Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.C([O-])(=O)C.[Na+].Cl.[NH2:18][OH:19]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH:9]=1)/[CH:7]=[N:18]/[OH:19]
Reactant: Cc1cc(Br)cc(C=O)c1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Br)cc(/C=N/O)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-bromo-2-fluoro-3-methylbenzaldehyde (3.5 g, 16.2 mmol) in ethanol (50.0 mL) were added sodium acetate (2.0 g, 24.3 mmol) and hydroxylamine hydrochloride (1.69 g, 24.3 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated on rotavapour to obtain crude compound, which was washed with water filtered and dried under vacuum to afford the title compound as a white solid: mp 126-127° C.; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 232.10 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9](=O)[NH:8][C:7]=2[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NCCCC2
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a solution of 8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (2 g) in THF (100 mL), lithium aluminum hydride (0.79 g) was added, and the reaction heated to reflux. After stirring for 1 hour, the heat was removed. Water (6 mL) was added followed by NaOH (10%, 15 mL), the flocculated solids removed by filtration, and the eluent concentrated to provide the title compound (1.9 g) as a pale brown oil: 1H NMR (DMSO-d6) δ 6.88 (d, 1H); 6.37 (d, 1H), 6.22 (dd, 1H), 5.14 (s, 1H), 3.62 (s, 3H), 2.90-2.85 (m, 2H), 2.57-2.53 (m, 2H), 1.67-1.59 (m, 2H), 1.52-1.45 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:29])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(OCCCCCCOc2cc(F)c(F)c(F)c2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCCCCCCOc2cc(F)c(F)c(F)c2)cc1
Temperature: 35 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
About 10 g (about 27.148 mmol) of 4-[6-(3,4,5-Trifluoro-phenoxy)-hexyloxy]-benzoic acid was dissolved in about 200 ml of methylene chloride, and then added with about 3.55 g (about 29.862 mmol) of thionyl chloride. The reaction mixture was stirred at about 35° C. for about 6 hours, and the solvent was removed. Through a vacuum drying process, the desired compound was obtained (Yield about 95%).
Reaction SMILES: Cl[C:2](Cl)=[N:3][C:4](=[O:7])[O:5][CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:21]=2)(=[O:19])=[O:18])=[CH:12][C:11]=1[NH2:33].C(N(CC)CC)C>C(Cl)Cl>[F:32][C:27]([F:31])([O:26][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:2]([NH:3][C:4]([O:5][CH3:6])=[O:7])[NH:33][C:11]=3[CH:12]=2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=1)[CH:28]([F:30])[F:29]
Reactant: Nc1ccc(OS(=O)(=O)c2cccc(OC(F)(F)C(F)F)c2)cc1N
Reactant: COC(=O)N=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3cccc(OC(F)(F)C(F)F)c3)cc2[nH]1
Reaction time: 1 h

Procedure:
A solution of 15.6 g of methyl N-dichloromethylenecarbamate in 50 ml of methylene chloride is added slowly, with stirring, to a mixture of 38 g of 1,2-diamino-4-[3-(1,1,2,2-tetrafluoroethoxy)phenylsulfonyloxy]benzene (see Example 2), 20.2 g of triethylamine and 300 ml of methylene chloride at a temperature of about 20° C. The mixture is stirred for one hour and the precipitate is filtered off with suction and washed with diisopropyl ether. For purification, it is recrystallized from methanol, melting point 186° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[N:9][NH:8][C:7]=12.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2=[N:8][N:9]([CH:12]([F:17])[F:16])[CH:10]=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2cn[nH]c12
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)n1cc2ccnc(Cl)c2n1
Temperature: 95 °C
Yield: 21.3 %

Procedure:
A mixture of 7-chloro-1H-pyrazolo[3,4-c]pyridine (4.99 g, 32.5 mmol), sodium chlorodifluoroacetate (14.86 g, 97 mmol), and cesium carbonate (40.2 g, 123 mmol) in DMF (81 ml) was heated at 95° C. for 4 h. The reaction was allowed to cool to rt and the solids were filtered. The filtrate was diluted with water and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (100 g), eluting with a gradient of 5% to 60% EtOAc in hexane, to provide a white solid (1.4117 g, 6.93 mmol, 21.34% yield). MS m/z=203.9 [M+H]+. Calculated for C7H4ClF2N3: 203.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:12]O>>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[NH2:1]
Reactant: Nc1ncccc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1cccnc1N
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The mixture of 138 mg of 2-aminonicotinic acid and 6 mL of hydrochloric acid-methanol solution was stirred overnight in a sealed-tube at 90° C. The reaction mixture was concentrated under reduced pressure, the residue was added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure, to obtain 106 mg of 2-aminonicotinic acid methylester [25-1]. The obtained compound [25-1] was used in the subsequent reaction without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:26]([NH2:28])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[C:10]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>[I-].[K+].CN(C)C=O>[Cl:25][C:21]1[CH:20]=[C:19]([C:17]2[N:18]=[C:14]([N:11]3[C:10]4[CH:29]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH:7]=[CH:8][C:9]=4[N:13]=[CH:12]3)[S:15][C:16]=2[C:26]([NH2:28])=[O:27])[CH:24]=[CH:23][CH:22]=1
Reactant: C1CCNC1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCCl)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCN4CCCC4)cc32)nc1-c1cccc(Cl)c1
Reaction time: 6 h
Yield: 74.7 %

