Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C@H:13]1[CH2:41][O:40][C@@:16]2([O:20][C@H:19]3[CH2:21][C@H:22]4[C@@H:27]5[CH2:28][CH2:29][C@H:30]6[CH2:35][C@@H:34]([OH:36])[CH2:33][CH2:32][C@:31]6([CH3:37])[C@H:26]5[CH2:25][CH2:24][C@:23]4([CH3:38])[C@H:18]3[C@@H:17]2[CH3:39])[CH2:15][CH2:14]1>C(Cl)Cl>[CH3:39][C@@H:17]1[C@:16]2([O:40][CH2:41][C@H:13]([CH3:12])[CH2:14][CH2:15]2)[O:20][C@H:19]2[CH2:21][C@@H:22]3[C@@:23]([CH3:38])([C@@H:18]12)[CH2:24][CH2:25][C@H:26]1[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@:31]1([CH3:37])[CH2:32][CH2:33][C:34](=[O:36])[CH2:35]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
Pyridinium chlorochromate (PCC) was added to a mixture of tigogenin (50.00 g, 120.0 mmol), celite (160 g), in CH2Cl2 (1000 mL) at 0° C. The reaction was allowed to come to ambient temperature and was stirred for 5 hours. The reaction was diluted with 1000 4 mL Et2 O and was filtered through a silica gel plug. The plug was washed with an additional 6000 mL Et2O. The flitrate was concentrated in vacuo to afford 45.00 g of the title compound (90.4%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 41.6 %

Procedure:
A mixture of 2-fluoro-5-formylbenzonitrile (1.0 g, 6.71 mmol), 3-(trifluoromethyl) phenol (1.087 g, 6.71 mmol), K2CO3 (2.78 g, 20.12 mmol) in DMSO (20 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was partitioned between EA (100 mL) and water (100 mL), the aqueous layer was extracted with EA (50 mL) twice. The combine the organic layers were washed with water, brine and dried over sodium sulfate, filtered, concentrated and purified via flash chromatography to afford the title compound (820 mg, 2.79 mmol, 41.6% yield). LCMS: rt=3.33 min, [M+H+]=292
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:27]=[CH:26][C:11]([C:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[C:23](O)=[O:24])=O)=[CH:10][CH:9]=1.Cl>C1COCC1>[F:7][C:8]1[CH:27]=[CH:26][C:11]([CH:12]2[C:14]3[C:15](=[CH:16][C:17]([CH2:18][OH:19])=[CH:21][CH:22]=3)[CH2:23][O:24]2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(F)cc2)c(C(=O)O)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Reaction time: 10 h
Yield: 8.3 %

Procedure:
To a suspension of lithium aluminum hydride (1.0 g) dispersed in THF (10 ml) was added dropwise at room temperature a solution of 4-(4′-fluorobenzoyl)isophthalic acid (3.0 g) in THF (30 ml), and the mixture was stirred for 10 hr. To the reduced reaction mixture was added 10% hydrochloric acid (10 ml) and the mixture was passed through celite. THF was evaporated under reduced pressure, and 85% phosphoric acid (10 g) was added. The mixture was stirred at 60° C. for 5 hr. To the reaction mixture was added water (50 ml) and the resulting crystals were collected by filtration and dried. The objective compound was separated by silica gel column chromatography to give 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (0.21 g, 8%). The various spectrum data of the crystals were the same as those obtained in Example 12
Reaction SMILES: CC12CCCCN1C=CCNC2.[CH3:13][C:14](=[CH:16][CH2:17][CH2:18][N+:19]([O-:21])=[O:20])[CH3:15].[C:22]([O:27][CH3:28])(=[O:26])/[CH:23]=[CH:24]/[CH3:25]>CO>[CH3:25][CH:24]([CH:18]([N+:19]([O-:21])=[O:20])[CH2:17][CH:16]=[C:14]([CH3:15])[CH3:13])[CH2:23][C:22]([O:27][CH3:28])=[O:26]
Reactant: CC(C)=CCC[N+](=O)[O-]
Reactant: C/C=C/C(=O)OC
Agent: CC12CCCCN1C=CCNC2
Solvent: CO
Product: COC(=O)CC(C)C(CC=C(C)C)[N+](=O)[O-]
Reaction time: 144 h
Yield: 19.5 %

