Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.[Br:13]Br.N([O-])=O.[Na+].[OH-].[Na+]>Br.O>[Br:13][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(-c2ccncc2)s1
Reactant: BrBr
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1nnc(-c2ccncc2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
2-Amino-5-(4-pyridyl)-1,3,4-thiadiazole (2.0 g, 11.2 mmol) was suspended in 48% aqueous hydrobromic acid (5.6 mL) and stirred at 0° C. Bromine (5.06 mL, 98.8 mmol) was added dropwise into the mixture at 0° C. Water (15 mL) was added slowly followed by a solution of sodium nitrite (1.97 g, 28.6 mmol) in water (2.8 mL). Stirring at 0° C. was continued for another 30 minutes. Sodium hydroxide (10.0 g) in water (10 mL) was added slowly into the reaction mixture while the temperature was maintained below 20° C. The reaction mixture was then extracted with chloroform then the chloroform solution was washed with water, dried (magnesium sulfate), filtered, and the solvent was evaporated. The residue was purified by flash chromatography using a gradient of ethyl acetate in hexane to give the title compound as a brown solid (1.28 g), m/z 242, 244 (MH+).
Reaction SMILES: C[O-].[K+].[CH3:4][N:5]1[C:9]([O:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3N(C)N=C(C(F)(F)F)C=3)[CH:14]=[C:13]([O:28][C:29]3[N:33]([CH3:34])[N:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[N:12]=2)=[CH:8][C:7]([C:39]([F:42])([F:41])[F:40])=[N:6]1>CO>[CH3:34][N:33]1[C:29]([O:28][C:13]2[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]([O:10][C:9]3[N:5]([CH3:4])[N:6]=[C:7]([C:39]([F:40])([F:41])[F:42])[CH:8]=3)[N:12]=2)=[CH:30][C:31]([C:35]([F:38])([F:36])[F:37])=[N:32]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(Oc2cc(C(F)(F)F)nn2C)nc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(Oc2cc(C(F)(F)F)nn2C)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reaction time: 2 h
Yield: 43.4 %

Procedure:
A 3 ml aliquot of a 25% solution of potassium methylate (10 mmol) in dry methanol is added to a solution of 5.7 g (10 mmol) 2,4,6-tris-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine in 20 ml anhydrous methanol. After 2 hours at ambient temperature, the reaction mixture is heated to reflux. The solvent is removed under reduced pressure and ethyl acetate is added to the residue. The mixture is washed with a 2 N sodium hydroxide solution. After drying and filtration of the organic layer, the solvents are removed and the residue is washed with diisopropyl ether and pentane. Colorless crystals (1.9 g, 43% yield) of melting point 107° C. are obtained.
Reaction SMILES: C(N1CCCCC1)C.[C:9]([N:13]1[CH2:17][CH2:16][S:15][C:14]1=[S:18])(=[O:12])[CH2:10][CH3:11].C(O[C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:29])(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[Si:31]([O:30][C@@H:28]([C@@H:24]1[C@@H:23]([CH:10]([CH3:11])[C:9](=[O:12])[N:13]2[CH2:17][CH2:16][S:15][C:14]2=[S:18])[NH:26][C:25]1=[O:27])[CH3:29])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: CCC(=O)N1CCSC1=S
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CCN1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C(=O)N1CCSC1=S)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a suspension of stannous trifluoromethanesulfonate (8.35 g) and N-ethylpiperidine (3.79 ml) in dichloromethane (60 ml) was added dropwise a solution of 3-propionyl-2-thioxothiazolidine (4.12 g) in dichloromethane (35 ml) at -78° C. under nitrogen atmosphere. After stirring at -78° C. for 30 minutes, a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone (2.25 g) in dichloromethane (8 ml) was added to the reaction mixture, and the reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 20 minutes. The reaction mixture was poured into aqueous sodium bicarbonate solution (100 ml) and the precipitated white mass was removed by passing through a layer of celite. The organic layer was separated and washed with 10% aqueous sodium chloride solution (100 ml×2). The organic solution was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (185 g) eluting with a mixture of acetone and dichloromethane (2:98, V/V) to give (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1RS)-1-methyl-2-oxo-2-(2-thioxothiazolidin-3-yl)ethyl]-2-azetidinone (2.39 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([NH:20][C:21](=O)CC)[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:26])=[O:25])=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([NH:20][CH3:21])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:25])=[O:26])=[CH:4][CH:3]=1
Reactant: CCC(=O)Nc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CNc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Yield: 84 %