Procedure:
A mixture of 0.043 g (0.1 mmole) of 2-[6-(3-chloro-propoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.34a), 1 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.025 mL (0.3 mmole) of pyrrolidine was stirred at 100 degrees for 6 hours. The mixture was concentrated under reduced pressure, and diluted with 20 mL of water. The precipitate was collected by filtration and the solid triturated with diethyl ether to give 0.036 g of 4-(3-chloro-phenyl)-2-[6-(3-pyrrolidin-1-yl-propoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.34) as a white solid. MH+/Z=482
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH3:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:15](Br)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([O:1][CH2:17][C:16]#[CH:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#CCBr
Reactant: COCc1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(COC)c1C(=O)OC

Procedure:
A mixture of methyl 2-hydroxy-6-methoxymethylbenzoate (Intermediate 11, 1.46 g), propargyl bromide (80% solution in toluene, 1.24 mL) and potassium carbonate (1.55 g) in acetone (50 mL) was stirred and heated at reflux for 2 hours. Further propargyl bromide (80% solution in toluene, 0.9 mL) was added and the mixture was stirred and heated at reflux for 2 hours. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 0-30% to give methyl 2-methoxymethyl-6-propargyloxybenzoate (1.34 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Li])CCC.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.CCCCCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N1CCN([Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 20 g of 1-ethoxycarbonylpiperazine in 400 ml dry tetrahydrofuran is cooled to -65° and 61.5 ml of 2.1M solution of n-butyllithium in hexane is added dropwise over a period of 15 minutes. The mixture is stirred for 15 minutes and a solution of 16.44 ml of chlorotrimethylsilane in 68 ml of tetrahydrofuran is added dropwise over a period of 15 minutes. The mixture is then allowed to warm up to room temperature overnight and evaporated to dryness. Ethyl ether is added, the solids are filtered off, the filtrate is evaporated to dryness and the residue is distilled to give 1-ethoxycarbonyl-4-trimethylsilylpiperazine, b.p. 102°-107°/0.1 mm/Hg.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:13](=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c(CCCl)n[nH]c2ccccc12
Product: ClCCc1nnc2ccccc2c1Cl

Procedure:
3-(2-Chloroethyl)-4-oxo-(1H)-cinnoline (9 g, 0.043 mol) and phosphorus oxychloride (90 ml) were heated under reflux for 1 hour. After allowing to cool, the excess phosphorus oxychloride was evaporated under reduced pressure and the residue was poured onto ice (100 g), basified with concentrated ammonia solution, and extracted with chloroform (3×100 ml). The chloroform extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure to give a solid, 8.00 g. Recrystallization from diethyl ether gave the title compound, m.p. 81-82°.
Reaction SMILES: CC(C)=O.[C:5]1(=O)[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH:10]=[CH:9][CH:8]=[C:7]3[C:6]1=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[NH2:29])[C:23]([OH:25])=[O:24]>CN(C)C=O>[CH:8]1[C:7]2[C:6]3[C:5]([C:15]4[C:16]=2[C:11]([CH:12]=[CH:13][CH:14]=4)=[CH:10][CH:9]=1)=[N:19][C:20]1[C:28](=[CH:27][CH:26]=[C:22]([C:23]([OH:25])=[O:24])[CH:21]=1)[N:29]=3
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2nc3c(nc2c1)-c1cccc2cccc-3c12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
500 mL of dimethylformaldehyde was added to a mixture of 10 g of purified acenaphthenequinone and 84 g of 3,4-diaminobenzoic acid. The reactant continued to be stirred at room temperature for 21 hours. The precipitate was filtered to obtain a crude composition. This crude composition was dissolved in heated dimethylformamide, filtered again and purified by washing in dimethylformamide and water.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:31][CH2:30]1>CS(C)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: O=C(N[C@@H]1CCCNCC1)OCc1ccccc1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Solvent: CS(C)=O
Product: O=C(N[C@@H]1CCCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1)OCc1ccccc1
Temperature: 95 °C

