Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.[OH-].[Na+].FC(F)(F)C(O)=O>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCNCC3)cc12
Reaction time: 3 h

Procedure:
A mixture of Example 87C (400.0 mg, 0.710 mmol) and 20% sodium hydroxide (0.7 mL) solution in dioxane (6 mL) was heated at 90° C. for 6 hours. The mixture was concentrated and the residue was treated with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated until most of solvent was evaporated. The solids were filtered, washed with ethyl acetate/heptane, and dried under vacuum to afford the protected intermediate. The intermediate was dissolved in dichloromethane (8 mL) and treated with trifluoroacetic acid (0.547 mL, 7.10 mmol) and the mixture was stirred for 3 hours and concentrated. The residue was dissolved in 2.5 mL methanol and treated with 4 mL 1M hydrogen chloride in ether. After stirring for 15 minutes, the mixture was treated with ether. The solids were filtered, washed with ether, and dried under vacuum to afford the title compound as a hydrochloride salt. 1H NMR (400 MHz, CD3OD) δ 2.93-2.83 (m, 2H), 3.50 (t, J=6.1 Hz, 2H), 3.83 (s, 3H), 4.01-3.96 (m, 2H), 6.65-6.59 (m, 1H), 6.74 (s, 1H), 7.38-7.21 (m, 3H), 7.58 (d, J=6.1 Hz, 1H), 8.36 (d, J=6.1 Hz, 1H). MS (ESI+) m/z 324.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].[CH3:27][P:28](Cl)(Cl)=[O:29].[OH2:32]>C1COCC1>[CH3:27][P:28](=[O:29])([OH:32])[O:20][C:17]1[CH:18]=[CH:19][C:14]2[C:13]3[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=3[CH2:7][CH2:6][C@H:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=2[CH:16]=1
Reactant: O
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: CP(=O)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OP(C)(=O)O)cc1[C@@H](NC(C)=O)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of N-acetyl-colchicinol (0.36 g; 1.0 mmol) in THF (40 ml) under argon was cooled to 0° C. and treated with a 1.0M solution of lithiumHMDS in THF (1.1 ml; 1.1 mmol). The mixture was stirred at 0° C. for 1 hour and then added in portions over about 2 hours to a solution of methylphosphonic dichloride (0.53 mg; 4.0 mmol) in THF (150 ml). The mixture was stirred at ambient temperature for 15 minutes. After addition of water (200 ml) the THF was removed by evaporation. After removal of the insoluble material by filtration, the filtrate was purified on HP20 SS resin eluting with a gradient of 0–60% methanol/water. The methanol was removed by evaporation and the mixture was adjusted to pH7.14 with sodium hydroxide (0.1 M). The appropriate fractions were freeze-dried to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl hydrogen methylphosphonate as a beige solid (180 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]1[O:16][CH:10]1[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1>FC(F)(F)C(O)C(F)(F)F>[OH:16][CH:9]1[C:8](=[O:17])[C:7]2[CH:6]=[CH:5][N:4]3[C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=[C:3]3[C:2]=2[NH:1][CH:10]1[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1
Reactant: Cc1nc2c(N)c(C(=O)C3OC3c3ccsc3)ccn2c1C
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: Cc1nc2c3c(ccn2c1C)C(=O)C(O)C(c1ccsc1)N3
Reaction time: 19 h
Yield: 6.4 %