Procedure:
To a solution of 2-(4-chlorophenyl)-4-methyl-6-(N-methylacetylamino)-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (0.14 g) in ethanol (2.8 ml) was added conc. hydrochloric acid (2.8 ml). The mixture was refluxed for one hour and neutralized with aqueous saturated NaHCO3 solution. The resulting crystals were collected by filtration to give 2-(4-chlorophenyl)-4-methyl-6-(N-methylamino)-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (0.105 g) as colorless powder.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([OH:10])=[N:8][O:9][C:5]=2[CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[N:8]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][O:30]3)[O:9][C:5]=2[CH:4]=1
Reactant: C1=COCCC1
Reactant: Oc1noc2cc(CCl)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: O=c1c2ccc(CCl)cc2on1C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 75 mL of methylene chloride, 5.00 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol was suspended, and to this was added 0.137 g of pyridinium p-toluenesulfonic acid and 2.98 mL of 3,4-dihydro-2H-pyran. This was stirred for 8 hours at room temperature. To the reaction mixture was added 30 mL of water and an organic layer was separated. An aqueous layer was extracted with 10 mL of methylene chloride, and this along with the organic layer was washed with an aqueous saturated sodium chloride solution and dried with anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and 20 mL of diisopropyl ether was added to the obtained residue. A seed crystal was added and, after 30 minutes of stirring at room temperature, solids were filtered to obtain 6.65 g of 6-(chloromethyl)-2-(tetrahydro-2H-pyran-2-yl)-1,2-benzisoxazol-3(2H)-one in the form of a pale yellowish-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:25]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCC1CCN(C)CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.22 g, 3.65 mmol), (prepared as described for the starting material in Example 241), 4-fluoro-5-hydroxy-2-methylindole (723 mg, 4.38 mmol), (prepared as described for the starting material in Example 237), in DMF (20 ml) containing potassium carbonate (756 mg, 5.48 mmol) was stirred at 95° C. for 3 hours. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) followed by methylene chloride/methanol/methanol saturated with ammonia (90/5/5). The fractions containing the expected product were combined and evvaporated. The residue was triturated with ether, filtered, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride/ethyl acetate and the minimum of methanol, filtered and the volatiles were removed under vacuum. The solid was triturated with ether, filtered, washed with ether and dried under vacuum at 50° C. to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.06 g, 62%).
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C@@H:10]1[CH2:14][C@@H:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][N:11]1[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)([OH:4])=[O:3]>Cl>[ClH:25].[C:2]([CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]1[CH2:14][CH:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:12][N:11]1[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)([OH:4])=[O:3]
Reactant: O=C(O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Agent: Cl
Product: O=C(O)CCC/C=C\C1CC(NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 169.1 %