Procedure:
A solution containing 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (0.075 g, 0.20 mmol) and (R)-benzyl azepan-4-ylcarbamate (0.298 g, 1.20 mmol) in Dimethyl sulfoxide (1.20 mL) was heated at 95° C. for 18 h. The reaction was quenched with water and then extracted with EtOAc 2×. The combined organic layer was dried with Na2SO4, filtered and concentrated. The crude product was dried under high vacuum overnight to give benzyl (4R)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate which was dissolved in Methylene chloride (2.56 mL) at −10° C. and treated with slowly with 1.00 M of Boron tribromide in Methylene chloride (0.600 mL). The reaction was stirred at RT for 7 h. The mixture was concentrated. The crude product was diluted in water and washed with EtOAc. The aqueous layer was basified to pH 11 then extracted with EtOAc. The combined organic layers was dried Na2SO4, filtered, and concentrated. The crude product was submitted for rHPLC to give 249 (21 mg, 27% yield). ESI MS m/z=386.1 (M+1). 1H NMR (500 MHz, DMSO) δ 9.21 (d, J=12.7 Hz, 2H), 8.96 (s, 1H), 8.59 (d, J=3.8 Hz, 1H), 8.38 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.58-7.51 (m, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H), 4.00-3.78 (m, 2H), 3.76-3.57 (m, 2H), 2.89 (s, 1H), 2.00 (d, J=30.7 Hz, 2H), 1.85-1.55 (m, 3H), 1.44-1.31 (m, 1H)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C@@H:5]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][C@H:4]2[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:3]1[C:2](=[O:1])[CH2:7][O:6][C@@H:5]2[CH2:8][NH:9][CH2:10][CH2:11][C@@H:4]12
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2NC(=O)CO[C@@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CO[C@@H]2CNCC[C@H]2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 249C (70.0 mg, 0.0.27 mmol) in 1 mL of CH2Cl2 at room temperature was added TFA (2.00 mL, 25.9 mmol). The mixture was stirred at room temperature for 1 hr and concentrated in vacuo to give crude 249D. This material was mixed with DMA to make a 2 mL stock solution and was used as is in next step reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: COC(=O)c1cncc(-c2cccc(OC(F)(F)F)c2)c1

Procedure:
2.61 g (12.09 mmol) of methyl 5-bromonicotinate and 2.49 g (12.09 mmol) of 3-(trifluoromethoxy)phenylboronic acid were reacted according to the General Method 1A. Yield: 2.44 g (68% of theory)
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH2:6])[CH:5]=1.CC([O-])(C)C.[K+].F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Br:22])[CH:15]=1.OS([O-])(=O)=O.[K+]>CS(C)=O>[N:1]1[N:2]=[CH:3][N:4]([NH:6][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Br:22])[CH:15]=2)[CH:5]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: Nn1cnnc1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Nn2cnnc2)cc1Br
Reaction time: 1 h

Procedure:
To a solution of 4H-1,2,4-triazol-4-amine (4.204 g, 50.0 mmol) in DMSO (50 mL) was added KOtBu (5.51 g, 50.0 mmol). The mixture was stirred for 0.5 hours at room temperature before 4-fluoro-2-bromobenzonitrile (5.00 g, 25.0 mmol) was added and stirring was continued for 1 hour. The mixture was poured into crushed ice and neutralized with 2M KHSO4 solution. The precipitate was filtered off and recrystallised from MeOH to give CAB05094 (4.82 g, 73%) as a light yellow crystalline solid. Mp. 234-236° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.66 (dd, J=8.6, 2.4 Hz, 1H), 6.79 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 8.86 (s, 2H), 10.45 (s, 1H); 13C NMR (100.6 MHz, DMSO-d6) δ 105.0, 111.5, 115.4, 117.8, 126.0, 136.2, 143.9, 151.8; LRMS (APCI−): m/z 261.8 (100%, [C9H579BrN5]−), 263.8 (90%, [C9H581BrN5]−); HRMS (ES+) calcd for C9H779BrN5 [M+H]+: 263.9879. found 263.9870;
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1.[OH:16][C:17]([CH3:50])([CH3:49])[CH2:18][C@@:19]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:24][C:23](=[O:25])[N:22]([C@H:26]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH3:27])[CH2:21][CH2:20]1>CN(C)C=O>[CH:13]1([N:11]2[CH:12]=[C:8]([C:31]3[CH:30]=[CH:29][C:28]([C@@H:26]([N:22]4[CH2:21][CH2:20][C@:19]([CH2:18][C:17]([OH:16])([CH3:49])[CH3:50])([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[O:24][C:23]4=[O:25])[CH3:27])=[CH:33][CH:32]=3)[CH:9]=[N:10]2)[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)n1cc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2cnn(C3CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2 M aqueous Na2CO3 solution (0.37 mL) was added to a solution of 4-bromo-1-isopropyl-1H-pyrazole (0.15 g) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.35 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (20 mg) was added. The mixture was heated to 90° C. and stirred at this temperature for 2 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (tert-butyl methyl ether/dichloromethane/NH4OH 96:4:0.1->94:6:0.1) to afford the title compound as a solid. Yield: 0.18 g (55% of theory); Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1O
Yield: 100.1 %

