Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=1[OH:10])([CH3:7])([CH3:6])[CH3:5].[CH3:16][C:17](O)([C:20]#[N:21])[CH:18]=[CH2:19].P(=O)(O)(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:10][C:9]1[CH:11]=[C:12]2[C:13](=[CH:14][C:8]=1[C:4]([CH3:7])([CH3:5])[CH3:6])[O:15][C:17]([CH3:16])([C:20]#[N:21])[CH2:18][CH2:19]2
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: C=CC(C)(O)C#N
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1(C#N)CCc2cc(O)c(C(C)(C)C)cc2O1
Yield: 30 %

Procedure:
Using the method described in the last paragraph of Example 1, but with methylene chloride instead of toluene, 56.0 g (0.338 mole) of tert.-butyl hydroquinone were reacted with 33.6 g (0.338 mole) of methyl vinyl ketone cyanohydrin, which was stabilized with 1 g of phosphoric acid. After chromatography of the crude product over silica gel, using toluene/ethyl acetate, 6-hydroxy-7-tert.-butyl-2-methyl-2-cyanochromane was obtained in 30% yield, as colorless crystals of melting point 153°-155° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([CH3:32])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[O:8])[CH3:5].[OH-].[Na+]>O1CCCC1.CO>[CH3:32][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:31])[F:30])=[CH:25][CH:26]=1)=[O:8])([CH3:5])[C:3]([OH:33])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2c(c1OCc1ccc(OC(F)(F)F)cc1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc2c(c1OCc1ccc(OC(F)(F)F)cc1)CCCC2)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
0.13 g 2-methyl-2-{[1-(4-trifluoromethoxy-benzyloxy)-5,6,7,8-tetrahydro-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester was dissolved in 5 ml of tetrahydrofuran and 0.5 ml of methanol. To this was added 0.42 ml of 2 M NaOH (aq), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, diluted with 5 ml of ethyl acetate and 5 ml of water and acidified to pH 3 with 1N HCl (aq). The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to give 99 mg of 2-methyl-2-{[1-(4-trifluoromethoxy-benzyloxy)-5,6,7,8-tetrahydro-naphthalene-2-carbonyl]-amino}-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl)[C:9]([N+:23]([O-:25])=[O:24])=[C:8]([CH3:26])[NH:7][C:6]=1[NH2:27])=[O:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH2:19][CH2:20][CH2:21][N:39]2[CH2:38][CH2:37][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[O:29][CH3:28])[CH2:41][CH2:40]2)[C:9]([N+:23]([O-:25])=[O:24])=[C:8]([CH3:26])[NH:7][C:6]=1[NH2:27])=[O:4]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1SCCCCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1SCCCCN1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5 liter 4-neck round-bottom flask fitted with mechanical stirrer, reflux condenser and thermowell, under a nitrogen atmosphere, was added 37.87 g of 2-amino- 1,4-dihydro-4-(2-[(4-chlorobutyl)thio]phenyl)-6-methyl-5-nitro-3-pyridinecarboxylic acid methyl ester, 3.5 liters of isopropanol, 35.35 g of 1-(2-methoxyphenyl)piperazine, 27.57 g of sodium iodide and 15.45 g of sodium bicarbonate. The reaction mixture was heated at reflux for 6.5 hr., then stirred overnight at room temperature. The solvent was removed by rotary evaporation and the residue was partitioned between dichloromethane and water. The aqueous layer was washed with dichloromethane (2×300 ml), the organic layers combined, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography, eluting with 5% methanol in ethyl acetate. The product (Ex. No. 1, Table 1) was isolated as an orange solid, 37.23 g. 1H-NMR (d6 -DMSO) δ 1.60(m,4H); 2.33(m,2H); 2.40(s,3H); 2.45(m,4H); 2.92(m,6H); 3.43(s,3H); 3.76(s,3H); 5.59(s,1H); 6.73-6.95 (m,6H); 7.09(m,2H); 7.35(m,1H); 9.50(br s,1H). Mass spectrum: 568 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[N:12]([CH3:32])[CH:13]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]([F:44])([F:43])C1C=CC=CC=1CN>>[CH3:32][N:12]1[CH:13]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)[CH:15]=[C:11]1[C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:34]([F:44])([F:43])[F:33])=[O:10]
Reactant: Cn1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1C(=O)NCc1ccccc1