Procedure:
1.1 g of 8-amino-7-[2,3-epoxy-1-oxo-3-(3-thienyl)propyl]-2,3-dimethylimidazo[1,2-a]pyridine are dissolved in 20 ml of hexafluoroisopropanol at room temperature, the solvent is stripped off after 19 hours and the residue is purified on silica gel (eluent: methylene chloride/methanol=100/3). 70 mg of the title compound of m.p. 222–25° C. (diethyl ether) are obtained.
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]([C:6]1[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:4]2[CH:3]=[CH:2][S:1][C:8]=2[CH:7]=1)=[O:10]
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc2sccc2[nH]1
Product: COC(=O)c1cc2sccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, methyl 4H-thieno[3,2-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-naphthalene to give 4-naphthalen-1-ylmethyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 306.3 ([M−H]−).
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:6]1[CH2:11][CH2:10][C@H:9](O)[CH2:8][CH2:7]1)[CH2:4][CH3:5].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17]Br.O.CN([CH:27]=[O:28])C>>[CH2:3]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:17]([O:28][CH:27]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]2)[C:19]2[CH:16]=[CH:15][C:14]([F:13])=[C:21]([F:22])[CH:20]=2)[C:16]2[CH:19]=[CH:20][C:21]([F:22])=[C:14]([F:13])[CH:15]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CCC[C@H]1CC[C@H](O)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC[C@H]1CC[C@H](C(OC(c2ccc(F)c(F)c2)[C@H]2CC[C@H](CCC)CC2)c2ccc(F)c(F)c2)CC1
Reaction time: 3 h

Procedure:
0.6 g of sodium hydride (60%) was added to 30 ml of anhydrous N,N'-dimethylformamide. While stirring sufficiently, to the solution was added a solution of 2.13 g of trans-4-propylcyclohexanol dissolved in 10 ml of anhydrous N,N'-dimethylformamide. This mixture was continued to stirring at 50° C. for one hour and then 3.1 g of 3,4-difluorobenzyl bromide was added thereto, and the reaction was carried out at the same temperature for 3 hours with stirring. After completion of the reaction, 100 ml of water was added to the reaction mixture, the mixture was extracted with toluene, washed with a saturated NaCl aqua, dried and the solvent was removed under reduced pressure. The residue was purified by silica gel column to obtain 1.0 g of trans-4-propylcyclohexyl-3,4-difluorobenzyl ether.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1([CH:11](O)[CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(OCCCCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[OH:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=1>C(Cl)Cl>[ClH:3].[N:5]1([CH2:11][CH2:12][O:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=S(Cl)Cl
Reactant: CC(O)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCOC(C)=O
Solvent: ClCCl
Product: Cl
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 135 °C
Reaction time: 12 h
Yield: 68.1 %

Procedure:
Into a 500 ml round bottom flask is placed 23.38 g (197 mmol) of thionyl chloride and 140 ml of methylene chloride. The resulting solution is cooled with an ice bath as 21.91 g (170 mmol) of 1-piperidinoethanol in 30 ml of methylene chloride is added over 30 minutes. After the addition is complete, the ice bath is removed and the mixture is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a solid residue. Amyl acetate (225 ml), potassium carbonate (34.4 g, 249 mmol), and methyl 4-hydroxybenzoate (14.1 g, 92 mmol) are added to the residue. The resulting slurry is heated to 135° C. for 5 hours. The reaction mixture is cooled to room temperature and washed twice with 100 ml of water. The organic layer is extracted with 53 ml of 8N hydrochloric acid. The aqueous layer is heated at gentle reflux for 4 hours. The resulting slurry is cooled to 50° C. and 50 ml of acetone is added. The slurry is cooled to 0°-5° C. and stirred for 1 hour. The product is filtered, washed with cold acetone, and dried at 50° C. in vacuo to yield 17.9 g of product, (67%). 1H NMR. Compares to reference solution: HPLC potency 97.9%, TRS 1.50%.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[ClH:49]>CO>[ClH:49].[CH3:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:24]=1
Reactant: Cc1ccnc(F)c1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccnc(-n2c(/C=C/c3ccccc3)nc3ccccc32)c1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-fluoro-4-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OC)=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH:3]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:22])=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH:3]=1
Reactant: COC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)C)n1
Reactant: N
Solvent: CO
Product: CC(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 109.6 %