Procedure:
Methyl 3,7-Diazabicyclo[5,4,0]undec-5-ene (4 ml) is added to a solution of 2-methyl-5-nitro-2-pentene (25.0 g, 0.193 m) in methanol (200 ml). The resulting mixture is heated to 60° and methyl crotonate (30.85 g, 0.308 m) is added under nitrogen. The mixture is then stirred for 6 days at 60° after which it is cooled to room temperature and most of the methanol is removed in vacuo. The residue is treated with ether (500 ml) and washed with 2 N HCl (250 ml) and water (250 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give 42.5 g of crude product. The crude product is purified by column chromatography on silica gel (500 g, ethyl acetate/hexane 2:98) to give methyl 3,7-dimethyl-4-nitro-6-octenoate (8.65 g, 42%).
Reaction SMILES: [CH:1]1([O:7][CH:8](C)[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(CO)OC1CCCCC1
Solvent: ClCCl
Product: O=S(=O)(OCCOC1CCCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 2-cyclohexyloxy-1-propanol (4.0 g, 28 mmol) in triethylanine (5.8 ml) and dichloromethane (250 ml) was added 4-bromobenzenesulfonyl chloride (7.87 g, 31 mmol) at 0° C. under nitrogen, and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine (100 ml each), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by silica (200 g) column chromatography using a gradient elution of hexane:ethyl acetate (6:1 to 1:1) to give the title compound as a white crystalline solid (8.0 g, 80%).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[N:4][CH:3]=1.[CH:13]([O:16][C:17]1[CH:18]=[C:19]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=1)([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.[Cl-].[Na+].O>[C:11]([C:10]1[C:5]2[N:6]([C:2]([C:21]3[CH:20]=[C:19]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[O:34])[CH:18]=[C:17]([O:16][CH:13]([CH3:15])[CH3:14])[CH:22]=3)=[CH:3][N:4]=2)[CH:7]=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1cccn2c(I)cnc12
Reactant: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(C#N)cccn23)c1
Temperature: 110 °C
Yield: 32.1 %

Procedure:
To a mixture of 3-iodoimidazo[1,2-a]pyridine-8-carbonitrile (100 mg, 373 μmol), 1-(3-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2,2,2-trifluoroethyl)urea (90 mg, 224 μmol), PdCl2 (dppf)-CH2Cl2Adduct (30.5 mg, 37.3 μmol) in Dioxane (3 ml), was added 2M Na2CO3 (0.559 ml, 1119 μmol). The vial was degassed for 5 minutes then capped and heated to 110° C. for 30 minutes in microwave. After cooling to ambient temperature reaction was partioned between EtOAc and brine, separated and organics washed with brine×2. Combined organics were dried directly on to silica and purified via flash chromatography (0-100% Hex/EtOAc; 12 g column). Recovered the title compound (30 mg, 71.9 μmol, 32.1% yield) as a brown solid. MS (ES+) C20H18F3N5O2 requires: 417. found: 418 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.ON1C2N=CC=CC=2N=N1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>ClCCl>[N:21]1([C:8]([C@@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)=[O:10])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: O=C([C@H]1CC[C@@H](O)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of cis-4-hydroxycyclohexanecarboxylic acid (720 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (1.33 g, 6 mmol) and 1-hydroxy-7-azabenzotriazole (816 mg, 6 mmol) in dichloromethane (6 ml) was treated with morpholine 1.3 ml, 15 mmol). After stirring at room temperature for 18 hours, the crude reaction was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo, and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (D55); MS (ES+) m/e 214 [M+H]+.
Reaction SMILES: [H-].[Na+].N#N.[CH2:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:14]1[N:22]=[C:21]([NH2:23])[N:20]=[C:19]2[C:15]=1[NH:16][CH:17]=[N:18]2>C1(C)C=CC=CC=1>[CH2:5]([O:12][C:14]1[N:22]=[C:21]([NH2:23])[N:20]=[C:19]2[C:15]=1[NH:16][CH:17]=[N:18]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: OCc1ccccc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 115 °C
Reaction time: 0.17 h