Reactant: NCc1ccccc1C(F)(F)F
Product: Cn1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1C(=O)NCc1ccccc1C(F)(F)F

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using the carboxylic acid intermediate from example 310 and 2-trifluoromethyl-benzylamine to provide 311. LC-MS (M+H=492, obsd.=492).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2.[Li]CCCC.[C:28](=[O:30])=[O:29]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]([C:28]([OH:30])=[O:29])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]1=2
Reactant: Cc1cccc(C)c1N1c2ccccc2Cc2ccccc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1c2ccccc2C(C(=O)O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
A solution of 4.28 g of N-(2,6-dimethylphenyl)acridan (15 mmol) in 100 mL of THF under argon was cooled to −78° C. After 10 min, 7.6 mL of n-BuLi (18.7 mmol) was added. The black solution stirred 30 min and then the temperature was raised to 0° C. for 40 min. The reaction was again cooled to −78° C. and 270 g of crushed dry ice was added to the reaction mixture to form a yellow solution with a white precipitate that dissolved once the reaction was warmed to room temperature. The reaction was stirred for 16 h at room temperature, and then concentrated and taken up in a mixture of water and diethyl ether. The aqueous portion was acidified with HCl to afford a white precipitate, which was filtered and dried to give 4.8 g of N-(2,6-dimethylphenyl)acridan-9-carboxylic acid as a white solid (97%).
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]([O:23][CH2:24][CH2:25][CH3:26])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:15][CH2:16][C:17]([O:19]CCC)=[O:18].C(O)(=O)C>C(O)CC>[O:3]=[C:4]([O:23][CH2:24][CH2:25][CH3:26])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCOC(=O)CCc1[nH]c2ccccc2c1CC(=O)OCCC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCO
Product: CCCOC(=O)Cc1c(CCC(=O)O)[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Aqueous 8N KOH (1.05 equiv.) was added to a stirred solution of propyl 3-[3-(2-oxo-2-propoxyethyl)-1H-indol-2-yl]propanoate from Step 2 in n-propanol (0.5 M). The mixture was stirred at 50° C. for 4 h. The reaction mixture was cooled to rt, quenched with acetic acid (1.2 equiv.) and concentrated. The residue was purified on a pad of silica gel using CH2Cl2, then CH2Cl2/EtOAc (9/1) and finally CH2Cl2/EtOAc/MeOH (88/10/2) to afford after evaporation of the volatiles, the desired material (68%) as yellow oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:4]([NH:6][CH:7]1[C:25](=[O:26])[N:9]2[C:10]([C:22]([OH:24])=[O:23])=[C:11]([CH2:14][S:15][C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)[CH2:12][S:13][C@H:8]12)=[O:5].[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([O:1][N:2]=[C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:4]([NH:6][CH:7]1[C:25](=[O:26])[N:9]2[C:10]([C:22]([OH:24])=[O:23])=[C:11]([CH2:14][S:15][C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)[CH2:12][S:13][C@H:8]12)=[O:5])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3cccc(O)c3)[C@H]2SC1
Product: CC(=O)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 7-[2-hydroxyimino-2-(3-hydroxyphenyl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (9.83 g.) and acetic anhydride (200 ml.) was stirred for 5 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added ether and the mixture was stirred overnight at ambient temperature. Precipitates were collected by filtration, washed thoroughly with ether and dried to give 7-[2-acetoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (8.5 g.).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[Br:14]Br.N([O-])=O.[Na+]>Br>[Br:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: Nc1cccc(-c2ccccc2)n1
Reactant: BrBr
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1cccc(-c2ccccc2)n1
Temperature: -20 °C
Yield: 80.1 %

Procedure:
48% HBr 50 mL was added to 6.9 g (40 mmol) of 2-amino-6-phenylpyridine and stirred. The solution was cooled down to −20° C., and 7.7 g (48 mmol) of bromine was dropwise added thereto. Further, 2.8 g (40 mmol) of sodium nitrite was dropwise added thereto. The solution was stirred for 3 hours while elevating the temperature up to room temperature. After finishing the reaction, the solution was extracted with ethyl acetate, and the aqueous layer was removed. The organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was refined by silica gel chromatography to obtain 7.5 g (yield: 80%) of 2-bromo-6-phenylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([NH:8][CH:9]=[O:10])[CH:7]=1.N([O-])=O.[Na+].[CH2:23]([O:25][C:26](=[O:32])[CH:27](C)[C:28](C)=O)[CH3:24].[OH-].[K+].[Cl-].[Na+].C(OC(=O)C(=NNC1C=CC(OCC2C=CC=CC=2)=C(NC=O)C=1)C)C.C(OC(=O)C(N=NC1C=CC(OCC2C=CC=CC=2)=C(NC=O)C=1)(C)C(=O)C)C.C(=O)(O)[O-].[Na+]>Cl.C(O)=O>[CH2:23]([O:25][C:26]([C:27]1[NH:1][C:2]2[C:3]([CH:28]=1)=[CH:4][C:5]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[C:6]([NH:8][CH:9]=[O:10])[CH:7]=2)=[O:32])[CH3:24]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1ccc(OCc2ccccc2)c(NC=O)c1
Agent: CCOC(=O)C(C)(N=Nc1ccc(OCc2ccccc2)c(NC=O)c1)C(C)=O
Agent: CCOC(=O)C(C)=NNc1ccc(OCc2ccccc2)c(NC=O)c1
Agent: Cl
Solvent: O=CO
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)c(NC=O)cc2[nH]1
Reaction time: 0.5 h

Procedure:
To a solution of N-(5-amino-2-benzyloxyphenyl)-formamide (3.35 g, 13.8 mmol) in 0.3N HCl (91 mL) is added sodium nitrite (0.285 g, 4.13 mmol) at 0° C. The mixture is stirred for 0.5 h. This mixture is added to a solution prepared by mixing ethyl-2-methylacetoacetate (0.72 g, 4.99 mmol) with potassium hydroxide (0.28 g, 4.99 mmol) at 0° C. The combined mixture is stirred for ˜1 h. To the reaction mixture is added saturated aqueous sodium chloride and extracted with EtOAc. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford a mixture of 2-[(4-benzyloxy-3-formylaminophenyl)-hydrazono]-propionic acid ethyl ester and 2-(4-benzyloxy-3-formylaminophenylazo)-2-methyl-3-oxo-butyric acid ethyl ester as a dark oil. The mixture of 2-[(4-benzyloxy-3-formylaminophenyl)-hydrazono]-propionic acid ethyl ester and 2-(4-benzyloxy-3-formylaminophenylazo)-2-methyl-3-oxo-butyric acid ethyl ester, is dissolved in formic acid (10 mL) and stirred at 80° C. for 4.5 h. The reaction mixture is neutralized with saturated sodium bicarbonate and the resulting mixture is extracted with EtOAc and washed with brine and water. The organic phase is separated and dried over MgSO4 and concentrated to afford 5-benzyloxy-6-formylamino-1H-indole-2-carboxylic acid ethyl ester as a grey solid: (M−H)−=337.1.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]([C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:27]1[CH:28]=[C:24]([CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]=[CH:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(CCC(c2ccccc2)c2c[nH]cn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CCC(c2ccccc2)c2cn(Cc3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,0 g of benzylbromide in 5 ml of toluene is added dropwise to the mixture of 4-(1,3-diphenylpropyl)-1H-imidazole (2,6 g), 48% NaOH (10 ml), toluene (20 ml) and tetrabutylammoniumbromide (0,2 g) at room temperature. After addition the reaction mixture is stirred at room temperature for 3 hours. Water is added and the toluene layer is separated. The toluene phase is then washed with water and evaporated to dryness. The residue contains the isomers 1-benzyl-4-(1,3-diphenylpropyl)-1H-imidazole and 1-benzyl-5-(1,3-diphenylpropyl)-1H-imidazole and the former is separated and purified by flash chromatography (methylene chloride-methanol 9,5:0,5).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Li+].[Li+]>O.C1COCC1.C(#N)C.ClCCl>[CH:16]1[CH:17]=[CH:18][C:11]([Cl:10])=[C:12]([CH2:13][N:6]2[CH2:5][C:4]3[CH:3]=[CH:2][S:1][C:9]=3[CH2:8][CH2:7]2)[CH:15]=1
Reactant: c1cc2c(s1)CCNC2
Reactant: ClCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC#N
Product: Clc1ccccc1CN1CCc2sccc2C1

Procedure:
In a preferred alkylation procedure, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in a solvent (e.g., a polar solvent, such as THF, dichloromethane or acetonitrile; preferably 5-15% wet THF) and a compound of Formula 4 (preferably o-chlorobenzyl chloride) are added to a molar excess of a base (e.g., potassium carbonate, sodium carbonate, or lithium carbonate; preferably potassium carbonate) that has been wetted with water (about 5 to 15%, preferably about 10% of the volume charge) and the reaction mixture is refluxed until disappearance of the starting materials is confirmed by tlc (about 8 to 42 hours, preferably about 18-24 hours). The solvent is removed (by vacuum or by displacement with another solvent such as toluene), and the product is washed with water and then concentrated in vacuo. Using the preferred compound of Formula 4, ticlopidine free base (Formula III) is formed (about 90-95% yield) as a light yellow oil. ##STR6##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCOC(/[N:17]=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)[NH2:17]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: COc1cc(O)cc(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(N)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
2 g of dry 3,5-dimethoxyphenol was dissolved in 25 mL dry THF and cooled in an ice bath. To this solution was added 2.25 g of diethylazodicarboxylate (DEAD), 6 g of triphenylphosphine and 1 mL of ammonium chloride (NH4Cl). The mixture was stirred for 20 minutes. The mixture was warmed to room temperature and stirred for an additional 30 minutes. Silica gel was added to remove DEAD, triphenylphosphine, and excess ammonia, yielding 3,5-dimethoxyaniline.
Reaction SMILES: [H-].[Na+].Cl[C:4]1C=C(C(C2C=C(C)C3NC(=O)OC=3C=2)=O)C(C)=CN=1.[Cl:24][C:25]1[C:30]([CH3:31])=[C:29]([C:32]([C:34]2[CH:43]=[C:42]([CH3:44])[C:37]3[NH:38][C:39](=[O:41])[O:40][C:36]=3[CH:35]=2)=[O:33])[CH:28]=[CH:27][N:26]=1.IC>CN(C=O)C>[Cl:24][C:25]1[C:30]([CH3:31])=[C:29]([C:32]([C:34]2[CH:43]=[C:42]([CH3:44])[C:37]3[N:38]([CH3:4])[C:39](=[O:41])[O:40][C:36]=3[CH:35]=2)=[O:33])[CH:28]=[CH:27][N:26]=1
Reactant: Cc1c(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)ccnc1Cl
Reactant: Cc1cnc(Cl)cc1C(=O)c1cc(C)c2[nH]c(=O)oc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)ccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.10 g (2.2 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.61 g (2.0 mmol) 6-(2-chloro-5-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in admixture with 6-(2-chloro-3-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 5 mL DMF at RT. The reaction mixture was stirred for 30 min at RT. Then 0.17 mL (2.6 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then a further 0.1 mL iodomethane were added and the mixture was stirred further at RT. Ice water was added to the reaction mixture and the precipitate formed was suction filtered. The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down, triturated with diethyl ether, suction filtered and dried. The product was obtained in admixture with 6-(2-chloro-3-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and reacted further as such.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19]O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:33][C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([CH2:19][S:33][C:34]2[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[N:35]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:12][CH2:13][CH2:14][O:15]1
Reactant: CCCC1(CCOc2ccnc(CO)c2C)OCCO1
Reactant: Sc1nc2ccccc2[nH]1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCCO1
Reaction time: 0.83 h
Yield: 79.8 %

Procedure:
The (3-methyl-4-(2-(2-propyl-1,3-dioxolan-2-yl)ethoxy)pyridin-2-yl)methanol (450 mg, 1.6 mmol) obtained in the step (3e) was mixed with tetrahydrofuran (10 ml). The mixture was cooled on ice in a nitrogen atmosphere. To this, triethylamine (0.446 ml, 3.2 mmol), and methanesulfonyl chloride (0.186 ml, 2.4 mmol) were added and stirred for 50 minutes under ice-cooling. To the reaction mixture, 2-mercaptobenzimidazole (240 mg, 1.6 mmol) was added and stirred at room temperature overnight. To the reaction mixture, an aqueous solution of sodium hydrogen carbonate was added and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. After silica gel was added to the solution, the solution was concentrated. The dried residue was subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (528 mg, 79.8%) as a colorless viscous oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[CH:7][C:5]=1[NH2:6].[Br:14][C:15]1[C:19]2=[N:20][CH:21]=[C:22]([C:25]#[N:26])[C:23](Cl)=[C:18]2[S:17][CH:16]=1.BrC1C2=NC=C(C#N)C(Br)=C2SC=1.[Cl-].[Na+]>O1CCCC1>[Br:14][C:15]1[C:19]2=[N:20][CH:21]=[C:22]([C:25]#[N:26])[C:23]([NH:6][C:5]3[CH:7]=[C:8]([O:12][CH3:13])[C:9]([Cl:11])=[CH:10][C:4]=3[Cl:3])=[C:18]2[S:17][CH:16]=1