Procedure:
In 1N-hydrochloric acid (44 ml)-purified water (16 ml) was dissolved crude crystal of (2S,4R)-2-[(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)-1-(3-pyridylmethyl)pyrrolidine hydrochloride (8.0 g, 0.016 mol) followed by addition of activated carbon (0.8 g) and the mixture was stirred at 25° C. for 1 hour. Then, clarification-filtration was carried out using a 0.25μmembrane prefilter and the filtrate was washed with 1N-hydrochloric acid (4 ml)-purified water (8 ml). While the filtrate was stirred, 1N-aqueous sodium hydroxide solution was added dropwise so as to adjust the solution to pH 2.0 (pH prior to adjustment: 0.4). The mixture was stirred at 20°-25° C. for crystallization and ripening (about 1 hour, pH decreases to 1.51). Then, 1N-aqueous sodium hydroxide solution was added thereto dropwise so as to adjust the solution to pH 2.20. The solution was cooled to 5° C. and 1N aqueous sodium hydroxide solution was added thereto dropwise so as to maintain the solution at pH 2.20. The solution was cooled to 5° C. and 1N-aqueous sodium hydroxide solution was added thereto dropwise so as to maintain the solution at pH 2.20. The solution was then allowed to stand at 0°-5° C. overnight. The next morning the crystal was collected by filtration and washed with cold purified water (8 ml). The washed crystal was dried in vacuo overnight to provide pure crystal (6.77 g) of [(Z)-5-carboxy-l-pentenyl]-4-(4-chlorophenylsulfonylamino)-1-(3-pyridylmethyl)pyrrolidine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:15])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].CI.[C:20](O)(=O)C>CN(C)C=O.O>[CH3:20][N:11]1[CH:12]=[C:13]([C:14]#[N:15])[C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10]1
Reactant: N#Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1cc(C#N)c(-c2ccc([N+](=O)[O-])o2)n1
Temperature: 0 °C
Yield: 57 %

Procedure:
Add 15.4 g of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carbonitrile portionwise to a suspension of 2.5 g of sodium hydride (80% in liquid paraffin) in 90 ml of dimethylformamide while stirring and under nitrogen at from -2° C to -5° C. Stir the thus-obtained reaction mixture for 30 minutes and then add dropwise thereto a solution of 11.8 g of methyl iodide in 20 ml of dimethylformamide. After stirring for 30 minutes, admix therewith 0.6 g of glacial acetic acid and stir the resulting solution into 220 g of ice and water. Remove formed precipitate by vacuum filtration and recrystallize residue twice from dimethylformamide and water. Dry the residue in vacuo. Recrystallize the resulting 13.5 g of product three more times from dimethylformamide and water to obtain a 57% yield of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carbonitrile [m.p. 176.5° to 177.5° C].
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].Cl.[NH2:6][C:7]1[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:10].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O>[C:1]([NH:6][C:7]1[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20][CH2:19]2)=[CH:16][CH:17]=1)=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: Nc1ccccc1C(=O)Nc1ccc(N2CCN3CCC2CC3)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CC(=O)Nc1ccccc1C(=O)Nc1ccc(N2CCN3CCC2CC3)cc1

Procedure:
Acetic acid (2 ml) was added to a mixture of 2-Amino-N-[4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenyl]-benzamide hydrochloric acid salt (365 mg, 1.1 mmol), sodium acetate (4.4 g, 54.2 mmol) and water (100 ml) at 0° C. The mixture was made alkaline by adding saturated sodium bicarbonate (20 ml). The mixture was extracted with ethyl acetate (3×50 ml). The product was isolated. Yield 95 mg (23%). Mp. 191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[CH2:27][O:26][CH3:25])=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC[C@@H]1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, (S)-2-methoxymethylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.56 minutes; C22H22Cl2N4O3 (461.35); mass spectrum: (M+H)+=461.1.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([S:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1)#[N:3].C([OH:30])(C)(C)C.[OH-].[K+]>O>[ClH:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([S:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=1)(=[O:30])[NH2:3]
Reactant: CC(C)(C)O
Reactant: CN(C)CCSc1nc2ccccc2cc1-c1ccc(C#N)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCSc1nc2ccccc2cc1-c1ccc(C(N)=O)cc1