Procedure:
Methyl 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (99 mg, 322 μmol) was added to a pressure tube followed by ammonia (7M in methanol, 3.94 g, 5 mL, 35.0 mmol). The mixture was heated to 50° C. for 18 h, and then additional 7 N ammonia in methanol (7.5 mL) was added. After 24 h, the mixture was cooled, filtered and dried to afford 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (103 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.58 (br. s., 1H) 9.41 (s, 1H) 8.20 (br. s., 1H) 7.60 (t, J=7.83 Hz, 1H) 6.90 (d, J=7.33 Hz, 1H) 6.77 (d, J=8.08 Hz, 1H) 5.72 (br. s., 1H) 3.01-3.16 (m, 1H) 1.37 (d, J=6.82 Hz, 6H). LCMS (EI/CI) m/z: 292 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11]OC)[C:3]=1[CH:4]=[O:5].CC(C)([O-])C.[K+].BrC[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.O>CS(C)=O>[CH:4]([C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:6]=1[O:10][CH2:11][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: COCOc1cccc(O)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(COc2cccc(O)c2C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-hydroxy-6-methoxymethoxybenzaldehyde (0.91 g, 5.1 mM) in dry dimethyl sulphoxide (8 ml) was added potassium t-butoxide (0.57 g, 5.1 mM) with exclusion of moisture. After 10 mins, ethyl 4-bromomethylbenzoate (1.22 g, 5 mM) was added and the whole stirred at room temperature (18 hrs). The reaction mixture was poured into water (100 ml) and the liberated oil extracted into ether. The combined extracts were washed with 5% sodium carbonate solution, water, dried (sodium sulphate) and evaporated. The residual oil (ethyl 4-(2-formyl-3-methoxymethoxyphenoxymethyl)benzoate was dissolved in ethanol (30 ml) and treated with 3 M hydrochloric acid (30 ml) with stirring at 60° C. (30 mins). The solid was filtered off, washed with water, dried, and recrystallised from ethanol/water to give ethyl 4-(2-formyl-3-hydroxyphenoxymethyl)benzoate, m.p. 105°-ω° C. (identical to a sample previously prepared, Example 5(B)).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]([C:17]2[S:18][C:19]([CH3:22])=[CH:20][N:21]=2)=O)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:23]([OH:26])(=[O:25])[CH3:24].O.[CH2:28](O)[CH3:29]>C1COCC1.[Pd]>[OH:8][C:9]1[N:14]=[C:13]([CH:15]([C:17]2[S:18][C:19]([CH3:22])=[CH:20][N:21]=2)[CH2:24][C:23]([O:26][CH2:28][CH3:29])=[O:25])[CH:12]=[CH:11][CH:10]=1
Reactant: CCO
Reactant: Cc1cnc(C(=O)c2cccc(OCc3ccccc3)n2)s1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(c1cccc(O)n1)c1ncc(C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of (6-(benzyloxy)pyridin-2-yl)(5-methylthiazol-2-yl)methanone (8.0 g, 21 mmol), acetic acid (1.5 mL), H2O (3 mL), and Pd/C (10%, 4 g) in ethanol (90 mL) and THF (60 mL) was stirred under H2 atmosphere at room temperature overnight. After filtration through a pad of Celite and evaporation of the solvent, the residue was washed with MTBE and petroleum ether to afford A030-7 (3 g) as a white solid. The filtration (mixture of A030-6 and A030-7) was mixed with TFA (20 mL) and the resulting mixture was refluxed for 2 h. After cooling down, the mixture was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was washed with MTBE and petroleum ether to afford ethyl 3-(6-hydroxypyridin-2-yl)-3-(5-methylthiazol-2-yl)propanoate (1.4 g, total 71%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH2:9])[CH:3]=1.[C:10](=O)([O-])[O-:11].[Na+].[Na+]>C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH:10]=[O:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: NCc1cc(Br)ccn1
Agent: [Na+]
Solvent: O=CO
Product: O=CNCc1cc(Br)ccn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a 500-mL round-bottom flask, was placed (4-bromopyridin-2-yl)methanamine (compound 39.1, 8.0 g, crude) and formic acid (200 mL). The solution was stirred for 2 h at 100° C., then cooled and the pH was adjusted to 7 by careful and slow addition of aqueous sodium carbonate (sat.). The aqueous phase was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine (3×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as the eluent to yield the title compound as a yellow oil (8.0 g, 90% pure, 65% yield over 2 steps).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Nc2c(C)cccc2C)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)c1ccc(O)cc1
Temperature: -75 °C
Yield: 80 %