Reactant: N#Cc1cnc2c(Br)csc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: N#Cc1cnc2c(Br)csc2c1Br
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3c(Br)csc23)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (438 mg of a 60% dispersion in mineral oil, 10.96 mmol) in 60 mL of tetrahydrofuran is added 2,4-dichloro-5-methoxyaniline (2.10 g, 10.96 mmol). The mixture is heated at reflux for 1 hour and then cooled to room temperature and 1.50 g of a 1 to 2.4 mixture of 3-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile and 3,7-dibromothieno[3,2-b]pyridine-6-carbonitrile is added. The reaction mixture is heated at reflux for 2 hours then cooled to room temperature and treated with saturated aqueous sodium chloride. The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of ethyl acetate in hexane to provide 1.78 g of 3-bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a tan solid, mp 265–266° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.44 (s, 1H), 7.79 (s, 1H), 8.31 (s, 1H), 8.72 (s, 1H), 9.93 (s, 1H); MS 427.9, 429.9, 431.8 (M+H)+.
Reaction SMILES: S([Cl:5])(C)(=O)=O.O[CH2:7][C:8]1[N:13]=[C:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.CO>C(Cl)Cl.CCOC(C)=O>[Cl:5][CH2:7][C:8]1[N:13]=[C:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)c1cccc(CO)n1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mesyl chloride (0.924 mmol, 71.5 μl, 106 mg) was added to a stirred solution of 6-(hydroxymethyl)-N,N-dimethylpicolinamide (0.616 mmol, 111 mg) and DIPEA (1.232 mmol, 204 μl, 159 mg) in DCM (2000 μl) at 0° C. The reaction was allowed to warm to room temperature and stirred for two hours. The mixture was diluted with EtOAc (20 mL) and an excess of MeOH added. Stirring was continued for 15 minutes then the mixture washed with water. Organics were dried over sodium sulphate and solvent evaporated. NMR showed desired product obtained but MsCl remaining. The residue was re-dissolved in DCM and MeOH and heated to 40° C. for 15 minutes. Solvent was evaporated under reduced pressure to yield 6-(chloromethyl)-N,N-dimethylpicolinamide. 1H NMR (CDCl3) δ: 7.88 (t, 1H), 7.62 (d, 1H), 7.52 (d, 1H), 5.34 (s, 2H), 3.15 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1F.[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.[Mg].[NH4+].[Cl-]>C1COCC1>[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]12[O:15][CH:16]([C:2]3[C:7]1=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:17]=[CH:18]2
Reactant: c1coc(C2OCCO2)c1
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=CC2(C3OCCO3)OC1c1ccccc12
Reaction time: 1 h
Yield: 77.1 %

Procedure:
2-Bromofluorobenzene (36.0 g, 0.222M) in THF (200 ml) was added dropwise over one hour to a refluxing mixture of the above furan (28.0 g, 0.200M) and magnesium turnings (5.4 g, 0.206M) in dry THF (200 ml) under nitrogen. After the addition was complete, refluxing was continued for one hour. The cooled mixture was then poured onto saturated NH4Cl solution (250 ml), the organic layer separated and the aqueous layer re-extracted with ether. The combined organic extract was washed with saturated NH4Cl solution, dried over anhydrous K2CO3 -Na2SO4 and concentrated in vacuo. The residue was purified on the Waters Prep 500 HPLC using two columns and eluting with EtOAc/hexane (1:4). A total of 33.3 g of 1-(1,3-dioxolan-2-yl)-1,4-epoxy-1,4-dihydronaphthalene was obtained as a pale yellow oil. Crystallization of the oil from hexane gave 32.5 g (75% yield) as white crystals, mp 48°-49° C.