Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][CH2:5][CH:6]([NH2:16])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[CH2:34][O:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[CH2:19]([O:18][CH2:17][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:16][C:37](=[O:38])[CH2:36][O:35][CH2:34][C:33](=[O:40])[NH:1]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(CNCC(N)COCc1ccccc1)COCc1ccccc1
Reactant: O=C(Cl)COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1COCC(=O)NC(COCc2ccccc2)CNCC(COCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,5-diamino-1,5-dibenzyloxymethyl-3-aza-pentane (0.57 g, 1.7 mmol) (Example 6(d)) and triethylamine (0.34 g, 3.4 mmol) in dichloromethane (10 ml) and a solution of diglycolic acid dichloride (0.29 g, 1.7 mmol) in dichloromethane (10 ml) were added simultaneously over 2.5 hours to vigorously stirred dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature overnight, washed with water (2×30 ml), dried with sodium sulphate and evaporated. Yield 0.59 g (78%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].[H-].[Na+]>CN(C)C=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
After adding 4,6-dichloropyrimidine (750 mg) to a suspension of 4-nitrophenol (700 mg) and sodium hydride (60%) (200 mg) in dimethylformamide (13 ml) at 0° C., the mixture was heated and stirred at 80° C. for 1.5 hours. The reaction solution was poured into saturated saline and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The obtained residue was passed through an NH silica gel column (Fuji Silicia Chemical), eluted with a solvent (ethyl acetate-hexane=1-4) and concentrated to obtain 700 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:7]2O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[CH:7]2
Reactant: OC1c2cccc(F)c2CCC1CCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cccc2c1CCC(CCN1CCCC1)=C2
Yield: 67.6 %

Procedure:
To a solution of 5-fluoro-1,2,3,4-tetrahydro-2-[2-(1-pyrrolidinyl)ethyl]-1-naphthalenol (20.0 g) in toluene (250 ml) was added p-toluenesulfonic acid. monohydrate (16.2 g), and the mixture was refluxed overnight. After cooling, the reaction solution was washed successively with 1N aqueous sodium hydroxide solution, water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate=5:1), and the fractions containing the desired compound were combined, concentrated under reduced pressure to give the desired compound (12.6 g), as an oily product.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:31](Br)[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:31][C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:33])=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCC(=O)c5ccccc5)cc4)cc3)n(C)c(=O)c12
Yield: 59 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (413 mg), phenacyl bromide (315 mg) and potassium carbonate (436 mg) in DMF (7 ml) was stirred at room temperature for 15 hours. This reaction mixture was concentrated and the residue was dissolved in chloroform, washed with water, dried, and concentrated. The residue was recrystallized from chloroform-ethyl acetate to provide the title compound as colorless solid (313 mg).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9](=[O:11])[CH3:10])[C:5]([O:7][CH3:8])=[O:6].[I-].[Na+].C(N(CC)CC)C.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[Si:25]([O:11][C:9](=[CH2:10])[C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH3:8])=[O:6])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON=C(C(C)=O)C(=O)OC
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(O[Si](C)(C)C(C)(C)C)C(=NOC)C(=O)OC