Procedure:
A solution of 6.4 g of N-(2,6-dimethylphenyl)-4-methoxybenzamide in methylene chloride was cooled to -75° C. Boron tribromide (25 g) was added over a 15 minute period. The reaction mixture was allowed to warm over 2 hours and then heated at reflux for 2 hours. The reaction was again cooled to -75° C. and 50 ml of water were added. The mixture was allowed to warm and the layers were separated. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from methanol/water affording the desired title product in 80% yield, m.p. 232-234° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[CH2:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]2[CH:44]=[C:43]([N:45]([CH3:47])[CH3:46])[S:42][C:41]=2[CH:48]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>ClC(Cl)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:44]2[C:40]3[CH:39]=[CH:38][C:37]([O:36][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:48][C:41]=3[S:42][C:43]=2[N:45]([CH3:46])[CH3:47])=[O:7])[CH:9]=[CH:10][C:11]=1[O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:21])[CH3:22])[CH:14]([CH3:15])[CH3:16]
Reactant: COc1cc(C(=O)O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of 3-methoxy-4-triisopropylsilyloxybenzoic acid (9.75 g, 30 mmol; Part A) in 300 mL of dichloroethane and 1 drop of DMF was treated with oxalyl chloride (13.1 mL, 150 mmol) and stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo and suspended in 300 mL of chlorobenzene. 6-Benzyloxy-2-(N,N-dimethylamino)benzo[b]thiophene (8.5 g, 30 mmol) was added, and the resulting mixture was heated at 105° C. for 5 h. After cooling to ambient temperature, the reaction mixture was poured into 500 mL of saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CHCl3 (3×150 mL). The combined organics were dried over K2CO3, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2; gradient of 5% to 10% EtOAc in hexanes) afforded 6.05 g (10.3 mmol; 34%) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A commercially available solution of 2-phenylethylamine (2 ml, 15.8 mmol) in pyridine (5 ml) is added with acetic anhydride (2 eq., 3 ml) and the solution is stirred at room temperature for 12 hours. The solvent is evaporated off under reduced pressure and the residue is taken up with water (40 ml) and the aqueous phase is extracted with EtOAc (4×25 ml). The organic extracts are pooled, anhydrified over Na2SO4 and evaporated under reduced pressure. The residue is crystallised from petroleum ether to give compound 28 as white solid (2.56 g, quantitative yield).
Reaction SMILES: [OH-:1].[Na+].S(O)(O)(=O)=O.[NH2:8]O.NO.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:15]=[C:16]([C:24]([C:42]([F:45])([F:44])[F:43])=[CH:25][C:26]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([C:38]([O:40][CH3:41])=[O:39])=[CH:30][CH:29]=2)=O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.Cl>O.O1CCCC1>[F:22][C:20]([F:23])([F:21])[C:18]1[CH:17]=[C:16]([C:24]2([C:42]([F:45])([F:43])[F:44])[O:1][N:8]=[C:26]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]([C:38]([O:40][CH3:41])=[O:39])=[CH:30][CH:29]=3)[CH2:25]2)[CH:15]=[C:14]([C:13]([F:12])([F:46])[F:47])[CH:19]=1
Reactant: COC(=O)c1ccc(C(=O)C=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)c2ccccc12
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12