Procedure:
60% Sodium hydride in mineral oil (2.36 g, 0.059 moles) was charged to a 500 mL 3-neck flask equipped with magnetic stirring, temperature probe, condenser, and N2 inlet. Toluene (250 mL) was added. Benzyl alcohol (50 mL) was added dropwise over 30 minutes. After addition of benzyl alcohol, the reaction was stirred 10 minutes. Then 6-chloro-2-aminopurine (5.00 g, 0.029 moles) was added and the reaction mixture was heated to reflux (115° C.) for 4.5 hours. The reaction mixture was filtered hot through a coarse glass fritted funnel and 11.65 g of wet off-white solids were obtained. The wet solids were triturated with CH2Cl2 (100 mL) and water (100 mL). After 10 minutes of stirring the solids had dissolved. The aqueous layer was separated and the pH was lowered to 9 over 3 minutes with 6 M HCl. A white solid precipitate formed. The slurry was filtered, washed with water (50 mL), and dried (in vacuo at 50° C.) to a constant weight to provide the desired product as off-white crystals (5.15 g).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.[OH-].[NH4+:32].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.CO.ClCCl>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:32])[C:17]=2[N:26]=1
Reactant: CC(C)Cn1c(CCl)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chlioroperoxybenzoic acid (mCPBA) (16.4 g of 77% max, 73.1 mmol) was added to a solution of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (10 g, 36.5 mmol) in chloroform (250 mL). The reaction mixture was stirred at ambient temperature overnight. Ammonium hydroxide (100 mL) was added and the reaction was stirred vigorously for 15 minutes. Para-toluenesulfonyl chloride (8.4 g, 43.8 mmol) was added in portions over a period of 10 minutes. The reaction mixture was stirred at ambient temperature for 1 hour and then filtered to remove a precipitate. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organics were dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 16 g of crude product as a yellow foam. The foam was dissolved in 10% methanol in dichloromethane (20 mL). The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g), (available from Biotage, Inc, Charlottesville, Va., USA). The cartridges were eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 2% methanol in 1:1 ethyl acetate:hexanes, and 5% methanol in 1:1 ethyl acetate:hexanes. The fractions containing product were combined and then concentrated under reduced pressure to provide 6.4 g of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as an orange foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([NH:24][CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'carbonyldiimidazole (2.69 g, 0.0166 mole), and dry tetrahydrofuran (100 ml) was stirred at room temperature for 1.75 hours with a stream of nitrogen bubbling through it. A solution of methylamine in tetrahydrofuran (33 ml of a 3.03M solution, 0.996 mole) was added and the reaction mixture was stirred at room temperature overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol, charcoaled, and filtered while hot. Water was added to the cloud point, and upon cooling, solid precipitated. The solid was collected by filtration and dried under high vacuum at 50° C. overnight to give 3.21 g (62%) of title compound, mp 217°-218° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: C1CNCCN1
Product: Brc1cccnc1N1CCNCC1

Procedure:
Alternatively, 3-bromo-2-chloropyridine may be used as shown in Scheme VIII. Thus, 3-bromo-2-chloropyridine (27) is heated with piperazine to provide 1-(3-bromopyridin-2-yl)piperazine (28), followed by Suzuki coupling of the phenyl moiety to provide the phenylpiperazine intermediate (25).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.CCCCCCC.C([N-]C(C)C)(C)C.[Li+].O1CCCC1.C(C1C=CC=CC=1)C.[C:37](=[O:39])=[O:38]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:37]([OH:39])=[O:38]
Reactant: Clc1cccc(Br)c1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: O=C(O)c1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The mixture of 500 mg of 3-bromochlorobenzen and 3 ml of tetrahydrofuran was cooled down to −78° C. and 1.3 ml of 2.0M lithium diisopropylamide heptane/tetrahydrofuran/ethylbenzene was added. After stirring it for 2 hours, the mixture was put into dry ice and washed and extracted as described in Referencial Example 1 to obtain a crude material. The crude material was washed with a mixed solvent of hexane-ethyl acetate to obtain the said compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:18])[CH2:14][CH2:15][S:16][CH3:17])[C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:18])[CH2:14][CH2:15][S:16][CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCCC(=O)C1CCN(C(=O)OC(C)(C)C)C1=O
Solvent: C1CCOC1
Product: CSCCC(O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.6 %

Procedure:
3-(3-Methylsulfanylpropionyl)-2-oxo-pyrrolidine-1-carboxylic acid t-butyl ester (188 mg, 654 μmol) was dissolved in THF (531 μL) under nitrogen. 2M BH3-Me2S in THF (981 μL) was added via syringe over 15 minutes. The mixture was stirred at room temperature for 1 hour, then heated at 65° C. for 1 hours, then cooled to room temperature. The mixture was cooled on an ice bath and the reaction was slowly quenched with cold MeOH (100 mL). The mixture was stirred overnight and then diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation to yield a yellow oil (300 mg), which was used without further purification. LCMS m/z: [M+H]+ calcd for C13H25NO3S, 275.40. found 276.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[CH3:14][N:15]1CCCC1=O.[Cu]C#N>CCOC(C)=O.O.[NH4+].[OH-]>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:14]#[N:15])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1cccc(C#N)c1
Temperature: 190 °C
Reaction time: 1 h

