Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:43])[C:32]3[N:36]=[C:35]([C@@H:37]4[CH2:41][CH2:40][CH2:39][O:38]4)[NH:34][C:33]=3[CH:42]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:43])[C:32]6[N:36]=[C:35]([C@@H:37]7[CH2:41][CH2:40][CH2:39][O:38]7)[NH:34][C:33]=6[CH:42]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc([C@@H]6CCCO6)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
63 mg (0.23 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 70 mg (0.21 mmol) (S)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 0.08 mL (0.46 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT and for 2 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.[CH2:13]([NH:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[CH:23][C:22]=1[NH2:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH2:13]([NH:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:24]=[CH:23][C:22]=1[NH:33][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cnc(N2CCOCC2)cc1NCc1ccccc1
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cnc(N3CCOCC3)cc2NCc2ccccc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Propylphosphonic acid anhydride, cyclic trimer (0.356 ml; 0.610 mmol) is added to a mixture of 1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (85.000 mg; 0.508 mmol), N4-Benzyl-6-morpholin-4-yl-pyridine-3,4-diamine E-2.3 (133.000 mg; 0.468 mmol) and triethylamine (0.176 ml; 1.271 mmol) in THF (3.000 ml). The reaction mixture is stirred overnight (16 h) at RT. The reaction is quenched with 1M NaOH (2 ml) and diluted with water, then extracted twice with ethyl acetate. The organic layer is dried over Na2SO4 and concentrated in vacuum. The residue is purified on silica chromatography Combiflash (Column: Redisep Rf, 12 g; gradient: DCM/MeOH=100%/0% to 90%/10%; flow rate=30 ml/min; 28 column volumes; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduce pressure.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].[H-].[Na+].[C:17]([S:20][CH2:21][C@H:22]([CH3:26])[C:23](Cl)=[O:24])(=[O:19])[CH3:18].C(SC[C@@H](C)C(O)=O)(=O)C.S(Cl)(Cl)=O>O1CCCC1>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([C:23](=[O:24])[C@H:22]([CH3:26])[CH2:21][S:20][C:17](=[O:19])[CH3:18])[C:3]1=[O:14]
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Agent: CC(=O)SC[C@@H](C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)SC[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Yield: 44.7 %

Procedure:
1.3 g of tert.-butyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 15 ml of tetrahydro-furan, and 0.35 g of sodium hydride (62% oil dispersion) is added thereto under ice-cooling and stirring. A solution of (2S)-3-acetylthio-2-methylpropionyl chloride (prepared by heating a mixture of 1.5 g of (2S)-3-acetylthio-2-methylpropionic acid and 6 ml of thionyl chloride at 50° C. for 3 hours and then evaporting excess thionyl chloride under reduced pressure) in 5 ml of tetrahydrofuran is added dropwise to the mixture. Then, the mixture is treated in the same manner as described in Example 1-(4). 1.0 g of tert.-butyl (4S)-1-methyl-3-[(2S)-3-acetylthio-2-methylpropionyl]-2-oxoimidazolidine-4-carboxylate is obtained as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].C1(C)C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:27](=[C:9]([C:10](=[O:11])[CH3:12])[C:8]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=CCOC(=O)CC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)C(=[N+]=[N-])C(C)=O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 94.9 %