Procedure:
A mixture of 3-(p-cyanophenyl)-2-(2-dimethylaminoethylthio)quinoline hydrochloride (see Ex. 30, 0.65 g.), t-butanol (25 ml.) and potassium hydroxide (0.6 g.) was heated at 40° for 1 hr. Water (20 ml.) was added to the mixture and the t-butanol was evaporated. Additional water (20 ml.) was added, and the mixture was extracted with chloroform (3×30 ml.). The chloroform extract was washed with water (2×10 ml.) and dried (MgSO4). The solvent was evaporated and the residue was crystallised from ethanol. The crystalline material was dissolved in ethanol (50 ml.) and ethereal hydrogen chloride was added to the solution. The solvents were evaporated and the residue was crystallised from ethanol-diethyl ether to give 3-(p-carbamoylphenyl)-2-(2-dimethylaminoethylthio)quinoline hydrochloride, m.p. 253°-5°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:18][CH3:19])=[CH:11][C:12](Br)=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCOCC.[B:30](OCC)([O:34]CC)[O:31]CC>O1CCCC1.C(COC)OC>[CH2:1]([O:8][C:9]1[C:10]([CH2:18][CH3:19])=[CH:11][C:12]([B:30]([OH:34])[OH:31])=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOB(OCC)OCC
Reactant: CCc1cc(Br)c(OC)cc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(B(O)O)c(OC)cc1OCc1ccccc1
Temperature: -78 °C

Procedure:
The resulting 5-benzyloxy-2-bromo-4-ethyl-1-methoxybenzene (4) is allowed to react with n-butyl lithium in a polar solvent such as ether, glyme or tetrahydrofuran (THF), preferably THF, at a temperature of about −78° C. Triethyl borate is then added to the reaction mixture, and the reaction mixture is allowed to stir at a temperature of about −78° C. The reaction mixture is then allowed to warm to about room temperature. The reaction yields 4-benzyloxy-5-ethyl-2-methoxy-phenylboronic acid (5).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH:2]=[CH2:3].C(C1CCCC([Cl:21])C1=O)(C)(C)C>>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([Cl:21])[C:5]1=[O:10])[CH:2]=[CH2:3]
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Reactant: C=CCC1CCCCC1=O
Product: C=CCC1CCCC(Cl)C1=O

Procedure:
The chlorination of 2-allylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [BrH:1].C1(O)C=CC=CC=1.C[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[O:20]C)[CH2:16][N:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:14]2>C(O)(=O)CC>[BrH:1].[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[OH:20])[CH2:16][NH:15][CH2:14]2
Reactant: COc1cc2c(cc1OC)CN(S(=O)(=O)c1ccc(C)cc1)C2
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: Oc1cc2c(cc1O)CNC2
Yield: 61.4 %