Procedure:
To a mixture of of (3-bromo-phenyl)-acetic acid ethyl ester (15.3 g, 62.9 mmol) and 1-methyl-2-pyrrolidinone (125 mL) was added copper (I) cyanide (8.46 g, 94.4 mmol). The reaction mixture was stirred in an oil bath at 190° C. for 1 h. The reaction was cooled to room temperature and was diluted with EtOAc and 2:1 H2O/NH4OH. The mixture was stirred for 10 minutes and was filtered through Celite. The aqueous layer was washed with EtOAc (2×). The organic solution was washed with 2:1 H2O/NH4OH until the aqueous extracts were no longer blue. The organic solution was dried over MgSO4, filtered and concentrated to afford (3-cyano-phenyl)-acetic acid ethyl ester (11.95 g). 1H NMR (400 MHz, CDCl3) δ 7.51–7.58 (m, 3H), 7.43 (t, 1H), 4.16 (q, 2H), 3.63 (s, 2H), 1.25 (t, 3H).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[OH-].[K+].[O:21]=[CH:22][C:23]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:25]([OH:26])[CH:24]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([O:26][C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][C:27]=1[O:28][CH3:29])[CH:22]=[O:21])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18--Crown-6 ether (0.14 g, 0.00052 mols) and potassium hydroxide (1.35 g, 0.024 mols) is added to a stirred solution of isovanillin (201) (2.0 g, 0.013 mols) in THF (20 ml) at 0° C. The reacton becomes cloudy and turns bright yellow. Benzyl bromide (1.69 ml, 0.0143 mols) is added dropwise to the reaction at 0° C. After one hour, the ice bath is removed and the reaction is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with water and 10% HCl followed by brine solution. The organic extract is dried over sodium sulfate, filtered, concentrated and dried in vacuo no a yellow crystalline solid (3.0471 g, 96.9%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of isovanillin (200 g) in dimethylformamide (500 ml) is added potassium carbonate (236 g) under ice-cooling, and thereto is added dropwise benzyl bromide (203 ml), and the mixture is stirred overnight. The insoluble materials in the resulting residue are removed by filtration, and washed with acetone, and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is washed again with ether and water, and concentrated under reduced pressure to remove the solvent to give 3-benzyloxy-4-methoxybenzaldehyde as an oily product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([NH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1CCCC2
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 24.39 g of 1-amino-5,6,7,8-tetrahydronaphthalene and 18.6 ml of acetic anhydride in 230 ml of DCM is left stirring for 1 hour at RT. It is concentrated under vacuum, the residue is taken up with ether and the precipitate formed is drained. 26.8 g of the expected product are obtained, m.p.=158° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=O)[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([Br:18])=[CH:7][CH:8]=2)[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].CS(C)=O>O>[Br:18][C:6]1[CH:5]=[C:4]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([C:16]4[S:28][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=4)=[CH:14][C:15]=3[C:3]2([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:8][CH:7]=1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Solvent: O
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(-c3nc4ccccc4s3)cc21
Temperature: 195 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A mixture of 9,9-diethyl-7-bromo-fluorene-2-carboxaldehyde (49.35 g., 0.15 mol.), 2-amino-thiophenol (20 ml. 0.187 mol., 1,25 eq.), and DMSO (110 ml) was heated in an oil bath to a bath temperature of 195° C., held there for 45 minutes, and then poured into water. The separated solids were collected, reslurried in 1:4 acetic acid-water (1000 ml.) filtered, and washed with water and dilute sodium bicarbonate solution. These solids, 80.05 g., were then reslurried in hot ethanol, (600 ml), cooled and filtered to get the benzothiazole product, 45.69 g., m.p. 133.6–135° C. An additional 6.6 g., m.p. 134.6–135.5° C., was obtained by chromatography of the ethanol filtrate. Total recovery was 52.29 g. (80.3% yield). Mass Spec: m/z 433, 435, (M+). Calculated for C24H20BrNS: C, 66.37; H, 4.64; Br, 18.40; N, 3.23; S, 7.37%. Found: C, 66.46; H, 4.52, Br, 18.54; N, 3.14; S, 7.19%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(OCC)C>O1CCCC1>[C:11]1([NH:17][NH:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NNc1ccccc1)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
30 ml. (0.25 mole) of 4-fluorobenzoyl chloride is added dropwise over a 30 minute period to a mixture of 25 ml. (0.25 mole) of phenylhydrazine and 35 ml. (0.25 mole) of triethylamine in 500 ml. of anhydrous diethyl ether stirred at -10° C. under nitrogen. The reaction mixture is allowed to warm to 20°-25° C. and stirred under nitrogen for 3 hours. The obtained solids are collected by filtration, washed with diethyl ether and dissolved in about 600 ml. of methylene chloride. The methylene chloride solution is filtered and evaporated at reduced pressure to near dryness, and n-hexane is added to obtain the crude solid product (26 g.). The crude product is dissolved in tetrahydrofuran and filtered to remove the triethylamine hydrochloride, the tetrahydrofuran is evaporated at reduced pressure, and the obtained product is recrystallized from acetone (12 g.), m.p. 181°-186° C. A second crop is also obtained (6 g.).