Procedure:
55.4 ml (0.4 mole - 2 equivalents) of triethylamine were added dropwise to a solution, which had been cooled to 0° C., of 28.43 g (0.2 mole) of allyl acetoacetate and 43.39 g (0.22 mole - 1.1 equivalents) of p-toluenesulphonyl azide in 400 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 3.5 h, then 50 g of kieselguhr were added, evaporation in vacuo was carried out and then chromatography on 400 g of silica gel (toluene:ethyl acetate 96:4). 31.9 g (95%) of the title compound were obtained as a pale yellow oil, Rf: 0.36 (toluene:ethyl acetate 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[I:26]Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:12]=2)=[CH:4][C:3]=1[I:26]
Reactant: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: ClI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (50 mg, 0.15 mmol) [See Ex. 28 above] in glacial acetic acid (5 mL) was added a solution of ICl (24 mg, 0.15 mmol) in glacial acetic acid (1.5 rot,). The resulting mixture was stirred at rt for 1 h, then poured into saturated aqueous Na2S2O5. The pH was adjusted to neutral by the addition of 2.5N NaOH and extracted with EtOAc. The organic extract was concentrated under reduced pressure, and the residue was purified by flash chromatography, eluting with a solvent gradient of 2-10% MeOH/CHCl3. The material that was isolated was recrystallized from Et2O/Hex to afford the title compound: 1H NMR (CDCl3): δ8.42 (d, 2H); 8.18 (d, 1H); 7.68 (dd, 2H); 7.42 (m, 4H); 7.09 (t, 2H); 6.77 (d, 1H).
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1.CN(C)C=O.S(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:20][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccsc2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: ClCc1cc(-c2ccsc2)cs1

Procedure:
100 mg of 2-hydroxymethyl-4-(3-thienyl)thiophene was suspended in 5 ml of chloroform, and with stirring under ice cooling, 2 microliters of dimethylformamide and 80 microliters of thionyl chloride were added. The mixture was stirred for 30 minutes, and neutralized with a saturated aqueous solution of sodium hydrogen carbonate under ice cooling. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the chloroform was evaporated to give 2-chloromethyl-4-(3-thienyl)thiophene as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].N>CN(C)C=O>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 180 °C
Yield: 73.7 %

Procedure:
10.0 g of 4'-bromo-4-biphenylcarboxaldehyde and 5.31 g of copper(I) cyanide were dissolved in 80 ml of dimethylformamide while gassing with argon and the solution was heated to reflux for 15 hours at 180° C. bath temperature. Thereafter, the reaction mixture was poured cautiously into 200 ml of 25 percent ammonia and extracted three times with 200 ml of methylene chloride each time. The organic phases were washed once with 200 ml of 25 percent ammonia and twice with 200 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the yellowish, crystalline residue (8.7 g) on silica gel gave 5.85 g (74%) of 4'-cyano-4-biphenylcarboxaldehyde as slightly yellowish crystals; Rf-value (toluene/ethyl acetate vol. 90:10) 0.27.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:7]([CH:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:17][CH:18]=2)[CH2:9][C:10]([OH:12])=[O:11])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCCOc1ccc(C(N)CC(=O)O)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a stirred solution of sodium carbonate (1.45 g, 13.7 mmol) in 500 mL of water-acetonitrile (1:1, v/v) was added 3-amino-3-(4-propoxyphenyl)propionic acid (3.05 g, 13.7 mmol) as a solid. The mixture was warmed to 30-40° C. to dissolve the solids. The reaction mixture was allowed to cool to room temperature and N-carboethoxyphthalimide (3.00 g, 13.7 mmol) was added and the reaction mixture was stirred for one hour at room temperature. The reaction mixture was then partially concentrated to remove the acetonitrile and the pH of the resulting solution was adjusted to approximately 3 with 4N hydrochloric acid. The resulting slurry was stirred overnight and then filtered and the solid was washed with copious amounts of water. The solid was dried in vacuo (60° C.,<1 mm) to afford 3.64 g (75%) of 3-phthalimido-3-(4-propoxyphenyl)propionic acid as a white powder: mp 142.5-143.6° C., 1H NMR(DMSO-d6, 250 MHz)δ 12.43 (br s, 1H), 7.80-7.95 (m, 4H), 7.34 (d, 2H, J=9 Hz), 6.89 (d, 2H, J=9 Hz), 5.63 (overlapping dd, 1H), 3.88 (t, 2H, J=7 Hz), 3.45 (dd, 1H, J1=9 Hz, J2=16.5 Hz), 3.30 (dd, 1H, J1=7 Hz, J2=16.5 Hz), 1.60-1.85 (m, 2H), 0.95 (t, 3H, J=7 Hz); 13C (DMSO-d6)δ 171.8, 167.6, 158.6, 134.7, 131.1, 130.8, 128.3, 123.2, 114.4, 68.9, 49.7, 36.0, 22.0, 10.3; Anal. Calcd. for C20H19NO5. Theoretical: C, 67.98; H, 5.42; N, 3.96. Found: C, 67.90; H, 5.40; N, 4.00.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=1)#[N:21]
Reactant: N#Cc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 52.2 %

