; H, 5.56; N, 14.49. The starting material was prepared as follows: 2,4-Diemthylphenyl boronic acid was made in a similar manner as that of Example 24(a), step (vii), except 2,4-dimethyl bromobenzene was used as starting material. 1H NMR (CD3OD) δ 7.13 (d, 1H, J=7.43 Hz), 7.00 (s, 1H), 6.97 (d, 1H. J=7.49 Hz), 2.28 (s, 3H), 2.28 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 151, found 151. To fuming nitric acid (1 ml) cooled to −40° C. was added TFA (1 ml). The resulting mixture was allowed to warm slightly to −35° C. and 2,4-dimethyl phenyl boronic acid (150 mg, 1 mmol) was added in one portion. After 1 h, ice was added and the heterogenous mixture was filtered. The resulting solid was suspended in Et2O and extracted with 3N NaOH (aq) (1 ml) then water (2 ml). The aqueous phase was acidified with 3N HCl (aq) (1 ml) and back extracted with EtOAc (3×5 ml). The pooled organics were washed with brine, dried with Na2SO4 decanted and concentrated to give 2,4-dimethyl-5-nitro-phenyl boronic acid (93 mg, 47%). LCMS (ESI+) [M+H]/z Calc'd 196, found 196. 3-Amino-4,6-dimethylphenyl boronic acid was prepared in a similar as that described for Example 40(b), step (i). 1H NMR (CD3OD)δ 6.83 (s, 2H), 6.64 (s, 1H), 2.17 (s, 3H), 2.13 (s, 3H).