Procedure:
In 20 ml of acetonitrile were dissolved 795 mg of methyl 2-methoxyimino-3-oxobutyrate and 2.25 g of sodium iodide, followed by addition of 2.1 ml of triethylamine. Then, a solution of 1.13 g tert-butyldimethylchlorosilane in 10 ml acetonitrile was added dropwise and the mixture was refluxed for 6.5 hours. The reaction mixture was concentrated under reduced pressure and 20 ml of hexane and 20 ml of water were added to dissolve the residue. The organic layer was separated, washed with 20 ml of 5% aqueous sodium hydrogen carbonate solution, 20 ml of 1N hydrochloric acid and 20 ml of water in the order mentioned, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column and elution was carried out with 100 ml of hexane-ether (5:1, v/v). The eluate was concentrated under reduced pressure to give methyl 3-tert-butyldimethylsilyloxy-2-methoxyimino-3-butenoate as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1(CN)CC1.C([N:34]([CH:37]([CH3:39])[CH3:38])[CH2:35]C)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH:37]1[CH2:38][CH2:39]1)[CH3:35])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: NCC1CC1
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N(C)C2CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, N-cyclopropylmethylamine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.33 minutes; C21H20Cl2N4O2 (431.32); mass spectrum: (M−H)−=430/432/434 (chlorine isotope).
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:27]([OH:29])[CH3:28])[C:14]([NH:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[O:26][C:14]([C@H:13]([NH:12][C:6]3[C:7]4[CH:11]=[CH:10][S:9][C:8]=4[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C@@H:27]([OH:29])[CH3:28])=[N:16][N:17]=2)=[CH:24][CH:23]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
To a solution of N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-fluorobenzohydrazide (0.53 g, 1.29 mmol) in THF (90 mL) was added PS-BEMP (1.76 g, 3.87 mmol, ˜2.2 mmol/g) and p-TsCl (265 mg, 1.39 mmol) at room temperature. The mixture was stirred at room temperature for 8 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (139 mg, 27%) and the dehydration product 4-(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (8 mg, 2%). Title compound: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.03 (dd, J=5.3, 8.8 Hz, 2H), 7.88 (d, J=5.7 Hz, 1H), 7.73 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.32 (t, J=8.8 Hz, 2H), 6.83 (d, J=8.2 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 5.20 (dd, J=4.7, 8.4 Hz, 1H), 4.78 (b, 1H), 4.63 (m, 1H), 1.41 (d, J=6.4 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.11 (dd, J=5.3, 8.6 Hz, 2H), 7.96 (d, J=5.6 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.37 (t, J=8.6 Hz, 2H), 7.01 (q, J=7.1 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 1.93 (d, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Br)n1
Product: CC(=O)Nc1cccc(Br)n1
Yield: 68 %

Procedure:
20 g (0.116 mole) of 2-amino-6-bromopyridine was dissolved in 140 ml. acetic anhydride and heated at 70° C for 45 minutes. 2-Acetamido-6-bromopyridine was isolated by filtration as white flakes, m.p.=159.2°-160.0° C, in 68% yield. The excess acetic anhydride present in the reaction mixture was hydrolyzed by the addition of 300 ml. water to the filtrate; the reaction mixture was agitated and an additional 27% yield of 2-acetamido-6-bromopyridine was collected by filtration, giving a 95% yield of reaction product, 2-acetamido-6-bromopyridine which was recrystallized from benzene.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Br)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1COc1ccc(C(C)=O)cc1
Yield: 73.9 %

Procedure:
3.0 g (0.022 mol) of 4-hydroxyacetophenone and 6.0 g (0.021 mol) of methyl 2-bromomethylphenylglyoxylate O-methyloxime are dissolved in 30 ml of dimethylformamide, and 5.5 g (0.040 mol) of potassium carbonate are added. The mixture is stirred at room temperature for 24 hours, hydrolyzed with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 5.3 g (78%) of methyl 2-(4-acetylphenoxymethyl)phenylglyoxylate O-methyloxime are obtained as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH3:11])=[N:8][C:7]=2[CH:12]=1.[K].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>CN(C=O)C>[CH3:11][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])=[CH:12][C:7]=2[N:8]=1
Reactant: Cc1nc2cc(CBr)ccc2o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc(CN3C(=O)c4ccccc4C3=O)ccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(bromomethyl)-2-methylbenzo[d]oxazole (400 mg; 1.76 mmol) in anh. DMF (2 ml) was treated portionwise with phthalimide potassium salt (327 mg; 1.76 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 18 h. Water was added, and the resulting precipitate was collected by filtration, and washed with water. Drying under HV afforded 2-((2-methylbenzo[d]oxazol-5-yl)methyl)isoindoline-1,3-dione as a brown solid. LC-MS (conditions E): tR=0.66 min.; [M+H]+: 293.15 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.C(N(CC)C1C=CC=CC=1)C.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=O>C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:24]=[C:25]([C:26]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc3ccccc3[nH]2)c1
Temperature: 100 °C