Procedure:
A mixture of methyl thiosalicylate (0.65 g, 3.9 mmol), 2,4-dicyanopyridine (0.50 g, 3.9 mmol), triethylamine (0.81 ml, 5.8 mmol) and toluene (2.0 ml) was refluxed for 2.5 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from acetone-chloroform to give the titled compound (0.54 g, 53%).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O.[Cr]>[Cl:14][CH2:15][C:16]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: OC(CCl)COc1ccccc1
Agent: O=[Cr](=O)=O
Agent: [Cr]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCl)COc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 49.7 %

Procedure:
8N Jones reagent (100 ml.) was added dropwise to a stirred solution of 1-chloro-2-hydroxy-3-phenoxypropane (28.3 g.) in acetone (100 ml.) during 1 hour while maintaining the reaction temperature at 20° C. The mixture was then stirred for 4 hours, and then sufficient water was added to dissolve the precipitated chromium salts. The mixture was extracted three times with diethyl ether and the combined ethereal extracts were dried over sodium sulphate, concentrated under reduced pressure, dried again over sodium sulphate, and concentrated further and distilled, to give 1-chloro-3-phenoxyacetone (13.9 g.), b.p. 150°-155° C./20 mm.Hg.
Reaction SMILES: [Na].[C:2]([O:23]CC)(=O)[CH2:3][CH2:4]/[CH:5]=[CH:6]/[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][C:17]([O:19]CC)=O.Cl[Si](C)(C)C.CO>C1(C)C=CC=CC=1>[OH:19][CH:17]1[C:2](=[O:23])[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)CC/C=C/CCCCCC/C=C/CCC(=O)OCC
Agent: C[Si](C)(C)Cl
Agent: O=C1CC/C=C/CCCCCC/C=C/CCC1O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1CCC=CCCCCCCC=CCCC1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 2 L Morton flask a mixture of sodium (7.48 g, 0.34 mole) in toluene (600 ml) was heated to reflux and stirred vigorously for 1 hour. To this solution was added dropwise (very slowly) a mixture of diethyl hexadeca-4E,12E-diene-1,16-dioate (24.86 g, 0.073 mole) and chlorotrimethylsilane (41.7 ml, 0.33 mole) in toluene (100 ml) over 2 hours. The reaction was heated to reflux for an additional 4 hours, then cooled to room temperature and stirred for an additional 16 hours. To the reaction mixture was added methanol (˜100 ml), the mixture is stirred 1 hour, and then left to stand for 1 hour. The resulting bi-phasic mixture was separated and the top layer is washed with 10% aqueous hydrochloric acid. The aqueous wash was re-extracted with ether and the organic layers are combined. The bottom layer from the bi-phasic mixture described above was combined with the aqueous wash and extracted again with diethyl ether. All organic layers were combined, dried with magnesium sulfate, filtered and evaporated to give the 16-hydroxycyclohexadeca-4E,12E-dien-1-one (20.0 g, 93% yield) as a brown oil which can be used directly in the next step. If desired, the material can be purified via reduced pressure distillation (210-220° C./0.3 mm Hg). C16H26O2 (250.38 g/mole). bp. 210-220° C./0.3 mm Hg. HNMR (500 MHz, CDCl3): 1.20-1.80 (m, 10H), 1.90-2.09 (m, 4H), 2.10-2.30 (m, 4H) 2.35 (m, 2H), 2.50 (m, 2H), 4.10 (m, 1H), 5.40 (m, 4H) ppm. 13CNMR (125 MHz, CDCl3): 27.8, 27.9*, 28.1, 28.5*, 31.4, 31.5, 32.8, 37.9, 76.2, 127.6, 128.8, 132.6, 133.1, 214 ppm. IR (νmax(cm−1)): 3450(b), 2940(s), 2910(s), 2850(s), 1720(s), 1440(m), 970(s). MS(m/z): 250(M+), 232, 221, 203, 189, 176, 161, 149, 135, 121, 109, 95, 81, 67, 55, 41.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCC(=O)CC1
Yield: 98.7 %