Procedure:
360 ml of 47% hydrobromic acid, 45 m1 of phenol and 60 ml of propionic acid were added to 60 g (0.18 mol) of 5,6-dimethoxy-2-p-tolylsulfonylisoindoline, and the mixture was refluxed for 4 hours under vigorous stirring under a nitrogen atmosphere. The reaction solution was evaporated under reduced pressure to dryness, and 120 ml of 47% hydrobromic acid was added to the residue. The mixture was again refluxed under a nitrogen atmosphere for 3 hours. The reaction solution was cooled, and then 300 ml of water and 300 ml of chloroform were added thereto. The water layer was separated, and subjected to active carbon treatment. The water layer was evaporated under reduced pressure to dryness, and the crystalline residue was washed with ether/ethanol (1/1) to obtain 25.62 g (yield: 61.4%) of the above identified compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>CO.CN1CCOCC1>[C:15]([CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([C:6]2[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[OH:8])=[CH:19][CH:18]=1)([OH:17])=[O:16]
Reactant: COc1ccc(C(=O)c2ccc(OCC(=O)O)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Product: COc1ccc(C(O)c2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.2 g of 4-(4-methoxybenzoyl)phenoxyacetic acid are dissolved in 600 ml of 80% strength methanol (reflux), and 4.4 ml of N-methylmorpholine are added. 6 g of sodium borohydride are added in portions over the course of two hours, and the reaction is continued under reflux conditions for 3 hours. The mixture is cooled to room temperature and acidified to pH 2.5 with 3N HCl. The methanol is distilled off, the aqueous phase is extracted with ethyl acetate, and the organic phase is washed with brine and dried over sodium sulfate. After removal of the ethyl acetate by distillation there remains a white amorphous powder. The product is used directly for the next reaction.
Reaction SMILES: [OH-].[CH3:2][N+:3]([CH3:9])([CH3:8])[CH2:4][CH2:5][CH2:6][CH3:7].C([O:12][Si:13]([O:20]CC)([O:17]CC)[O:14]CC)C>O>[Si:13]([O-:20])([O-:17])([O-:14])[O-:12].[CH3:2][N+:3]([CH3:9])([CH3:8])[CH2:4][CH2:5][CH2:6][CH3:7].[CH3:2][N+:3]([CH2:4][CH2:5][CH2:6][CH3:7])([CH3:9])[CH3:8].[CH3:2][N+:3]([CH2:4][CH2:5][CH2:6][CH3:7])([CH3:9])[CH3:8].[CH3:2][N+:3]([CH2:4][CH2:5][CH2:6][CH3:7])([CH3:9])[CH3:8]
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CCCC[N+](C)(C)C
Agent: [OH-]
Solvent: O
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
Trimethylbutylammonium hydroxide, (25.66%), 366.4 g, was diluted with 564.8 g deionized water and to it there were added 500.0 g of tetraethylorthosilicate, (98%) with stirring. After hydrolysis was complete, the solution was placed on a rotary evaporator to remove the alcohol. Elemental analysis showed the solution to contain 7.04 wt % Si.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13]C(=O)C.Cl>CCO>[NH2:13][C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(C)=O
Agent: Cl
Solvent: CCO
Product: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Yield: 92 %

Procedure:
A solution of methyl-2-(acetylamino)-3-nitrobenzoate (2.6 g) in EtOH (50 ml) was treated with concentrated hydrochloric acid (10 ml) then heated at reflux for 16 h. The reaction mixture was cooled, reduced in vacuo and azeotroped with toluene (2×50 ml) to give 2-amino-3-nitrobenzoic acid (1.83 g) as a bright yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:5]([C:7]1[S:17][C:16]2[N:18]3[C:9](=[CH:10][N:11]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH:8]=1)=[O:6].C(N(CC)CC)C.Br[CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)C>[CH3:3][N:4]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:22][CH2:21]1)[C:5]([C:7]1[S:17][C:16]2[N:18]3[C:9](=[CH:10][N:11]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH:8]=1)=[O:6]
Reactant: BrCCCc1ccccc1
Reactant: CN(CC1CCNCC1)C(=O)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(CC1CCN(CCCc2ccccc2)CC1)C(=O)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 464.3 mg (1.16 mM) of N-methyl-N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 0.8 ml (5.74 mM) of triethylamine in ethanol was added 0.21 ml (1.38 mM) of l-bromo-3-phenylpropane at room temperature, and the mixture was refluxed under nitrogen for 15 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 20-50%) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(Br)ccc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
5-bromo-2-chlorobenzoic acid (E-Merck 8.14989.0101, 20 g; 84.94 mmol; 1 eq.) was dissolved in MeOH (400 mL). The solution was cooled down to 0° C. SOCl2 (18.49 mL; 254.82 mmol; 3 eq.) was added dropwise (addition took 30 min and IT increased to 9° C.). After addition, the reaction mixture was stirred at RT for 2 days. The reaction mixture was concentrated and the crude mixture was dissolved in EtOAc (400 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), brine (100 mL), dried over MgSO4 and concentrated affording the title compound as a white solid (20.15 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 7.98-7.97 (d, J=2.40 Hz, 1H), 7.80-7.67 (dd, J=8.74 Hz, 2.40 Hz, 1H), 7.56-7.54 (d, J=8.23 Hz, 1H), 3.86 (s, 3H). HPLC (Method A) Rt 4.15 min (Purity: 99.9%).