Procedure:
Sodium hydroxide (50%, 1.53 g, 38.2 mmol) was added to hydroxylamine sulfate (1.57 g, 9.57 mmol) in water (18 mL). A portion of the solution (˜51%, ˜9.8 mmol of hydroxylamine) was added dropwise to methyl 4-[3-[3,5-bis(trifluoromethyl)phenyl]-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-1-naphthalenecarboxylate (i.e. the product of Step A) (5.00 g, 9.61 mmol) in tetrahydrofuran (45 mL). After ˜45 min the mixture was poured into hydrochloric acid (1 N, 100 mL) and was extracted with ether (3×80 mL).
Reaction SMILES: [O:1]=O.ON1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[C:15]([OH:18])(=[O:17])[CH3:16]>CC1C=CC=CC=1C>[C:8]([OH:1])(=[O:9])[C:7]1[C:16](=[CH:11][CH:12]=[CH:13][CH:6]=1)[C:15]([OH:18])=[O:17].[CH3:8][C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[C:5]([OH:14])=[O:17]
Reactant: CC(=O)O
Reactant: O=O
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: Cc1ccccc1C
Product: Cc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1C(=O)O
Temperature: 100 °C
Reaction time: 6 h
Yield: 71 %
Yield: 18 %

Procedure:
In an oxygen atmosphere, a mixture of 1.06 grams (10 millimoles) of o-xylene, 0.16 gram (1 millimole) of N-hydroxyphthalimide, 0.018 gram (0.05 millimole) of acetylacetonatocobalt(III) Co(AA)3 and 25 milliliters of acetic acid was stirred at a temperature of 100° C. for 6 hours. As a result, o-xylene was transformed into phthalic acid (yield 18%) and o-methylbenzoic acid (yield 71%) with a transformation rate of 92%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH2:6].CC1C=CC(C)=CC=1N.[C:20](OC(=O)C)(=[O:22])[CH3:21].[C:27]([O-])(=[O:29])[CH3:28].[K+]>C(Cl)(Cl)Cl>[C:20]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH:6][C:27](=[O:29])[CH3:28])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(CO)cc1N
Agent: Cc1ccc(C)c(N)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(COC(C)=O)ccc1C
Yield: 92.4 %

Procedure:
To a solution of an approximately 1:1 mixture of 3-(hydroxymethyl)-6-methylaniline, (8.05 g, 58.8 mmol) (2) and 2,5-dimethylaniline in chloroform (290 mL), was added acetic anhydride (20 mL, 206 mmol) and potassium acetate (20 g, 202 mmol). The resulting mixture was heated at reflux for 2 hours. The mixture was then concentrated and purified by a flash column chromatography (1:1 of hexane-ethyl acetate) to give the title compound (12.02 g, 92%). TLC Rf: 0.52 (ethyl acetate); MS (electrospray) 222 (M+1); 1H N MR (CDCl3) δ 2.09 (s, 3H), 2.21 (s, 3H), 2.25 (s, 3H), 5.06 (s, 2H), 7.00 (br s, 1H, NH), 7.08 (d, 1H, J=7.6 Hz), 7.18 (d, 1H, J=7.6 Hz), 7.81 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 17 h
Yield: 97.7 %

Procedure:
To a suspension of 2-chloroisonicotinic acid (20 g, 0.127 mol), N,O-dimethyl-hydroxylamine HCl (19.8 g, 0.203 mol), 4-methylmorpholine (20.5 g, 0.203 mol) and DMAP (1.55 g, 0.013 mol) in dichloromethane (300 ml) at 0° C. was added EDCI HCl (29.2 g, 0.152 mol). The mixture was stirred at 0° C. for 10 min and at room temperature for 17 h. The mixture was poured into water/1M aqueous HCl and extracted with dichloromethane. The combined organic phases were washed with water, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (24.9 g) as a white solid. MS(m/e)=201.2 [M+H+].