Procedure:
To a solution of 4,4-dimethyl-2-cyclohexen-1-one (10 g) in ethanol (100 ml) was added 10% palladium on carbon (1 g), and hydrogen gas at atmosphere pressure for 4 hours. To the reaction mixture was filtered. The filtrate was concentrated by evaporation under reduced pressure to give 4,4-dimethylcyclohexanone (10.03 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:5])[CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cc(Br)ccc1F
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A round-bottomed flask was charged with 2-fluoro-5-bromobenzaldehyde (1.01 g) and tetrahydrofuran (50 mL), placed under a nitrogen atmosphere then cooled to −78° C. To this solution was added a 1M solution of phenylmagnesium bromide (5 mL). The reaction was stirred for 15 min then removed from the cold bath and allowed to warm to 0° C. Quenching was achieved by the addition of water and diethyl ether. The organic layer was collected, dried over magnesium sulfate then concentrated to an oil. The residue was dissolved in methylene chloride (100 mL) and treated with Dess-Martin periodinane (2.12 g) at room temperature. The reaction mixture was stirred for 30 min then loaded directly onto a silica gel pad. The pad was eluted with methylene chloride, and the desired fractions were combined and concentrated to dryness to provide (5-bromo-2-fluorophenyl)(phenyl)methanone as a yellow oil (0.80 g). 1H NMR (400 MHz, DMSO-D6) δ ppm 7.8 (m, 1 H) 7.7 (m, 3 H) 7.6 (m, 1 H) 7.5 (m, 2 H) 7.3 (m, 1 H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:18]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
4-t-Butylbromobenzene (2.5 mmol), phenol (3.5 or 5.0 mmol), Cs2CO3 (3.5 or 5.0 mmol), (CuOTf)2 PhH (0.0625 mmol, 5.0 mol % Cu), ethyl acetate (0.125 mmol, 5.0 mol %), 1-naphthoic acid (3.5 mmol), molecular sieves (625 mg) and toluene (1.5 mL) were added to an oven-dried test tube which was then sealed with a septum, purged with argon, and heated to 110 C under argon until the aryl halide was consumed as determined by GC analysis. Upon cooling at room temperature, dichloromethane was added and the solvent was removed by filtration. The remaining molecular sieves were stirred with another portion of dichloromethane for 1 h at room temperature, and the solvent was removed by filtration. The combined organic phases were washed with 5% aqueous NaOH. The aqueous layer was then extracted three times with dichloromethane and the combined organic layers were washed with brine. The organic layer was dried over Mg2SO4 and concentrated under vacuum to give the crude product. Purification by flash column chromatography (2% EtOAc/hexane) gave the analytically pure product as a clear oil (457 mg, 81% yield). 1H NMR (300 MHz, CDCl3) δ 7.22-7.34 (m, 4H), 6.90-7.05 (m, 5H), 1.30 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 157.6, 154.7, 146.0, 129.6, 126.5, 122.9, 118.6, 118.5, 34.3, 31.5; IR (neat): 3068, 3962, 8867, 1590, 1508, 1489, 1240 cm−1.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1C=CC=CC=1>[CH:4]([O:6][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:5])[CH3:3]
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
In a 250-mL flask, 35% aqueous sodium hydroxide (29.3 g, 256 mmol), propan-2-ol (0.785 ml, 10.3 mmol) tetrabutylammonium chloride (0.214 g, 0.769 mmol), and tert-butyl 2-bromoacetate (1.00 g, 5.13 mmol) were taken up in benzene (25 mL). The mixture was stirred at ambient temperature overnight. The reaction was concentrated to remove most of the benzene. The aqueous residue was diluted further with water (100 mL) and the aqueous phase was extracted with 75% ether-hexane (3×33 mL). The organics were combined, washed with water (10 mL) then with saturated brine (10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated to afford the title compound (119 mg, 0.683 mmol, 13%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=2)[C:17]([NH:19][C:20]2[CH:21]=[C:22]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=3)=[O:29])[CH:23]=[CH:24][C:25]=2[CH3:26])=[O:18])[CH2:9][CH2:8]1.CS(C)=O>O>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=2)[C:17]([NH:19][C:20]2[CH:21]=[C:22]([NH:27][C:28]([C:30]3[CH:31]=[CH:32][N:33]=[C:34]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:35]=3)=[O:29])[CH:23]=[CH:24][C:25]=2[CH3:26])=[O:18])[CH2:9][CH2:8]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Reactant: C1CCNC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 120 °C
Yield: 2.6 %