Procedure:
The intermediate 2-(3-methylphenyl)-benzimidazole was prepared by first mixing reacting 1-amino-2-nitrobenzene (8.50 g, 61.54 mmol) with toluene (180 ml) and heating to 100° C. To this mixture was then added 20 ml of N,N-diethylaniline and the reaction vessel was placed under a nitrogen atmosphere. To this solution was then added 3-methylbenzoyl chloride (24 ml, 132 mmol) and this mixture was then stirred overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of (2R)-(4-amino-phenyl)-tert-butoxycarbonylamino-acetic acid (100 mg, 0.376 mmol) in dichloromethane (2 mL) was added pyridine (36 μL, 0.45 mmol) and acetic anhydride (42 μL, 0.44 mmol) and the mixture stirred at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromethane, washed with 1M aqueous citric acid solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 0 to 10% v/v methanol in dichloromethane to afford (2R)-(4-acetylamino-phenyl)-tert-butoxycarbonylamino-acetic acid as a yellow solid (59 mg, 51%).
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:24])[N:7]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:44]([Si:47]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[O:48][CH2:49][CH2:50]O)([CH3:46])[CH3:45].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]([C:4]1[CH:14]=[C:13]([O:15][CH2:50][CH2:49][O:48][Si:47]([CH:52]([CH3:53])[CH3:54])([CH:44]([CH3:46])[CH3:45])[CH:55]([CH3:56])[CH3:57])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:24])[N:7]([CH2:16][S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: CC(C)[Si](OCCO)(C(C)C)C(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of 4-isopropyl-6-hydroxy-2-phenylthiomethylsaccharin.(2.0 g, 5.509 mmol) in THF (35 mL) containing triphenylphosphine (1.59 g, 6.06mmol) and 2-(triisopropylsilyloxy) ethanol (1.13 g, 6.0 mmol) at room temperature was added diethylazodicarboxylate (1.04 mL, 6.6 mmol). The mixture was stirred overnight (16 hours), the solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 10% ethyl acetate/hexane to afford 2.66 g (86%)of 4-isopropyl-6-[2-(triisopropylsilyloxy)ethoxy]-2-phenylthiomethylsaccharin as an oil
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:32])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:31])[C:22](=[O:30])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[O:13].C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1)CCC>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:41]1[CH:42]=[CH:43][N:44]=[CH:45][C:40]=1[C:2]1[N:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:32])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:31])[C:22](=[O:30])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCN(c4c(-c5ccccc5)c(=O)c4=O)CC3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cnc(-c2cnccn2)c2[nH]cc(C(=O)C(=O)N3CCN(c4c(-c5ccccc5)c(=O)c4=O)CC3)c12
Temperature: 90 °C
Yield: 6.7 %