Procedure:
2-methyl-3-nitrophenol (25 g, 0.163 mol) was dissolved in 170 ml of absolute ethanol in a 1 l Parr hydrogenation flask. The flask was purged with nitrogen. 10% palladium on charcoal (1.73 g, 1.6 mmol) was added and the mixture was hydrogenated (40 psi H2) for 1.5 hr in a Parr apparatus. The flask was evacuated and purged with nitrogen. The catalyst was removed by filtration through a Whatman GF/F filter. After removal of the ethanol at reduced pressure, 20.1 g (100% yield) of 2-methyl-3-aminophenol was obtained as a lightly brown solid.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:27][C@@H:24]([O:25][CH3:26])[C@H:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:22]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:21]1[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH2:29]([O:28][C@@H:23]1[C@@H:22]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:21]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:20]([CH2:19][OH:18])[O:27][C@H:24]1[O:25][CH3:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a stirred solution of methyl 6-O-tert-butyldiphenylsilyl-2,3,4-tri-O-benzyl-β-D-glucopyranoside(2.81 g, 3.98 mmol) in dry THF (40 ml, 0.1M) at room temperature was added tetrabutyl ammonium fluoride (4.37 ml, 4.37 mmol, 1M solution in THF). After stirring for 3 hours, the reaction solution was diluted with ethyl acetate (300 ml) and washed with water (1×100 ml) and saturated aqueous NaCl (1×100 ml), and dried with magnesium sulfate. Concentration and flash chromatography (silica, 50% ether in petroleum ether) provided pure target compound (1.62 g, 88%) as a white solid.
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:14][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCCc2ccccc21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ClC1CCCc2ccccc21
Reaction time: 2 h

Procedure:
One hundred grams of 1,2,3,4-tetrahydro-1-naphthol were dissolved in 1 liter of chloroform and 53.9 ml of pyridine. The mixture was cooled with an external ice bath and 98.6 ml of thionyl chloride were added over a 1 hour period. The reaction mixture was stirred an additional 2 hours with cooling, concentrated in vacuo, and the residue taken up in 1 liter of methylene chloride. The methylene chloride solution was washed with water, a 5% sodium bicarbonate solution, water again, dried over sodium sulfate, and evaporated to dryness to provide the desired intermediate 1,2,3,4-tetrahydro-1-chloronaphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:15](Br)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)Br
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Yield: 77 %

Procedure:
20 g of 4-bromo-4'-hydroxybiphenyl, 12 g of isopropyl bromide, 45 g of potassium carbonate and 200 ml of N,N'-dimethylformamide are reacted in an analogous manner to Example 1(a) to give 18 g of 4-bromo-4'-(isopropoxy)biphenyl.
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C:21]3[CH:26]=[CH:25][C:24]([O:27]CC4C=CC=CC=4)=[CH:23][C:22]=3[Cl:35])=[CH:15][CH:14]=2)=[O:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[Cl:35])=[CH:15][CH:14]=2)=[O:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(OCc4ccccc4)cc3Cl)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(O)cc3Cl)cc2)cc1
Yield: 80 %

Procedure:
To 25 mL of dehydrated ethanol, 2.5 g (4.7 mmol) of 4-benzyloxy-2-chloro-benzoic acid 4-(4-pentyl-phenoxycarbonyl)-phenyl ester, 20 mL of cyclohexene, and 0.13 g of palladium hydroxide/carbon were added. Then, the mixture was refluxed for 12 hours under argon. The resulting reaction mixture was filtered, and the filtered liquid was concentrated. The residue was recrystallized from hexane/ethyl acetate. As a result, 1.65 g of a white solid was obtained.