Procedure:
Pyrrolidine (0.3 g) was added to a stirred mixture of N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-2-chloropyridine-4-carboxamide (0.5 g) and DMSO (5 ml) and the mixture was stirred and heated to 120° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water and extracted with methylene chloride. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.014 g); Mass Spectrum: M+H+513.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)=O.[C:21]([O:28][CH3:29])(=[O:27])[CH2:22][CH2:23][C:24]([CH3:26])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:26][C:24]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:23]=1[CH2:22][C:21]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)c(Cl)c1)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(Cl)c(Cl)c1)CCCC3
Yield: 65.9 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone (0.228 g; 0.7 mmol), methyl levulinate (0.099 mL; 0.77 mmol), chlorotrimethylsilane (0.357 mL; 2.8 mmol) in DMF (2.8 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.194 g (66%) of the title compound as a yellow solid.
Reaction SMILES: BrC1C=CC(Br)=CN=1.NN.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18]N)=[N:16][CH:17]=1.N(C1C=CC=CN=1)N.[CH3:28][CH:29]([CH3:33])[C:30](=O)[CH3:31]>COCCO.C1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]2[C:29]([CH3:33])([CH3:28])[C:30]([CH3:31])=[N:18][C:15]2=[N:16][CH:17]=1
Reactant: CC(=O)C(C)C
Reactant: NNc1ccc(Br)cn1
Agent: Brc1ccc(Br)nc1
Agent: NN
Agent: NNc1ccccn1
Solvent: c1ccccc1
Solvent: COCCO
Product: CC1=Nc2ncc(Br)cc2C1(C)C
Temperature: 110 °C

Procedure:
To 40 g of 2,5-dibromopyridine in 200 mL of 2-methoxyethanol is added 53 mL of anhydrous hydrazine and the mixture is heated at 110° C. for 3 hours to generate the 5-bromo-2-hydrazinopyridine. A mixture of 10 g of this hydrazinopyridine is heated at reflux overnight with 11 mL of 3-methyl-2-butanone in 40 mL of benzene equipped, using a condenser equipped with a Dean-Stark trap. All of the volatile components are removed under reduced pressure and the resulting residue is heated in 62 g of polyphosphoric acid at 140° C. for 45 minutes. The reaction mixture is poured into water, neutralized with sodium hydroxide and extracted with ethyl acetate. The resulting crude residue is purified by chromatography on silica gel, eluting with 1:1 ethyl acetate/hexanes, to yield 1.44 g of the product.