Procedure:
A solution of 3-[4-[2-(7-bromo-4-methoxy-6-azaindol-3-yl)-2-oxoacetyl]piperazin-1-yl]-4-phenyl-cyclobut-3-ene-1,2-dione (0.030 g, 0.057 mmol) and 2-tributylstannylpyrazine (0.025 g, 0.069 mmol) in dioxane (3 mL) was purged with Ar and then Pd(PPh3)4 (0.020 g, 0.017 mmol) was added, the reactor was sealed and the mixture was heated at 90° C. for 16 h. The cooled reaction mixture was diluted with EtOAc, washed (1M aqueous KF, brine), dried (Na2SO4) and evaporated to give a solid. Purification of this material by preparative HPLC (C-18/10-90% MeCN-5 mmolar aqueous NH4OAc) gave the title compound (0.002 g, 7%) as a yellow solid:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:26](=[O:27])[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:29])([F:17])[F:30])=[CH:24][CH:23]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 2-[4-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.44 (d, J=7.1 Hz, 1H), 8.14 (td, J=7.7, 1.4 Hz, 1H), 8.01-8.10 (m, 2H), 7.70-7.76 (m, 2H), 7.60-7.63 (m, 2H), 3.86-3.87 (bs, 2H); MS (ESI) m/z 416 (M+H)+.
Reaction SMILES: B(F)(F)F.O(CC)CC.[CH:10]1([CH:16]([OH:18])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:19][C:20]1([O:23][CH2:22]1)[CH3:21]>C1CCCCC1>[CH:10]1([CH:16]([O:18][C:20]([CH3:21])([CH3:19])[CH2:22][OH:23])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC1(C)CO1
Reactant: CC(O)C1CCCCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(OC(C)(C)CO)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
BF3—OEt2 (2.0 ml) is added dropwise to a solution of 1-cyclohexylethanol (16.6 g, 127.0 mmol) and isobutylene oxide (2.9 g, 40.0 mmol) in cyclohexane (20 ml) that has been cooled to 0° C. The reaction mixture is now stirred at 0° C. for a further 30 minutes, and further, BF3—OEt2 (2.0 ml) is then added. After a further 3 hours at 0° C., the cooling is removed and the reaction solution is washed once with 1 M NaOH (15 ml). The organic phase is dried over Na2SO4, filtered off and freed from solvent in a rotary evaporator. The 1-cyclohexylethanol that has not completely reacted is removed from the crude product; thus, obtained by means of bulb tube distillation (BTD) and 5.3 g crude 2-(1-cyclohexylethoxy)-2-methyl-1-propanol is obtained which has a GC content of 75% and can be used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:11]([C:12]([NH2:14])=O)=[CH:10][CH:9]=[CH:8][N:7]2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>ClCCl>[C:1]([C:4]1[N:5]=[C:6]2[C:11]([C:12]#[N:14])=[CH:10][CH:9]=[CH:8][N:7]2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc2c(C(N)=O)cccn2c1-c1cccc(F)c1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1nc2c(C#N)cccn2c1-c1cccc(F)c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
A solution of 2-acetyl-3-(3-fluorophenyl)imidazo[1,2-a]pyridine-8-carboxamide (0.24 g, 0.81 mmol) in dichloromethane (12 mL) was treated with triethylamine (0.34 mL, 2.4 mmol) and cooled to −15° C. The reaction mixture was treated with trichloroacetyl chloride (0.18 mL, 1.6 mmol) dropwise and stirred between −15° C. to −10° C. for 1 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (2×50 mL) and brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (0.23 g, quantitative). This material was used without further purification. LCMS for C16H11FN3O (M+H)+: m/z=280.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[N:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+:30]1C=CC=CC=1.C(OCC)C>ClCCl>[NH2:30][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: c1cc[nH+]cc1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(CO)cc2)n1
Agent: O=[Cr](=O)([O-])Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(C=O)cc2)n1
Reaction time: 6 h
Yield: 6.7 %

Procedure:
To a suspension of the title compound of Example 41 (375 mg, 1.1 mmol) in dichloromethane (100 ml) was added pyridinium chlorochromate (810 mg, 2.7 mmol) and crushed molecular sieves (1.25 g, 3A). After stirring for 6 hours, diethyl ether (150 ml) was added and the mixture was filtered through a pad of silica gel under suction. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3 followed by 1:2 followed by 1:1) to provide the title compound (25 mg, 7% yield). 1H NMR (DMSO-d6) 10.10 (s, 1H), 9.86 (s, 1H), 8.07 (d, J=8.6 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.79 (s, 1H), 7.43 (m, 2H), 7.34 (m, 2H), 2.53 (s, 3H).